Treatment of COVID-19 in Marseille, France.

We retrospectively report on 1061 SARS-CoV-2 positive tested patients treated with HCQ (200 mg three times daily for ten days) + AZ (500 mg on day 1 followed by 250 mg daily for the next four days) for at least threedays. Outcomes were death, clinical worsening (transfer to ICU, and >10 day hospitalization) and viral shedding persistence (>10 days).

The mean age was 43.6 years and only 14% were hospitalized.

In this study, patients were relatively young. The mean age was 43.6 years with a standard deviation of 15.6 years. Only 152 of 1061 patients included in the study (14%) were hospitalized.

Only 152 of 1061 patients were hospitalized. Source: Million, 2020.

No corticosteroids. Anticoagulants only for severe cases.

“No patients were treated with steroids” (in Marseille, France).

High doses of preventive or curative anticoagulants were administered to severe patients (in Marseille, France).

In New York hospitals, the use of anticoagulants was sometimes in 90% of patients and many were treated with corticosteroids. For example, in the study by Geleris et al., 2020 (2), 26% of patients in one of the study groups received steroids and less than 10% received anticoagulants (see below). In the study by Carlucci et al., 2020 (3), 90% of patients received anticoagulants and less than 10% received steroids (see below). The approach was different in the hospital run by Didier Raoult in Marseille, France, reported in the study by Million et al., 2020 (1).

Table 1. (Part 1) Characteristics of Patients Receiving or Not Receiving Hydroxychloroquine, before and after Propensity-Score Matching.* Source: Geleris, 2020. * ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, Fio2fraction of inspired oxygen, HIV human immunodeficiency virus, IQR interquartile range, and Pao2partial pressure of arterial oxygen. † Data for patients included in the propensity-score–matched analysis were multiply imputed. ‡ Data on race and ethnic group, as reported by the patient, were obtained from the clinical data warehouse. § The body-mass index is the weight in kilograms divided by the square of the height in meters. ¶ Chronic lung disease was defined as chronic obstructive pulmonary disease, asthma, or chronic bronchitis. ‖ In the unmatched analysis, data on the d-dimer level were missing for 291 patients, on the ferritin level for 168, on the lactate dehydrogenase level for 153, on the C-reactive protein level for 150, on the procalcitonin level for 121, on the neutrophil count for 33, and on the lymphocyte count for 33. Multiple imputation was used to account for missing data in the propensity-score–matched analysis.

Table 1. (Part 2) Characteristics of Patients Receiving or Not Receiving Hydroxychloroquine, before and after Propensity-Score Matching.* Source: Geleris, 2020. * ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, Fio2fraction of inspired oxygen, HIV human immunodeficiency virus, IQR interquartile range, and Pao2partial pressure of arterial oxygen. † Data for patients included in the propensity-score–matched analysis were multiply imputed. ‡ Data on race and ethnic group, as reported by the patient, were obtained from the clinical data warehouse. § The body-mass index is the weight in kilograms divided by the square of the height in meters. ¶ Chronic lung disease was defined as chronic obstructive pulmonary disease, asthma, or chronic bronchitis. ‖ In the unmatched analysis, data on the d-dimer level were missing for 291 patients, on the ferritin level for 168, on the lactate dehydrogenase level for 153, on the C-reactive protein level for 150, on the procalcitonin level for 121, on the neutrophil count for 33, and on the lymphocyte count for 33. Multiple imputation was used to account for missing data in the propensity-score–matched analysis.

Table 1 (part 2): Comparisons of baseline characteristics and hospital medications. Data are represented as median (IQR) or mean +SD. Source: Carlucci, 2020.

Table 1 (part 3): Comparisons of baseline characteristics and hospital medications. Data are represented as median (IQR) or mean +SD. *measured on supplemental oxygen for 86.4% **measured on supplemental oxygen for 83.1% Source: Carlucci, 2020.

Mediterrannee Infections is a large infectious disease hospital network in the area of the city of Marseille.

Million et al. (the group of Didier Raoult), 2020 (1):

Three severe patients were treated by anti-IL1 (anakinra) and none of them died.

No patients were treated with steroids.

High dose preventive or curative anticoagulants were administered for severe patients.

Below, you can see the table with the baseline characteristics of patients and outcomes from the study by Million et al., 2020 (1).

Table 2. Baseline characteristics according to clinical and virological outcome of 1061 patients treated with HCQ+AZ ≥3 days at IHU Méditerranée infection Marseille, France with day 0 between March 3 and March 31, 2020. Source: Million, 2020. Poor virological outcome (PVirO): viral shedding persistence at day 10; Poor clinical outcome (PClinO):either death or transfer to intensive care unit (ICU) or hospitalization for 10 days or more; Good outcome: individuals who belonged neither to the PClinO group nor the PVirO group. SD: standard deviation. a Five patients belonged to both the PVirO and PClinOoutcome so the sum of frequencies may be above 1061. b Including 8 deaths. c Data available for 928 patients (56 patients who did not declare any symptom before treatment start were excluded and 77 with missing data), d for 714 patients, e for 992 patients and f for 263 patients. On low-dose pulmonary CTscanner, patients were classified as no involvement(lack of lung involvement (ground glass opacities,consolidation or crazy paving pattern); minimal involvement (subtle ground glass opacities); intermediate involvement (less than 50%of segment involvement in no more than 5 segments) and severe involvement (involvement of more than 5 segments). The denominator was mentioned when the result was not available for all patients. * p<0.05; **p<0.01; ***p<0.001 (Fisher’s exact test, Student t-test, Wilcoxon-Mann-Whitney where appropriate; reference group is good outcome).

