key: cord-0994569-zadogqiu
authors: Davido, Benjamin; Boussaid, Ghilas; Vaugier, Isabelle; Lansaman, Thibaud; Bouchand, Frédérique; Lawrence, Christine; Alvarez, Jean-Claude; Moine, Pierre; Perronne, Véronique; Barbot, Frédéric; Saleh-Mghir, Azzam; Perronne, Christian; Annane, Djillali; De Truchis, Pierre
title: nImpact of medical care including anti-infective agents use on the prognosis of COVID-19 hospitalized patients over time
date: 2020-08-02
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106129
sha: 187f6a7f43dc956216c1c1a351df8739d11e9d36
doc_id: 994569
cord_uid: zadogqiu

INTRODUCTION: Interest of anti-infective agents in COVD-19 showed discrepant results. However, there is no evaluation about the impact in changes of practices on the prognosis over time. METHODS: Single center, retrospective study, conducted from March 5(th) to April 25(th) 2020, in adults hospitalized in a medicine ward for a COVID-19. Patient characteristics were compared between 2 periods (before/after March 19(th)) considering French guidelines issued by learned societies. Aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission in intensive care unit (ICU) and/or death. RESULTS: One hundred thirty-two patients were admitted, mean age was 59.0 ± 16.3 years, mean CRP level was 84.0±71.1 mg/L, 46% had a lymphocyte count<1000/mm(3). When prescribed, anti-infective agents were lopinavir-ritonavir (n=12), azithromycin (AZI) (n=28) and AZI combined with hydroxychloroquine (HCQ) (n=52). Between the 2 periods we noted a significant decrease of ICU admission, from 43% to 12% (p<0.0001). Delays until transfer in ICU were similar between periods (p=0.86). Pulmonary CT-scan were significantly more performed (from 50% to 90%, p<0.0001), as oxygen-dependency (53% vs 80%, p=0.001) and prescription of AZI±HCQ (from 25% to 76%, p<0.0001) were greater over time. Multivariate analyses showed a reduction of unfavorable outcome in patients receiving AZI±HCQ (HR=0.45, 95%IC [0.21-0.97], p=0.04), especially among an identified category of individuals (lymphocyte≥1000/mm(3) or CRP≥100 mg/L). CONCLUSION: The present study revealed a significant decrease of admission in ICU over time probably related to multiple factors, including a better indication of pulmonary CT-scan, of oxygen therapy, and a suitable prescription of anti-infective agents.

Impact of medical care including anti-infective agents use on the prognosis of COVID-19 hospitalized patients over time

Introduction: Interest of anti-infective agents in COVD-19 showed discrepant results.

However, there is no evaluation about the impact in changes of practices on the prognosis over time.

Methods: Single center, retrospective study, conducted from March 5 th to April 25 th 2020, in adults hospitalized in a medicine ward for a COVID-19. Patient characteristics were compared between 2 periods (before/after March 19 th ) considering French guidelines issued by learned societies. Aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission in intensive care unit (ICU) and/or death.

Results: One hundred thirty-two patients were admitted, mean age was 59.0 ± 16.3 years, mean CRP level was 84.0±71.1 mg/L, 46% had a lymphocyte count<1000/mm 3 . When prescribed, anti-infective agents were lopinavir-ritonavir (n=12), azithromycin (AZI) (n=28) and AZI combined with hydroxychloroquine (HCQ) (n=52). Between the 2 periods we noted a significant decrease of ICU admission, from 43% to 12% (p<0.0001). Delays until transfer in ICU were similar between periods (p=0.86). Pulmonary CT-scan were significantly more performed (from 50% to 90%, p<0.0001), as oxygen-dependency (53% vs 80%, p=0.001) and prescription of AZIHCQ (from 25% to 76%, p<0.0001) were greater over time. Multivariate analyses showed a reduction of unfavorable outcome in patients receiving AZIHCQ (HR=0.45, 95%IC [0.21-0.97], p=0.04), especially among an identified category of individuals (lymphocyte≥1000/mm 3 or CRP≥100 mg/L).

