Conv. Plasma
Nigella Sativa

All HCQ studies
Meta analysis
study COVID-19 treatment researchHCQHCQ (more..)
Melatonin Meta
Metformin Meta
Azvudine Meta
Bromhexine Meta Molnupiravir Meta
Budesonide Meta
Colchicine Meta
Conv. Plasma Meta Nigella Sativa Meta
Curcumin Meta Nitazoxanide Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

All Studies   Meta Analysis    Recent:   

Impact of prophylactic hydroxychloroquine on ultrastructural impairment and cellular SARS-CoV-2 infection in different cells of bronchoalveolar lavage fluids of COVID-19 patients

Chaudhary et al., Scientific Reports, doi:10.1038/s41598-023-39941-6
Aug 2023  
  Source   PDF   All Studies   Meta AnalysisMeta
HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now known with p < 0.00000000001 from 421 studies, recognized in 42 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
Ex vivo analysis of HCQ showing preferential protection for early target cell types in the lung, consistent with the increased efficacy seen with early treatment.
Authors analyze various cell types in bronchoalveolar lavage fluid from COVID-19 patients, providing ultrastructural evidence that prophylactic HCQ can reduce SARS-CoV-2 infection in certain lung epithelial cell types like ciliated epithelium and type II pneumocytes, while no protection was seen in alveolar macrophages, neutrophils, and enucleated granulocyte fragments, although enucleated granulocyte fragments exhibited an enhanced ability to phagocytize and destroy mature, infectious SARS-CoV-2 virus.
Previous studies have shown HCQ preferentially accumulates in lung epithelial cells compared to immune cells, aligning with the cell-specific antiviral effects seen here. The differential impact likely contributes to heterogeneous clinical outcomes based on timing, severity, and patient factors.
Reduced SARS-CoV-2 infection in lung epithelial cells may help limit disease severity and progression for early treatment, while the lack of benefit to immune cells with the same dosage could explain poor results for late-stage infection involving immune hyperactivation.
The typical sequence of SARS-CoV-2 infection of the lung cells here is likely to be:
- Ciliated epithelium - cells lining the airways are likely the initial site of virus exposure and replication after inhalation of respiratory droplets.
- Type II pneumocytes - the virus spreads to infect type II pneumocytes underlying the epithelium.
- Alveolar macrophages - resident macrophages in the alveoli encounter and phagocytose infected dead cells and viruses, becoming infected themselves. As antigen presenting cells, they also trigger an inflammatory immune response.
- Neutrophils - circulating neutrophils are recruited as part of the inflammatory response, entering the lungs and also becoming infected.
By preferentially protecting early target cell types, HCQ may be most beneficial early in infection.
One theory for the antiviral activity of HCQ is alteration of endosomal pH Al-Bari, Shang which may inhibit replication of endosomal low pH dependent viruses like SARS-CoV-2 Al-Bari, Kreutzberger. The endosomal pH altering effects of HCQ may differ between cell types in a dose-dependent manner based on inherent biological properties of each cell lineage. For example, HCQ accumulation, endosomal pH dynamics, reliance on endosomes for viral entry vary across cell types like lung epithelial cells and immune cells, base levels of endosomal/lysosomal pH, and expression levels of key proteins involved in endosomal acidification. HCQ's effect on endosomal pH may also vary over time, with some studies showing an initial increase followed by a later decrease, which may explain the differential efficacy of early treatment vs. prophylaxis.
This study underscores the complexity of pharmacological responses in different cell types during viral infection, and provides further rationale for multi-drug combination therapies, and for early treatment in general before progression to other tissues, as used by the most successful physicians.
Ruiz et al. Ruiz and this study confirm that therapeutic levels of HCQ are obtained and provide protection in the lung focused on cells corresponding to earlier infection.
