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The unfinished story of hydroxychloroquine in COVID-19: The right anti-inflammatory dose at the right moment?

  • Nicolas Dauby
    Correspondence
    Corresponding author at: Department of Infectious Diseases, CHU Saint-Pierre, Rue Haute 322, 1000 Brussels, Belgium.
    Affiliations
    Department of Infectious Diseases, CHU Saint-Pierre, Brussels, Belgium

    Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Belgium

    Environmental Health Research Centre, Public Health School, ULB, Brussels, Belgium
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  • Emmanuel Bottieau
    Affiliations
    Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
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Open AccessPublished:October 16, 2020DOI:https://doi.org/10.1016/j.ijid.2020.10.032
      Dear Editor,
      Uncontrolled inflammation, partly related to activated macrophages, is widely recognised as an independent cause of clinical deterioration and mortality in hospitalised coronavirus disease (COVID-19) patients (
      • Webb B.J.
      • Peltan I.D.
      • Jensen P.
      • Hoda D.
      • Hunter B.
      • Silver A.
      • et al.
      Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.
      ,
      • Del Valle D.M.
      • Kim-Schulze S.
      • Huang H.-H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.
      • et al.
      An inflammatory cytokine signature predicts COVID-19 severity and survival.
      ). Following the results of the RECOVERY trial and of an additional meta-analysis, corticosteroids are now recommended as a standard of care for hospitalised patients with severe and critical COVID-19 (
      • World Health Organisation
      Corticosteroids for COVID-19: living guidance.
      ). Importantly, the benefit of this anti-inflammatory intervention has been observed with a low dose of dexamethasone, while observational studies using higher dosage of corticosteroids have not reported any favourable effect on mortality (
      • Hasan S.S.
      • Capstick T.
      • Ahmed R.
      • Kow C.S.
      • Mazhar F.
      • Merchant H.A.
      • et al.
      Mortality in COVID-19 patients with acute respiratory distress syndrome and corticosteroids use: a systematic review and meta-analysis.
      ).
      The observation by
      • Lammers A.J.J.
      • Brohet R.M.
      • Theunissen R.E.P.
      • Koster C.
      • Rood R.
      • Verhagen D.W.M.
      • et al.
      Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients.
      that early hydroxychloroquine (HCQ) treatment after admission at low dosage (2400 mg in total) is associated with a lower risk of admission to an intensive care unit coincides with large observational studies showing a lower mortality rate in patients exposed to HCQ therapy compared to no or other treatment. Of note, in all these studies and in contrast to the RECOVERY trial, low doses of HCQ (<2.5 g in total) were used, often soon after admission (
      • Arshad S.
      • Kilgore P.
      • Chaudhry Z.S.
      • Jacobsen G.
      • Wang D.D.
      • Huitsing K.
      • et al.
      Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
      ,
      • Ayerbe L.
      • Risco-Risco C.
      • Ayis S.
      The association of treatment with hydroxychloroquine and hospital mortality in COVID-19 patients.
      ,
      • Catteau L.
      • Dauby N.
      • Montourcy M.
      • Bottieau E.
      • Hautekiet J.
      • Goetghebeur E.
      • et al.
      Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants.
      ; COVID-19 RISK and Treatments (CORIST) Collaboration, 2020). Another recent large cohort study of patients on low-dose HCQ for inflammatory disorders reported an association between chronic HCQ use and reduced mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (
      • Gentry C.A.
      • Humphrey M.B.
      • Thind S.K.
      • Hendrickson S.C.
      • Kurdgelashvili G.
      • Williams R.J.
      Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study.
      ).
      As highlighted by the findings of
      • Lammers A.J.J.
      • Brohet R.M.
      • Theunissen R.E.P.
      • Koster C.
      • Rood R.
      • Verhagen D.W.M.
      • et al.
      Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients.
      , the timing of HCQ therapy (administration within 1 day of admission) could explain discrepancies between different studies. In the RECOVERY trial, the median time between symptoms onset and randomisation was 9 days and a substantial proportion of patients (16.7%) was already on mechanical ventilation at randomisation (
      • The RECOVERY Collaborative Group