Conclusion: The present study revealed a significant decrease of admission in ICU over time probably related to multiple factors, including a better indication of pulmonary CT-scan, of oxygen therapy, and a suitable prescription of anti-infective agents.

Management and medical care of COVID-19 pneumonia in hospitalized patients is currently still debated, especially because data regarding an emerging pathogen are constantly evolving over time and across countries. Numerous therapies including oxygen, anti-infective agents and corticosteroids have been proposed.

Historically, Gautret et al. [1, 2] and Million et al. [3] observed in Marseille (France) that a combination therapy using hydroxychloroquine (HCQ) and azithromycin (AZI) could potentially reduce viral shedding and the incidence of COVID-19 pneumonia.

Concomitantly, an observational study conducted by Mahevas et al. [4] evaluating HCQ alone prescribed in an in-hospital setting, showed no impact of HCQ on the transfer rate in intensive care unit (ICU) and/or death. This study is concordant with a publication issued in the United States by Geleris et al. [5] who concluded that HCQ administration was not associated with a greatly lowered risk of intubation or death.

Interestingly, although corticosteroids were considered potentially harmful in the early care of COVID-19 infected patients [6] , the RECOVERY trial (NCT04381936) stated that dexamethasone could reduce mortality rate up to 30% in severely-ill patients admitted for a COVID-19 pneumonia and revealed no interest of HCQ (data not published), meanwhile the azithromycin arm is still being investigated. Very recently a multicenter study in the United States reopened the debate concerning the efficacy of HCQ with or without AZI [7] . Furthermore antiviral therapies, notably lopinavirritonavir, revealed no benefit in comparison to standard of care in a large randomized trial [8] , whereas remdesivir showed a reduction in time to clinical improvement in 2 trials but no significant impact on mortality [9, 10] .

Overall those reports have raised concerns about the true interest of anti-infective agents in COVID-19 pneumonia in a context where medical practices between these different studies are heterogeneous and have evolved over time. Indeed, in the absence of a clear recommendation for treatment initiation, it is difficult to assume or to invalidate the effect of anti-infective agents on the prognosis of COVID-19 patients.

To our knowledge, there is no evaluation over time about changes of practices, including anti-infective agents, and their impact on the prognosis of patients admitted in a medical ward for a COVID-19 pneumonia. Considering controversies, we retrospectively evaluated the potential factors associated with an unfavorable outcome, namely admission in ICU and/or death, during this first wave of the epidemic.

We conducted a single center and retrospective study, from March 5 th to April 25 th 2020, regarding adults admitted in our medicine wards in a tertiary university hospital namely Hôpital Raymond Poincaré (AP-HP), Garches, France.

We included all the adults admitted in medicine for a COVID-19 infection confirmed by SARS-CoV-2 RT-PCR and/or a compatible pulmonary CT-scan. Exclusion criteria were: i) patients directly admitted in ICU; ii) patients discharged from ICU to a medicine ward; iii) opposition to collect data expressed by the patient.

The following data were collected from patient's medical charts: -Patient characteristics: age, sex, diabetes, cardiovascular risk factors, smoking habits, obesity, chronic pulmonary disease, Charlson comorbidity index (CCI) [11] , -Infection characteristics: delay between onset of symptoms and admission, presence of super-infection, C-reactive protein (CRP) and white blood cell count (WBC) at admission, percentage of lung injuries on CT-scan if applicable, positive PCR amplifying the betacoronavirus E gene and the SARS-CoV-2 RdRp gene on nasopharyngeal swab or sputum, -Treatment characteristics: requiring ICU support with invasive ventilation and associated therapeutic strategies (e.g. oxygen, anti-infective agents), -Endpoint was defined as unfavorable outcome assessed by the requirement of a transfer in ICU for invasive ventilation and/or death within 30 days, -Patients were followed-up until hospital discharge. After discharged, patients were monitored during 30 days by the telemedicine through the French covidom platform [12] , -Derived variables: moderate lymphocytopenia was based on a lymphocyte count with a threshold at 1000/mm 3 and high systemic inflammation was defined as a CRP threshold ≥ 100 mg/L.