Interestingly, in multivariate analysis, in this group of relatively young patients from the study by Million et al., 2020 (1), only the use of anti-hypertensive drugs was a strong independent predictor of poor outcomes of COVID-19. Hypertension itself and other comorbidities, such as obesity, cardiovascular disease, diabetes and others, were positively associated with poor outcomes only in univariable analysis, that is, before adjustment for other factors. Age was a weak independent predictor of poor outcomes.

Table 4. Multivariable logistic regressions of variables found statistically different in the univariate analysis. Source: Million, 2020. NS: not statistically significant (p> 0.05) after stepwise selection. a Missing values (n=69) were imputed based on the mean value (mean= 26.6, see Table 1).

The use of mechanical ventilation in Marseille: no more than 6.5% of hospitalized patients.

Million et al. (the group of Didier Raoult), 2020 (1):

Poor clinical outcome Forty-six patients (4.3%) were classified into the PClinO group including 10 patients transferred into ICU of whom 2 died, 6 who died in conventional hospital units, and 30 additional patients who were hospitalized for 10 days or more (update April 18 th ). Their median age (69.0 years; 31-95 years) was significantly higher than that of patients included into the GO group (42.0 years; 14-86, p < .001) (Table 2). Sex ratio (M/F) was 1.

Unfortunately, the study by Million et al., 2020 (1), does not contain information on the number of patients who were put on mechanical ventilation. But the authors mention that only 10 patients were transferred into an ICU. This is 10 out of 152 hospitalized patients or 6.5%. Even if we assume that all of the patients in an ICU were intubated, which is unlikely, it will still be 50% less then the proportion of hospitalized COVID-19 patients intubated in the New York area.

In the New York City area, 14.2% were treated in an ICU, 12.2% received invasive mechanical ventilation.

Richardson et al., 2020 (1):

During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation.

The eight patients who died.

Among the eight patients who died, some were hospitalized as early as 2 days after symptoms onset. Some of them had high levels of hydroxychloroquine two days after the treatment started (0.338 ug/mL is the maximum level measured). And yet, the patients who started treatment early and those who had high levels of hydroxychloroquine in the blood died. More detailed data, notably describing how each of this patients progressed through the course of the disease, would have been useful.

Table 5.Clinical data of eight patients who died from COVID19 infection out of 1,061 treated with hydroxychloroquine or azithromycin for at least three days. Day 0 between March 3 rd and March 31, 2020; Follow up regarding fatal issue: April 18 th , 2020. Source: Million, 2020.

SARS-CoV-2 strains (viral isolates) from various geographical origins were not associated with any specific viral variant linked to resistance to treatment.

It is also informative to learn that viral isolates from some of Marseille “non-treatment responding patients” and strains from different geographical locations could not be linked to a specific resistance to treatment.

Comparative genomics between viral isolates from 3 nontreatment-responding patients (both PVirO and PClinO), one PClinO patient, one PVirO patient and 10 treatment-responding patients as well as 56 SARS-CoV-2 strains from various geographical origins did not identify any specific viral variant linked to resistance to treatment (Figure 2).

Figure 2. Phylogenetic tree of SARS-COV-2 genomes including isolates from five persistent viral shedders and ten treatment-responding patients (green branches).*** = poor clinical outcome and ¶ = poor virological outcome. Phylogenetic reconstruction was performed using NEXSTRAIN (https://nextstrain.org/) and GISAID (Global Initiative; https://www.gisaid.org/) with acknowledgments [24]. . 23 TABLES Table 1. Reasons for exclusion of 350 patients from the study 94 previously published [13,14] 33 with cardiac contraindication 11 non specified 10 prolonged QTc 3 Brugada syndrome 1 myocarditis history 1 left ventricular hypertrophy 1 severe ischemic cardiopathy 1 left bundle branch block 1 right bundle branch block. Source: Million, 2020.

The verdict.

Being relatively young and healthy is not a guarantee against poor outcomes of COVID-19. The use of anti-hypertensive drugs is the only independent strong predictor of poor outcomes. The use of hydroxychloroquine in the treatment of COVID-19 patients produced contradicting results in different geographical locations.

If you need help with the design of your algorithm of actions in case of infection with SARS-CoV-2, with improving your blood pressure or with testing the qualifications of your doctor, do not hesitate to get in touch with us.

Selected references:

1. Million et al. (the group of Didier Raoult). Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Medicine and Infectious Disease Available online 5 May 2020, 101738 In Press, Journal Pre-proof.

2. Geleris et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.
The article was published on May 7, 2020, at NEJM.org. DOI: 10.1056/NEJMoa2012410

3. Carlucci et al. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. MedRxiv pre-print posted on May 8, 2020. doi: https://doi.org/10.1101/2020.05.02.20080036

4. Richardson et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. doi:10.1001/jama.2020.6775
Published online April 22, 2020.

The study by Million et al. (the group of Didier Raoult), 2020 (1).

“Outcomes were death, clinical worsening (transfer to ICU, and >10 day hospitalization) and viral shedding persistence (>10 days).”