Mortality 0%: A comprehensive strategy for the early treatment of COVID-19 with azithromycin/hydroxychloroquine and/or corticosteroids: results of a retrospective observational study in the French overseas department of Reunion Island

Source: Science Direct

A comprehensive strategy for the early treatment of COVID-19 with azithromycin/hydroxychloroquine and/or corticosteroids: results of a retrospective observational study in the French overseas department of Reunion Island

Dubernet A, Larsen K, Masse L, Allyn J, Foch E, Bruneau L, Maillot A, Lagrange-Xelot M, Thomas V, Jaffar-Bandjee M-Christine, Gauzere L, Raffray L, Borsu K, Dibernardo S, Renaud S, Andre M, Moreau D, Jabot J, Coolen-Allou N, Allou N, A ´

Comprehensive strategy for the early treatment of COVID-19 with azithromycin/hydroxychloroquine and/or corticosteroids: results of a retrospective observational study in the French overseas department of Reunion Island, Journal of Global Antimicrobial Resistance, doi:

10.1016/j.jgar.2020.08.001–> Arthur Dubernet, Kevin Larsen, Laurie Masse, Jer´ ome Allyn, Emilie ˆ Foch, Lea Bruneau, Adrien Maillot, Marie Lagrange-Xelot, Vincent Thomas, Marie-Christine Jaffar-Bandjee, Loraine Gauzere, Loic Raffray, Karine Borsu, Servane Dibernardo, Stephane Renaud, ´ Michel Andre, Diane Moreau, Julien Jabot, Nathalie Coolen-Allou, ´ Nicolas Allou

Background
Reunion Island (845,000 inhabitants) is a French overseas department located in the Indian Ocean at a distance of 10,000 km from Paris. On 17 April 2020, 398 cases of COVID-19 had been reported in Reunion Island (first case detected on 11 March 2020) [1]. More than 70% of these cases were imported from Europe, which was an epicentre of the epidemic at the time. The aim of this study was to evaluate the prognosis of COVID-19 patients in Reunion Island, with a particular focus on the medical management of patients with hypoxemic pneumonia.

Methods
The present study was approved by the Ethics Committee of the French Infectious Disease Society and was declared to the Commission nationale de l’informatique et des libertés (N°2206739). This retrospective observational study was conducted from 11 March to 17 April 2020 at the only hospital authorized to manage patients with COVID-19 in Reunion Island. Patients were systematically hospitalized in the following cases:
pneumonia; sepsis and comorbidities (age over 65 years, diabetes, heart disease, chronic respiratory disease, cancer, chronic kidney disease…). All patients with hypoxemic pneumonia due to COVID-19 were consecutively evaluated (i.e. pneumonia requiring oxygen to achieve oxyhemoglobin saturation > 94%).

Pharmaceutical interventions
In accordance with our protocol, all patients with hypoxemic pneumonia due to COVID-19 were treated with: (1) a 3 rd generation cephalosporin; (2) oral hydroxychloroquine for 10 days (400 mg twice on the first day, followed by 200mg twice a day for the next 9 days) in combination with azithromycin for 5 days (500 mg on the first day, followed by 250 mg daily for the next 4 days) in the absence of contraindications and if the symptoms lasted less than 10 days; and/or (3) corticosteroids, if more than 3L/min of oxygen was required 8 days after the onset of symptoms (1 mg/kg/day the first week, followed by 0.5 mg/kg/day the next 2 weeks). Patients were not treated by hydroxychloroquine/azithromycin if they didn’t need oxygen therapy. Abbreviations COVID-19: coronavirus disease 2019 ICU: intensive care unit

Keywords:
COVID-19;
SARS-CoV-2;
hydroxychloroquine;
azithromycin;
corticosteroids.

Statistical analysis
Results were expressed as total numbers (percentages) for categorical variables and as medians [25th -75th percentiles] for continuous variables. Continuous variables were compared using the nonparametric Wilcoxon-Mann-Whitney-test. Categorical variables were compared using the Fisher’s exact test. A P value < 0.05 was considered significant. Analyses were conducted using SPSS 15.0 (SPSS Inc©, Chicago, Il, USA).

Results
Over the study period, 398 patients were tested positive for COVID-19 in Reunion Island, with 285 cases (71.6%) imported from Europe. A total of 164 patients were hospitalized, of whom 36 (22%) developed hypoxemic pneumonia. The median time from onset of symptoms to diagnosis of hypoxemic pneumonia was 5.5 [3.8-8] days. Hydroxychloroquine/azithromycin treatment was initiated in 23 patients (63.9%) 8 days [6- 9.5] after the onset of symptoms. Hydroxychloroquine/azithromycin treatment was initiated with a median delay of 2 [1-3] days after the diagnosis of hypoxemic pneumonia. Of these, 17 were treated in a medical ward. Among the 13 hospitalized patients with hypoxemic pneumonia not treated by hydroxychloroquine/azithromycin : 2 were already treated by lopinavir/ritonavir, 7 had symptoms that lasted more than 10 days and 4 had contraindications. Hydroxychloroquine/azithromycin treatment was stopped on day 4 in 1 patient due to QT prolongation. Corticosteroid treatment was initiated in 12 patients (33.3%) 14 days [12-15] after the onset of symptoms. Of these, 6 were treated in a medical ward and 6 in ICU. A total of 5 patients received both hydroxychloroquine/azithromycin and corticosteroids.