Chaudhary et al., 5 Aug 2023, India, peer-reviewed, 9 authors. Contact:,
This PaperHCQAll
Impact of prophylactic hydroxychloroquine on ultrastructural impairment and cellular SARS-CoV-2 infection in different cells of bronchoalveolar lavage fluids of COVID-19 patients
Shikha Chaudhary, Arti Joshi, Kishore Sesham, Preeti Rai, Shailendra Kumar, Asit Ranjan Mridha, Upendra Baitha, Tapas Chandra Nag, Subhash Chandra Yadav
Scientific Reports, doi:10.1038/s41598-023-39941-6
Many drugs were recommended as antiviral agents for infection control and effective therapy to reduce the mortality rate for COVID-19 patients. Hydroxychloroquine (HCQ), an antimalarial drug, has been controversially recommended for prophylactic use in many countries, including India, to control SARS-CoV-2 infections. We have explored the effect of prophylactic HCQ from the cells of bronchoalveolar lavage fluids from COVID-19-induced acute respiratory distress syndrome patients to determine the level of infection and ultrastructural alterations in the ciliated epithelium, type II pneumocytes, alveolar macrophages, neutrophils, and enucleated granulocytes. Ultrastructural investigation of ciliated epithelium and type II pneumocytes showed lesser infections and cellular impairment in the prophylactic HCQ + group than HCQ -group. However, macrophages and neutrophils displayed similar infection and ultrastructural alterations in both patient groups. The enucleated fragments of granulocytes showed phagocytosis of the matured virus in HCQ + groups. The present report unveils the ultrastructural proof to complement the paradox regarding the role of prophylactic HCQ in COVID-19 patients. The COVID-19 outbreak caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly propagated with nearly half a billion infected human beings globally 1 . There were negligible reports on specific and effective treatments for this deadly infection. Due to sudden outbreaks and very high mortality (29%) 2 by delta variant, many random trials and repurposing of existing drugs were conducted to control and cure the COVID-19 disease 2,3 . Hydroxychloroquine (HCQ), an antimalarial drug, has gained significant attention in the initial phase of COVID-19 from May 2020 onwards 4,5 . This drug was earlier reported to be effective (in vitro) in reducing viral internalization (by blocking proteolytic activation of S-protein) and replication (increasing the acidic environment of the endosome to inhibit viral assembly), including the SARS-CoV-2 and MERS-CoV 6-8 . The anti-SARS-CoV-2 effect of HCQ (by inhibiting internalization and proliferation) was proposed due to its ability to increase endosomal acidification, reduction of cathepsin L activation, interference with ACE-2 terminal glycosylation, proteolytic self-activation of furin, and the blockage of clathrin-mediated endocytosis 4, [9] [10] [11] . The immunomodulatory effects, alkalinization of vacuolar pH, Zinc ionophores, and binding ability of HCQ to sialic acids were proposed to inhibit the COVID-19 infection in vitro non-specifically 9,12-14 . Many clinical trials were initiated in various countries to investigate the effect of HCQ in the control and cure of COVID-19 disease [15] [16] [17] . It was reported that HCQ was very effective in reducing the multiplication of the SARS-COV-2 virus under in vitro culture conditions using Vero E6 cells with 6.90 µM concentration (EC) 90 18 .
Author contributions S.C. performed the experiments for sample processing, PAP and IF imaging standardization, electron microscopy, interpretation of the data, management of clinical records, and generation of the microscopy figures. P.R. performed the immunofluorescence imaging, recorded the clinical data, and helped S.C. with electron microscopyrelated experiments. A.J. performed the PAP imaging. K.S. collected the sample from the ICU wards. S.K. was involved in designing the study and standardizing the sample collection strategies. A.R.M. and T.C.N. helped interpret the results and the images and correction of manuscripts. A.R.M. and U.B. also helped in the correction of the manuscript. S.C.Y. designed the study, performed, and supervised COVID-19 patient experiments, analyzed the data, generated the figures, wrote the manuscript, and directed the project. All authors read and approved the final draft of this manuscript. Competing interests The authors declare no competing interests. Additional information Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1038/ s41598-023-39941-6. Correspondence and requests for materials should be addressed to S.C.Y. Reprints and permissions information is available at Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Altulea, Maassen, Baranov, Van Den Bogaart, What makes (hydroxy)chloroquine ineffective against COVID-19: Insights from cell biology, J. Mol. Cell. Biol, doi:10.1093/jmcb/mjab016
Blanco-Melo, Imbalanced host response to SARS-CoV-2 drives development of COVID-19, Cell, doi:10.1016/j.cell.2020.04.026
Carcaterra, Caruso, Alveolar epithelial cell type II as main target of SARS-CoV-2 virus and COVID-19 development via NF-Kb pathway deregulation: A physio-pathological theory, Med. Hypotheses, doi:10.1016/j.mehy.2020.110412
Catteau, Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: A nationwide observational study of 8075 participants, Int. J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.106144
Chaudhary, Ultracellular imaging of bronchoalveolar lavage from young age COVID-19 patients with comorbidities showed greater SARS-COV-2 infection but lesser ultrastructural damage than the old age patients, Microsc. Microanal, doi:10.1017/S1431927622012430