      Effect of hydroxychloroquine in hospitalized patients with Covid-19.
      ).
      HCQ has been used as an anti-inflammatory drug for decades as a therapy for inflammatory disorders and its impact on inflammatory responses is well documented. HCQ inhibits the production of the pro-inflammatory cytokines interleukin (IL)-6, tumour necrosis factor-alpha (TNF-α), and IL-1-β by activated macrophages (
      • Sperber K.
      • Quraishi H.
      • Kalb T.H.
      • Panja A.
      • Stecher V.
      • Mayer L.
      Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells.
      ,
      • Jang C.-H.
      • Choi J.-H.
      • Byun M.-S.
      • Jue D.-M.
      Chloroquine inhibits production of TNF-α, IL-1β and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes.
      ), which are notoriously associated with COVID-19 severity (
      • Del Valle D.M.
      • Kim-Schulze S.
      • Huang H.-H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.
      • et al.
      An inflammatory cytokine signature predicts COVID-19 severity and survival.
      ,
      • Webb B.J.
      • Peltan I.D.
      • Jensen P.
      • Hoda D.
      • Hunter B.
      • Silver A.
      • et al.
      Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.
      ) and also the production of chemotactic cytokines involved in the recruitment of pro-inflammatory cells in the lungs (
      • Grassin-Delyle S.
      • Salvator H.
      • Brollo M.
      • Catherinot E.
      • Sage E.
      • Couderc L.-J.
      • et al.
      Chloroquine inhibits the release of inflammatory cytokines by human lung explants.
      ). Consistent with this, an Italian study suggests that the benefit of HCQ is restricted to patients with elevated C-reactive protein levels (
      • COVID-19 RISK and Treatments (CORIST) Collaboration
      Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: findings from the observational multicentre Italian CORIST study.
      ).
      Thrombotic events are another well-recognised complication of severe COVID-19 (
      • Llitjos J.-F.
      • Leclerc M.
      • Chochois C.
      • Monsallier J.-M.
      • Ramakers M.
      • Auvray M.
      • et al.
      High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
      ) and the presence of lupus anticoagulant has been reported in hospitalised COVID-19 patients (
      • Bowles L.
      • Platton S.
      • Yartey N.
      • Dave M.
      • Lee K.
      • Hart D.P.
      • et al.
      Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19.
      ). HCQ therapy has been associated with a decrease of lupus anticoagulant levels as well as of platelet activation and thrombotic events in lupus patients (
      • Broder A.
      • Putterman C.
      Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus.
      ). Interestingly, B cell abnormalities similar to those reported in autoimmune disease such as active lupus were reported in patients with severe COVID-19 (
      • Woodruff M.C.
      • Ramonell R.P.
      • Nguyen D.C.
      • Cashman K.S.
      • Saini A.S.
      • Haddad N.S.
      • et al.
      Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19.
      ).
      HCQ has no antiviral activity in vivo against SARS-CoV-2 as shown in pre-clinical models such as in Syrian hamsters, non-human primates and in human lung cells, and should therefore not be used as an antiviral therapy in COVID-19 (
      • Maisonnasse P.
      • Guedj J.
      • Contreras V.
      • Behillil S.
      • Solas C.
      • Marlin R.
      • et al.
      Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates.
      ). However, to further understand the positive effects observed in large observational studies that used HCQ off-label in the early months of the pandemic, the hypothesis of an anti-inflammatory action should not be discarded. We suggest that ongoing trials evaluating HCQ specifically look at its effect on inflammatory parameters with add-on studies if necessary. In the same vein, ongoing trials are investigating colchicine to prevent hospitalisation in SARS-CoV-2-infected subjects, and the rationale is based on anti-inflammatory properties that are partly shared by HCQ, i.e. inhibition of pro-inflammatory cytokines and chemotaxis of pro-inflammatory cells (
      • Ben-Zvi I.
      • Kivity S.
      • Langevitz P.
      • Shoenfeld Y.
      Hydroxychloroquine: from malaria to autoimmunity.
      ,
      • Parra-Medina R.
      • Sarmiento-Monroy J.C.
      • Rojas-Villarraga A.
      • Garavito E.
      • Montealegre-Gómez G.
      • Gómez-López A.
      Colchicine as a possible therapeutic option in COVID-19 infection.
      ).