All patients who required oxygen received systematically a beta-lactam for at least 5 days, using preferentially ceftriaxone or cefotaxime to treat a potential superinfection.

Patients were eligible to a supposed effective anti-infective agent against COVID-19 (HCQ, AZI, lopinavir-ritonavir), independently of biological abnormalities and considering the following indications: i) patient presenting a clinical pneumonia confirmed by SARS-CoV-2 PCR, requiring oxygen therapy (independently of the CT scan findings); ii) high suspicion of COVID-19 pneumonia considering the clinical presentation and/or pulmonary CT-scan showing ground-glass opacity affecting ≥ 10% of the whole parenchyma.

Patients were categorized as receiving an anti-infective agent once they received at least one dose. Patients who received lopinavir-ritonavir were categorized in no treatment group, considering this antiviral drug did not show any benefit for the treatment of COVID-19 [7] .

Before HCQ or AZI initiation, patients had systematically an electrocardiogram (ECG) to evaluate the corrected QT interval using the Framingham formula, and monitored 2 times per week during the whole treatment, as well as serum potassium levels. A loading dose at day 1 with 800 mg/day was administered followed by a maintenance dose of 400 mg/day up to 600 mg/day in case of obesity (body mass index (BMI) > 30) for a total 10 days. In addition, 500 mg of azithromycin was prescribed the first day, followed by 250 mg for 4 days. Patients were informed that HCQ and lopinavirritonavir were currently off-label for the treatment of COVID-19 pneumonia until the 25 th of March 2020 in France, where the ministerial decree #2020-314 authorized the in-hospital prescription of HCQ in this particular indication. In case they refused the prescription of HCQ or the latter was contraindicated (by ECG or drug interactions), it was noted into their medical chart and patients did not receive HCQ.

Aim of the study was to describe the medical care over time (oxygen therapy, antiinfective agents, pulmonary CT-scan) and to determine whether potential factors were related to an unfavorable outcome (transfer in ICU and/or death).

Descriptive statistics are presented as counts and percentages, or means and standard deviations, with skewed continuous data summarized as medians and interquartile ranges. Interactions between treatment and lymphocyte count or CRP level were tested and Kaplan-Meier curves were plotted to assess unfavorable outcome from admission depending on these biological parameters.

Statistical significance was set at 0.05 (two-tailed test). All statistical calculations were performed using R software version 4.2.0.

All procedures performed in studies involving human participants were in accordance with the ethical standards and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study has passed the CESREES/Health Data Hub regarding ethics committee approval (MR1811190620) and is registered on ClinicalTrials.gov (NCT04453501). As part of an anonymous and retrospective study, a non-opposition and information letter was sent to participants afterwards. greater than 100 mg/L. Seventy-two percent of patients were oxygen-dependent at admission, with 8% of patients with an oxygen flow therapy greater than 5 L/min.

Among the patients who underwent a pulmonary CT scan, 83% had lung injuries compatible with COVID-19 greater than 10% of the whole parenchyma. SARS-CoV-2

RT-PCR was positive in 95.5% (n=126) of cases.

Overall, 92 (70%) patients received one anti-infective agent. Among them, 12 (13%) received lopinavir-ritonavir, 28 (29%) azithromycin (AZI) and 52 (55%) AZI combined with HCQ ( During the first period, 40 (30%) patients were hospitalized whereas 92 (70%) were admitted thereafter. There were significantly more oxygen-dependent patients hospitalized during the second period than the first one (80% vs 53%, p=0.001). Also, a significant higher number of pulmonary CT scan performed was observed over time between periods of hospitalization from 50% to 90% (p<0.0001), independently of CT-scan severity (Table 1) . Concomitantly, prescription of AZI whether or not combined with HCQ increased over time, from 25% to 76% between the 2 periods (p<0.0001) (Figure 1 ).

