Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering.

Augusto Di Castelnuovo,Antonio Cascio,Nicola Schiano Moriello,Laura Carrozzi,Francesca Santilli,Giulia Righetti,Gabriele Giuliano,Lucia Caiano,Filippo Aucella,Massimo Mapelli,Emauele Graziani,Carlo Gaudiosi,Nausicaa Berselli,Anna Sabena,Filippo Minutolo,Claudia Ravaglia,Raffaella Sgariglia,Rosa Manuele,Sandro Mancarella,Annalisa Crisetti,Samir Al Moghazi,Gian Battista Danzi,Maria Musso,Rossella Marcucci,Andrea Vianello,Armando Leone,Ivan Gentile,Giuseppe Di Tano,Stefano Maitan,Giacomo Castiglione,Greta Barbieri,Emanuela Pasi,Marco Olivieri,Martina Barchitta,Raffaele Bruno,Ilaria Rossi,Antonella Palimodde,Claudia Colomba,Marianna Meschiari,Francesco Cipollone,Antonella Cingolani,Licia Iacoviello,Francesco Salinaro,Gloria Maccagni,Piergiuseppe Agostoni,Carlo Sanrocco,Roberta Mussinelli,Michele Spinicci,Anna Odone,Giovanni Guaraldi,Alessandro Mengozzi,Raffaele Pesavento,Arturo Ciccullo,Silvia Marongiu,Venerino Poletti,Roberto Vettor,Simona Costanzo,Giuseppe Patti,Enrica Tamburrini,Francesco Di Gennaro,Francesco Petri,Lorenzo Marra,Antonella Agodi,Claudia Marotta,Raffaele De Caterina,Laura Scorzolini,Carlo Torti,Paolo Bonfanti,Andrea Antinori,Walter Ageno,Marco Vinceti,Alessandro Gialluisi,Vincenzo Sangiovanni,Francesco Cacciatore,Marco Rossato,Carlo Signorelli,Ilaria My,Roberto Cauda,Riccardo Maragna,Katleen De Gaetano Donati,Marialaura Bonaccio,Francesca Crosta,Andrea Rognoni,Francesco Maria Fusco,Cristina Mussini,Rosa Arboretti,Lorenzo Menicanti,Lorenzo Blandi,Enrico Maria Trecarichi,Valerio Langella,Federica Magni,Agostino Virdis,Marianna Rossi,Giustino Parruti,Stefano Perlini,Franco Mastroianni,Gennaro Maresca ,G Larizza ,Paola Simeone ,Jovana Milić ,Luca Maria Aiello ,Damiano D’ardes ,Marco Mennuni,Alessandra Vergori,Giulio G Stefanini ,F Cannata ,Gianpiero D’offizi ,Carlo Andrea Pivato ,Francesco Gianfagna ,Gabriella Guarnieri,Cristina Colombo

doi:10.1155/2021/5556207

Abstract

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients' characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (p < 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.

Highlights

Hydroxychloroquine (HCQ) is an antimalarial drug suggested to be effective in inhibiting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) replication in vitro [1, 2]
Six patients with missing values on survival were removed. en, we modelled the risk of manifesting a bad outcome through a logistic regression (glm() function in R), modelling both additive and interactive models of Covid-19 patients cluster and HCQ use, as above. is analysis was motivated by the fact that the curse of disease often differs across patients, e.g., with some subjects with less severe forms suddenly worsening their conditions until death and others having severe manifestations but still surviving, possibly thanks to intensive cares. erefore, a composite outcome variable represented a robust way to measure potential risk/protective effects of patients’ clusters and HCQ use
Clusters were associated with severe Covid-19 disease manifestations, with 65.8% of patients in the smaller cluster presenting with either severe pneumonia or acute respiratory distress syndrome (ARDS), compared to 45.9% in the larger cluster (Chi-squared 76.4, p < 10−15; Table S1)

Summary

Introduction

Hydroxychloroquine (HCQ) is an antimalarial drug suggested to be effective in inhibiting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) replication in vitro [1, 2]. HCQ is characterized by antiviral, anti-inflammatory, and antithrombotic actions, contrasting the main disruptive effects of SARS-CoV-2 infection on the organism [3] For this reason, it has been heavily used in treating patients affected by SARS-CoV-2 infection related disease (commonly known as Covid-19), especially in the first phases of the current pandemics, when Covid-19 was quite unknown [4]. It is likely that the efficacy of HCQ treatment for Covid-19 may vary across patients and is influenced by subtypes of the disease, which in turn is largely dependent on patients’ characteristics and their nonlinear combinations [19]. The authors reported a reduction of in-hospital mortality within patients treated with HCQ, which was even more pronounced within those patients predicted to benefit most from the drug, in line with expectations [19]

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Results

Discussion

Conclusion