      Conflict of interest

      N.D. and E.B. are members of the Belgian Task Force for the Writing of Therapeutics Guidance for COVID-19 in Belgium. No other COI to declare.

      Funding source

      None.

      Ethical approval

      Not required.

      References

        • Arshad S.
        • Kilgore P.
        • Chaudhry Z.S.
        • Jacobsen G.
        • Wang D.D.
        • Huitsing K.
        • et al.
        Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
        Int J Infect Dis. 2020; 97: 396-403
        • Ayerbe L.
        • Risco-Risco C.
        • Ayis S.
        The association of treatment with hydroxychloroquine and hospital mortality in COVID-19 patients.
        Intern Emerg Med. 2020; 15: 1501-1506
        • Ben-Zvi I.
        • Kivity S.
        • Langevitz P.
        • Shoenfeld Y.
        Hydroxychloroquine: from malaria to autoimmunity.
        Clin Rev Allergy Immunol. 2012; 42: 145-153
        • Bowles L.
        • Platton S.
        • Yartey N.
        • Dave M.
        • Lee K.
        • Hart D.P.
        • et al.
        Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19.
        N Engl J Med. 2020; 383: 288-290
        • Broder A.
        • Putterman C.
        Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus.
        J Rheumatol. 2013; 40: 30-33
        • Catteau L.
        • Dauby N.
        • Montourcy M.
        • Bottieau E.
        • Hautekiet J.
        • Goetghebeur E.
        • et al.
        Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants.
        Int J Antimicrob Agents. 2020; 56106144
        • COVID-19 RISK and Treatments (CORIST) Collaboration
        Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: findings from the observational multicentre Italian CORIST study.
        Eur J Intern Med. 2020; 82: P38-P47
        • Del Valle D.M.
        • Kim-Schulze S.
        • Huang H.-H.
        • Beckmann N.D.
        • Nirenberg S.
        • Wang B.
        • et al.
        An inflammatory cytokine signature predicts COVID-19 severity and survival.
        Nat Med. 2020; 26: 1636-1643
        • Gentry C.A.
        • Humphrey M.B.
        • Thind S.K.
        • Hendrickson S.C.
        • Kurdgelashvili G.
        • Williams R.J.
        Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study.
        Lancet Rheumatol. 2020; 2: E689-E697
        • Grassin-Delyle S.
        • Salvator H.
        • Brollo M.
        • Catherinot E.
        • Sage E.
        • Couderc L.-J.
        • et al.
        Chloroquine inhibits the release of inflammatory cytokines by human lung explants.
        Clin Infect Dis. 2020; 71: 2265-2268
        • Hasan S.S.
        • Capstick T.
        • Ahmed R.
        • Kow C.S.
        • Mazhar F.
        • Merchant H.A.
        • et al.
        Mortality in COVID-19 patients with acute respiratory distress syndrome and corticosteroids use: a systematic review and meta-analysis.
        Expert Rev Respir Med. 2020; 14: 1149-1163
        • Jang C.-H.
        • Choi J.-H.
        • Byun M.-S.
        • Jue D.-M.
        Chloroquine inhibits production of TNF-α, IL-1β and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes.
        Rheumatology. 2006; 45: 703-710
        • Lammers A.J.J.
        • Brohet R.M.
        • Theunissen R.E.P.
        • Koster C.
        • Rood R.
        • Verhagen D.W.M.
        • et al.
        Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients.
        Int J Infect Dis. 2020; 101: 283-289https://doi.org/10.1016/j.ijid.2020.09.1460
        • Llitjos J.-F.
        • Leclerc M.
        • Chochois C.
        • Monsallier J.-M.
        • Ramakers M.
        • Auvray M.
        • et al.
        High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.
        J Thromb Haemost. 2020; 18: 1743-1746
        • Maisonnasse P.
        • Guedj J.
        • Contreras V.
        • Behillil S.
        • Solas C.
        • Marlin R.
        • et al.
        Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates.
        Nature. 2020; 585: 584-587
        • Parra-Medina R.
        • Sarmiento-Monroy J.C.
        • Rojas-Villarraga A.
        • Garavito E.
        • Montealegre-Gómez G.
        • Gómez-López A.
        Colchicine as a possible therapeutic option in COVID-19 infection.
        Clin Rheumatol. 2020; 39: 2485-2486
        • Sperber K.
        • Quraishi H.
        • Kalb T.H.
        • Panja A.
        • Stecher V.
        • Mayer L.
        Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells.
        J Rheumatol. 1993; 20: 803-808
        • The RECOVERY Collaborative Group
        Effect of hydroxychloroquine in hospitalized patients with Covid-19.
        N Engl J Med. 2020; 383: 2030-2040https://doi.org/10.1056/NEJMoa2022926
        • Webb B.J.
        • Peltan I.D.
        • Jensen P.
        • Hoda D.
        • Hunter B.
        • Silver A.
        • et al.
        Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.
        Lancet Rheumatol. 2020; 2: E754-E763https://doi.org/10.1016/S2665-9913(20)30343-X
        • World Health Organisation
        Corticosteroids for COVID-19: living guidance.
        (2 September 2020) World Health Organisation, 2020
        • Woodruff M.C.
        • Ramonell R.P.
        • Nguyen D.C.
        • Cashman K.S.
        • Saini A.S.
        • Haddad N.S.
        • et al.
        Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19.
        Nat Immunol. 2020; 21: 1506-1516https://doi.org/10.1038/s41590-020-00814-z