Chen, A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19, Zhejiang Da Xue Xue Bao Yi Xue Ban, doi:10.3785/j.issn.1008-9292.2020.03.03
Colson, Rolain, Raoult, Chloroquine for the 2019 novel coronavirus SARS-CoV-2, Int. J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.105923
Cortegiani, Ingoglia, Ippolito, Giarratano, Einav, A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19, J. Crit. Care, doi:10.1016/j.jcrc.2020.03.005
Falcao, De Goes Cavalcanti, Filgueiras Filho, De Brito, Case report: Hepatotoxicity associated with the use of hydroxychloroquine in a patient with COVID-19, Am. J. Trop. Med. Hyg, doi:10.4269/ajtmh.20-0276
Ferner, Aronson, Chloroquine and hydroxychloroquine in covid-19, BMJ, doi:10.1136/bmj.m1432
Ferreira, Oliveira, Bettencourt, Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection, J. Med. Virol, doi:10.1002/jmv.26286
Gao, Hu, Update on use of chloroquine/hydroxychloroquine to treat coronavirus disease 2019 (COVID-19), Biosci. Trends, doi:10.5582/bst.2020.03072
Gao, Tian, Yang, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Scientific Reports |, doi:10.5582/bst.2020.01047
Gautret, Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial, Int. J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.105949
Grau-Pujol, Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: A double-blind, placebo-controlled randomized clinical trial, Trials, doi:10.1186/s13063-021-05758-9
Guastalegname, Vallone, Could chloroquine/hydroxychloroquine be harmful in coronavirus disease 2019 (COVID-19) treatment?, Clin. Infect. Dis, doi:10.1093/cid/ciaa321
Hoffmann, Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, Nature, doi:10.1038/s41586-020-2575-3
Infante, Ricordi, Alejandro, Caprio, Fabbri, Hydroxychloroquine in the COVID-19 pandemic era: In pursuit of a rational use for prophylaxis of SARS-CoV-2 infection, Expert Rev. Anti Infect. Ther, doi:10.1080/14787210.2020.1799785
Jha, COVID mortality in India: National survey data and health facility deaths, Science, doi:10.1126/science.abm5154
Keyaerts, Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice, Antimicrob. Agents Chemother, doi:10.1128/AAC.01509-08
Keyaerts, Vijgen, Maes, Neyts, Van Ranst, In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine, Biochem. Biophys. Res. Commun, doi:10.1016/j.bbrc.2004.08.085
Kim, A rush to judgment? Rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for COVID-19, Ann. Intern. Med, doi:10.7326/M20-1223
Liu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov, doi:10.1038/s41421-020-0156-0
Maisonnasse, Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates, Nature, doi:10.1038/s41586-020-2558-4
Mauthe, Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion, Autophagy, doi:10.1080/15548627.2018.1474314
Mehta, COVID-19: Consider cytokine storm syndromes and immunosuppression, Lancet, doi:10.1016/S0140-6736(20)30628-0
Molina, No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection, Med. Mal. Infect, doi:10.1016/j.medmal.2020.03.006
Pandolfi, Broncho-alveolar inflammation in COVID-19 patients: A correlation with clinical outcome, BMC Pulm. Med, doi:10.1186/s12890-020-01343-z
Rojas-Serrano, Hydroxychloroquine for prophylaxis of COVID-19 in health workers: A randomized clinical trial, PLoS ONE, doi:10.1371/journal.pone.0261980
Ruiz, Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19, Int. J. Antimicrob. Agents, doi:10.1016/j.ijantimicag.2020.106247
Savarino, Boelaert, Cassone, Majori, Cauda, Effects of chloroquine on viral infections: An old drug against today's diseases?, Lancet Infect. Dis, doi:10.1016/s1473-3099(03)00806-5
Savarino, Di Trani, Donatelli, Cauda, Cassone, New insights into the antiviral effects of chloroquine, Lancet Infect. Dis, doi:10.1016/S1473-3099(06)70361-9
Schrezenmeier, Dorner, Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology, Nat. Rev. Rheumatol, doi:10.1038/s41584-020-0372-x
Tabatabai, An analysis of COVID-19 mortality during the dominancy of alpha, delta, and omicron in the USA, J. Prim. Care Community Health, doi:10.1177/21501319231170164
Tang, Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: Open label, randomised controlled trial, BMJ, doi:10.1136/bmj.m1849
Vabret, Immunology of COVID-19: Current state of the science, Immunity, doi:10.1016/j.immuni.2020.05.002
Verscheijden, Chloroquine dosing recommendations for pediatric COVID-19 supported by modeling and simulation, Clin. Pharmacol. Ther, doi:10.1002/cpt.1864
Vincent, Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol. J, doi:10.1186/1743-422X-2-69
Wang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell. Res, doi:10.1038/s41422-020-0282-0
Wolfram, A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery, Sci. Rep, doi:10.1038/s41598-017-14221-2
Yao, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin. Infect. Dis, doi:10.1093/cid/ciaa237
Yazdany, Kim, Use of hydroxychloroquine and chloroquine during the COVID-19 pandemic: What every clinician should know, Ann. Intern. Med, doi:10.7326/M20-1334
Zhao, Cell morphological analysis of SARS-CoV-2 infection by transmission electron microscopy, J. Thorac. Dis, doi:10.21037/jtd-20-1368
Zhou, Dai, Tong, COVID-19: A recommendation to examine the effect of hydroxychloroquine in preventing infection and progression, J. Antimicrob. Chemother, doi:10.1093/jac/dkaa114
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Vaccines and treatments are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop