key: cord-0998835-f79r1d7e
authors: Dauby, Nicolas; Catteau, Lucy; Hautekiet, Joris; Montourcy, Marion; Bottieau, Emmanuel; Goetghebeur, Els; Van Beckhoven, Dominique
title: Reply to the letter to the editor “Low‐dose hydroxychloroquine therapy and lower mortality in hospitalized patients with COVID‐19: association does not mean causality.”
date: 2020-12-13
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106261
sha: ae0e61a78972a7ff202cc5568f1f7c3a46981229
doc_id: 998835
cord_uid: f79r1d7e

nan

We thank the authors for their comments on our observational study about the use of hydroxychloroquine (HCQ) during the first wave of COVID-19 pandemic in Belgium [1] . Our study remains the largest observational study performed so far about off-lab use of HCQ and one of the few comparing HCQ use alone to a group of patients not exposed to any other anti-COVID-19 drugs.

The authors raise the following points regarding our study: 1) impact of long term data from patient still hospitalized at the time of analysis; 2) potential indication bias and impact of donot-escalate order; 3) discrepancies with other observational studies and randomized controlled trials such RECOVERY and SOLIDARITY 4) exceptionality of our findings. (Ref

Firstly, in our initial study, we did not only analyse patients with completed discharge data.

The supplementary material reports results from an analysis of all patients with admission data, accounting for the missing discharge information by either a) censoring the follow-up time at the final follow-up date, i.e. May 24 (assuming that patients without discharge data

had not yet been discharged at that time) or b) treating them as missing at random (Supplemental data of our article [1] ). Findings were qualitatively similar in each case.

Secondly, another researchers team from Sciensano recently carried out a retrospective casecontrol study on the outcomes of patients admitted to the ICU within the frame of the same COVID-19 hospital surveillance data [2] , registered up to the 9 th of August 2020 (n=1747). In a multivariable mixed effects analysis including demographic, clinical and biological factors, HCQ therapy was associated with lower in-hospital mortality (OR [95% CI]: 0.64 [0.45-0.92]). A sub-analysis including only patients who received invasive mechanical ventilation (n=999), HCQ therapy was still independently associated with decreased mortality (Manuscript submitted). This finding shows that the HCQ-mortality association remains sizeable in a subcohort which avoids (by regulation) any formal `do-not-escalate' orders.

Thirdly, the authors refers to the randomized controlled trials RECOVERY and SOLIDARITY trials in which no benefit of HCQ was found as compared to standard of care [3, 4] . It is important to remind that both trials, assuming a potential antiviral activity of HCQ, administered a higher dosage than what was given in our cohort, and often at a rather late stage of the disease. The antiviral effect of HCQ could meanwhile not be demonstrated in animals and in humans, closing definitively this hypothesis [5] [6] [7] .

Fourthly, regarding the "exceptionality" of our findings, it is of value to highlight that several other observational studies using low-dose HCQ in hospitalized patients have also found an association with lower mortality [8] [9] [10] or ICU transfer when administered early during hospitalization [11] . However, it has been clearly and repeatedly acknowledged in the manuscript that our observations do not confirm a beneficial causal effect of low-dose HCQ.

We pointed out the limitations of a retrospective observational study performed using data of a national surveillance [2] , which was primarily not designed as an efficacy study and therefore not registering other potential confounders (such as frailty or comedications contraindicating HCQ use).

We therefore fully agree with the title of your letter. Our conclusion was in fact that these observations should trigger new research questions on its long-known anti-inflammatory and anti-thrombotic properties. Indeed, we want to stress that there is a biological plausibility underlining a potential benefit of HCQ in COVID-19. HCQ activity shares similarities with the mechanisms of action of dexamethasone, the only intervention proven to be beneficial in severe COVID-19 patients [12] . These mechanisms include inhibition of chemokines and proinflammatory cytokines associated with poor prognosis (IL-6, TNF-α) [13] [14] [15] . Moreover, there is now increasing evidence that severe COVID-19 is associated with immune and coagulation abnormalities observed in auto-immune disease such as systemic lupus erythematous [16] [17] [18] . Antiphospholid (aPL) auto-antibodies are found in a high proportion of patients with severe COVID-19 and were associated platelet hyperactivity, more severe disease and acute kidney injury [18, 19] . Those aPL auto-antibodies isolated from COVID-19 patients have been shown to cause neutrophil extracellular traps release by neutrophils in vitro and induce thrombosis in mice model [19] . Animal, in vitro and human clinical studies have largely demonstrated the benefit of HCQ in the prevention of thrombotic complications related to anti-phospholipid syndrome [20] [21] [22] . This subgroup of patients with such immune abnormalities who could benefit from HCQ therapy might be underrepresented in small RCT that have not shown a benefit of low dose HCQ [23] .

In conclusion, our observational study provides results which fit the criteria for a coherent association according to Rosenbaum: temporal sequence, consistency of association (ICU vs non ICU), coherence with existing knowledge (anti-inflammatory and anti-thrombotic properties) and are analogous with other reports (observational studies using low dose HCQ).

It does not claim causality, but we encourage investigating the effect of low-dosage HCQ on inflammatory and coagulation parameters in COVID-19 to bring additional insights in its complex pathogenic pathways.

Ethical Approval: Na

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