Of note, among patients who did not receive HCQ, 5 had cardiac contraindication and 2 refused to be treated with this molecule. During the course of treatment using AZI in combination with HCQ, we report only 1 patient that presented an adverse event (a prolonged QT interval on ECG without clinical event) that led to discontinuation of HCQ within 48h, and was switched to azithromycin alone.

A total of 28 (21%) patients had an unfavorable outcome, among them 26 (93%)

were transferred to ICU and 2 (7%) died without being transferred in ICU. Mean delay between hospitalization and admission in ICU was 2.45 ± 1.45 days (2.4 ± 1.5 days during the first period vs 2.4 ± 1.6 days during the second one, p=0.86). A trend towards a lower frequency of admission to ICU was observed, from 43% in the first period to 12% in the second period (p<0.0001) (Figure 1 ).

Overall, the risk of death or admission to ICU was significantly related to the oxygen flow (p<0.001) and to lymphocyte count in a first model (i.e. lymphocyte 

There was a significant interaction between treatment and CRP level (p=0.02) and at the limit of statistical significance for the lymphocyte count (p=0.06) supporting a subgroup analysis. In univariate analysis, patients who benefited from AZI whether or not combined with HCQ with a lymphocyte count ≥ 1000/mm3, were less likely to have an unfavorable outcome compared to patients without any treatment (p=0.04) (Fig 2.a) . Concomitantly, patients who benefited from AZI whether or not combined with HCQ with a CRP ≥ 100 mg/L, were less likely to have an unfavorable outcome compared to patients without any treatment (p=0.009) (Fig 2.b) . However, these results are not reproducible in patients with a lymphocyte count < 1000/mm3 (p=0.80) and similarly in patients with a CRP level < 100 mg/L (p=0.50) ( Figure S3 .a, S3.b in Supplementary Data).

Our study highlights that unfavorable outcome (transfer to ICU and/or death) Because of lockdown, it looks like patients were admitted later in the second period than during the first period of the epidemic and it might explain why they required more oxygen therapy at baseline. We suggest that in case of a second wave, it could be relevant to introduce telemedicine monitoring of vital signs including pulse oximetry at home. Indeed, oxygen therapy at home, as proposed by the French covidom platform in patients discharged from the hospital during the first wave of the epidemic was of interest [12] .

In multivariate analyses, our models adjusted on the lymphocyte count or CRP, showed that patients who benefited from AZI whether or not combined with HCQ were 2.2 and 2.4 times less likely to have an unfavorable outcome than patients without treatment (p=0.04), respectively. This finding suggests that the lymphocyte count which is already known to be closely related to COVID-19 disease severity [14, 15] could be also a predictive factor of anti-infective therapy response. Indeed, patients with lymphocyte count ≥ 1000/mm 3 might be patients at an early stage of COVID-19, arguing for the earliest initiation of anti-infective agents, as previously demonstrated with oseltamivir treatment in severely-ill patients with 2009 pandemic influenza A (H1N1) [16] . However, we did not study whether there was a relationship between the lymphocyte count and the delay from first onset of symptoms to the admission, because this variable is declarative and thus not reliable. Likewise, AZI whether or not combined with HCQ showed interest in hospitalized patients with a high systemic inflammation (CRP level ≥ 100 mg/L), known as the so called -cytokine storm‖. This is one argument pleading for a possible immune-modulator effect of the treatment as previously described by Zhao et al. [17] . Interestingly, our study does focus on the potential interest of treatment with azithromycin whether or not combined depending on certain biological parameters.

Indeed, azithromycin's potential antiviral activity is concordant with previous in vitro studies regarding SARS-CoV-2 [19] or H1N1-pdm09 [20] and one clinical randomized trial in in the prevention of children respiratory infections [21] . In addition a recent publication emphasized the role of azithromycin against COVID-19 through the CD147 receptor of stem cell [22] . Moreover, one study published in the JAMA by

Rosenberg et al. [23] highlighted a potential trend to a decreased mortality in patients receiving azithromycin versus HCQ or standard of care despite being non-statistically significant (p=0.14). Moreover, authors discussed that the rapidity with which patients entered the ICU (within 48 hours) might have underestimated the treatment efficacy.

