key: cord-0917666-tfdrv176
authors: Manafi, Navid; Ghiasvand, Fereshteh
title: Reply to the letter to the editor “Azithromycin, treatment in COVID-19”
date: 2021-01-19
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2021.106279
sha: 5f6acc5bac7fc636e53058e21cbb277c20350c7e
doc_id: 917666
cord_uid: tfdrv176

nan

We thank the authors of this letter to the editor for their careful reading of our paper "Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial" and their precise and helpful comments. [1] We would like to discuss the issues the authors pointed out and provide further information and update for our paper;

Regarding the questions on the severity of COVID-19 at admission, all patients were hospitalized based on the concurrent national criteria and approved guidelines. During the pandemic, guidelines have changed due to rapidly evolving evidence crediting or discrediting certain options for COVID-19 management. Based on the protocols used during our study, patients were included based on the clinical criteria suggestive of COVID-19, O2 saturation below 93%, respiratory distress (rate above 30), and positive computed tomography (CT) scan findings suggestive of COVID-19. Since COVID-19 cannot be differentiated only by clinical manifestation from other infective diseases, any patients with clinical characteristics of the COVID-19 were tested and treated accordingly. The patients included in the study showed clinical signs of COVID-19 from seven to ten days before admission. Details of clinical signs suggestive for COVID-19 can be found in our paper. Also the quality and rate of hemoptysis and cough was not assessed as it was not defined as a separate variable in our study.

All patients included in our study fulfilled the admission criteria and showed severe disease; hence we could not withhold treatment. As the authors of the letter mentioned correctly, care was taken that all included patients are in their active phase of the disease. Some points were not explained as they have been explained in much detail elsewhere, including the findings suggestive of COVID-19 in CT scan. All scans where reviewed by trained radiologists with good experience of COVID-19 because of high patient load in our hospital. Also we know that the severity of pulmonary involvement does not necessarily imply more severe clinical condition, or vice versa. As stated in the study, the primary set point of our study was based on clinical condition, and not severity of findings on imaging.

The authors of the letter have criticized the randomization of our study. We would like to respectfully disagree for the following reasons. Despite random allocation, very small differences between two groups is an expected finding . The mean difference between O2 saturation of patients was 0.1 (P value = 0.920), which was statistically insignificant and also clinically unimportant. Also, regarding the five year difference between the ages in two groups, we point to the World Health Organization's (WHO) guideline for COVID-19 complications, which sets the age of 60 as a set point for increasing complications. [2] The Iranian national guidelines set this point at 65 years of age. [3] Both guidelines relate to patients aged over 60, and assessing the impact of treatment below that age was outside the scope of our study.

The authors of the letter mentioned that some of the patients were discharged with the lower O2 saturation that was set as the goal (92%). This statement is correct, the reason being their unwillingness to continue treatment in the hospital. However, all these patients continued treatment at home with the remote monitoring and under close follow-up. Regarding the difference in baseline characteristics like history of chronic diseases between the two groups, we would stress the correctness of random allocation and elimination of confounders. As a result, no statistically significant difference was witnessed between groups.

It must also be borne in mind that patient safety could not be sacrificied for this study, and hence care was taken to ensure the required medications were receive by all patients. As all patients enrolled in the study were severe cases, according to the concurrent national guidelines hydroxychloroquine and Ritonavir/Lopinavir needed to be initiated. It is crucial to have in mind that during the time of this study, a benefit from Ritonavir/Lopinavir on COVID-19 had been suggested by several studies. [4, 5] Although later studies discredited the efficacy of Ritonavir/Lopinavir for COVID-19, [6] use of this treatment was included in our national guidelines.

Regarding the complications of treatment, as stated in the paper, the most possible serious adverse event was anticipated to be heart arrhythmias, especially due to QT-prolongation by hydroxychloroquine and azithromycin. Hence high risk patients were excluded from the study from the beginning. The remaining patients were also monitored on a daily basis by electrocardiography (ECG) to ensure no arrhythmia or cardiac dysfunction has occurred as a side effect of treatment. No adverse events were witnessed that needed further discussion.

The authors have critiqued the use of some papers as reference in our discussion. We would like to state that no false claim has been made for discussion. The paper demonstrating effectiveness of azithromycin against Zika and Ebola viruses have been cited to be based on an in vitro study.

Although we agree that effectiveness in human models based on in vitro studies cannot be assumed, in vitro studies are a crucial step before progression to in vivo studies and clinical trials.

Also care was taken to use only credible and authentic resources as the reference for our paper.

We would also point out that even if the validity of certain references is doubted, no definite conclusion or treatment plan was based on those papers. The design and progression of the trial was performed only based on purposes of the study and away from any confounder effect.

We thank Sekhavati et al for pointing out that the correct proportion of patients with myalgia was 40%. However, we would like to state that despite this error, the statistical calculations were done correctly. Another requested statistics ws the number of patients receiving methylprednisolone, which were two in the case and seven in the control group. Lastly, we note that no study is perfect. However, we believe that our study provided useful information; all treatment modalities for COVID-19 need to be further tested and assessed by multiple larger clinical trials at other sites.

Funding: None

Safety and effectiveness of azithromycin in patients with COVID-19: An openlabel randomised trial

Clinical management of COVID-19; WHO Reference Number: WHO/2019-nCoV/clinical/2020

Iran's ministry of health therapeutics and clinical guidelines for COVID

Lopinavir/ritonavir use in Covid-19 infection: is it completely nonbeneficial?

Role of Lopinavir/Ritonavir in the Treatment of Covid-19: A Review of Current Evidence, Guideline Recommendations, and Perspectives

Lopinavirritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Ethical Approval: N/A