In bivariate analysis, hydroxychloroquine/azithromycin treatment was associated with a lower rate of intensive care unit (ICU) admission (P=0.008) (Figure 1). The factors predictive of ICU admission with P<0.05 are shown in Table 1. Ten of the 36 patients with hypoxemic pneumonia were admitted to ICU. Of these, 4 patients received high-flow nasal cannula oxygen therapy (50 L/min of oxygen) and 3 received invasive mechanical ventilation. Among the 10 patients admitted in ICU, hospital lengths of stay were 25 [15-35] days in the treated patients with hydroxychloroquine/azithromycin and 40 [25-55] days in the untreated patients (P=0.3). One patient under mechanical ventilation has been treated by tocilizumab. There were no deaths at follow-up (minimum 60 days). At the time of writing, 163 out of 164 hospitalized patients were discharged from hospital.

Discussion
The evolution of patients was excellent overall, as not a single death due to COVID-19 was reported in Reunion Island. It should be noted, however, that the number of COVID-19 and the number of hypoxemia pneumonia cases were relatively low on the island. Several hypotheses can be put forward to explain our results. Our results may be due to the care bundle used for the management of patients with COVID-19 in Reunion Island. The main intervention was early treatment with hydroxychloroquine/azithromycin. Indeed, following bivariate analysis, hydroxychloroquine/azithromycin treatment was associated with a lower rate of ICU admission (P=0.008). Some studies suggest that this drug combination is associated with viral load decrease and improved prognosis when administered early [2,3]. It should be noted, however, that the hydroxychloroquine/azithromycin treatment was not associated with better outcome in some retrospective studies [4]. Likewise, the administration of corticosteroids to patients with no improvement 8 days after the onset of symptoms may have contributed to the favourable outcome of patients with COVID-19 (none of the 6 patients treated with corticosteroids were hospitalized in ICU). One study has found corticosteroid treatment to be associated with decreased mortality in patients with hypoxemic pneumonia due to COVID-19 [5]. This study has many limitations. This was a retrospective study with a relatively small number of patients, which made it impossible to perform multivariate analyses. Despite the risk profile of COVID-19 patients with severe hypoxemic pneumonia, the mortality rate of the disease in Reunion Island was 0%. This may be due to the care bundle used in our hospital (early hospitalisation, treatment with hydroxychloroquine/azithromycin and/or corticosteroids, non-invasive respiratory support, etc.).

Declarations
Ethics approval and consent to participate
The present observational study was approved by the Ethics Committee of the French Society of Pulmonary Medicine and was declared to the Commission nationale de l’informatique et des libertés (French Data Protection Agency or CNIL MR004). Written and verbally informed consent was obtained from all the patients.

Availability of data and material
The dataset used in the current study are available from the corresponding author on reasonable request.

Competing interest
None declared.

Funding
This work was internally funded. Authors’ Contributions Drs. Arthur Dubernet, Kevin Larsen, Nathalie Coolen-Allou and Nicolas Allou had full access to all the study data and take responsibility for the completeness of the data and the accuracy of the analysis.

Study concept and design:
Kevin Larsen, Arthur Dubernet, Diane Moreau, Laurie Masse, Nathalie Coolen-Allou, Jérôme Allyn, Lea Bruneau, Adrien Maillot, Michel André, Marie Lagrange-Xelot,, Emilie Foch, Nicolas Allou. Acquisition of data: Kevin Larsen, Laurie Masse, Nathalie Coolen-Allou, Diane Moreau, Emilie Foch, Loraine Gauzere, Loic Raffray. Analysis and interpretation of data: Kevin Larsen, Loraine Gauzere, Loic Raffray, Laurie Masse, Nathalie Coolen-Allou, Jérôme Allyn, Lea Bruneau, Adrien Maillot, Michel André, Marie Lagrange-Xelot, Stéphane Renaud, Diane Moreau, Emilie Foch, Nicolas Allou, Karine Borsu, Servane Dibernardo. Drafting of the manuscript and critical revision of the manuscript for important intellectual content: Arthur Dubernet, Kevin Larsen, Laurie Masse, Nathalie Coolen-Allou, Jérôme Allyn, Lea Bruneau, Loic Raffray, Karine Borsu, Servane Dibernardo, Adrien Maillot, Michel André, Marie Lagrange-Xelot, Emilie Foch, Nicolas Allou, Stéphane Renaud. Statistical analysis: Nicolas Allou, Jérôme Allyn. Funding: Support was provided solely by institutional and/or departmental sources. Administrative, technical and material support and study supervision: Arthur Dubernet, Kevin Larsen, Laurie Masse, Nathalie Coolen-Allou, Jérôme Allyn, Lea Bruneau, Adrien Maillot, Michel André, Marie Lagrange-Xelot, Emilie Foch, Nicolas Allou.




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