Also, as azithromycin is commonly prescribed for bronchitis and authorized in ambulatory care, a study conducted among general practitioners could be relevant to evaluate early indication of this single therapy for the treatment of COVID-19 in fragile outpatients.

In addition, our experience does not report any serious side effect of this combination therapy as long as we take the necessary caution and perform follow-up ECG using a conventional dose of HCQ as proposed by Borba et al. [24] .

Our study has several limitations. The first limitation is the single center nature of the study, describing the experience of a unique center whose results might not be generalizable. However, it was carried out in a hospital specialized for decades in the Moreover, considering inherent limitation of a descriptive study with a limited sample size (n=132), we could not infer causality in the association between the use of AZI±HCQ and the ameliorated prognosis in COVID-19 patients. Besides, we also noted that some unforeseen confounders (e.g., pre-hospital medication and delay to admission) may still potentially alter the magnitude of azithromycin effects on the outcome of COVID-19 pneumonia. Also, choices in anti-infective agents have differed between the first and second period, notably because prior to March 25 th , HCQ was not authorized by the French minister of Health and explained partly the common use of lopinavir-ritonavir at this period.

Finally, we decided to choose a multivariate model rather than a propensity score because the aim of this study was not to evaluate the effect of AZI±HCQ on the prognosis but to evaluate all factors which could have impacted on medical care.

In conclusion, findings from this study showed that rate of admission in ICU All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Authors would like to thank Pr Xavier Paoletti for his proofreading of the manuscript and his particular attention to the statistical analyses. (24) <0.0001 AZI ± HCQ 10 (25) 70 (76) † In first period is define between 03/05 to 03/19; ‡In second period is define between 03/20 to 04/25; AZI, Azithromycin; HCQ, Hydroxychloroquine; N, number; %, percent; SD, standard deviation; M, men; Obesity with body mass index ≥ 30 kg/m²; *CCI, Charlson Comorbidity Index; PMN, polymorphonuclear leukocyte; CRP, c-reactive protein; CT : computerized tomography; pulmonary CT scan category normal [0%], limited <10%, mild 10% -25%, Moderate 25% -50%, Severe >50%; A Student test (equal variance) or a Welche-Satterthwaite t test (unqual variance) was used to analyze the quantitative variables, a Mantel-Haenszel Chi-Square test was used to analyze the qualitative variables and the exact test of Fisher was used when the sample sizes were small (<5). Test significant (p<0.05) 

Infection & Inflammation-U-1173

Centre d'Evaluation et de Traitement de la Douleur-U-987

Handicap Neuromusculaire-U-1179

Centre d'Investigation Clinique

Clinique de la Muette

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France

Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Remdesivir for the Treatment of Covid-19 -Preliminary Report

A new method of classifying prognostic comorbidity in longitudinal studies: development and validation

Assistance Publique-Hôpitaux de Paris' response to the COVID-19 pandemic

Recommandations d'experts portant sur la prise en charge en réanimation des patients en période d'épidémie à SARS-CoV2 2020:29

Hematological Findings and Complications of COVID-19

Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study

Early versus late oseltamivir treatment in severely ill patients with 2009 pandemic influenza A (H1N1): speed is life n.d

Cytokine storm and immunomodulatory therapy in COVID-19: Role of chloroquine and anti-IL-6 monoclonal antibodies

Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis

In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication

Azithromycin, a 15-membered Macrolide Antibiotic, Inhibits Influenza A(H1N1)pdm09 Virus Infection by Interfering With Virus Internalization Process

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial

CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

/N number/total; 1* indicates the reference category

No treatment defined as patients who have had no treatment or lopinavir-ritonavir

Multivariate Cox model regression was used to identify the potential factors associated with unfavorable outcome (ICU admission or death after ICU), adjusted on CCI (including age), obesity, oxygen and treatment strategies groups according to CRP