Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering

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

doi:10.1155/2021/5556207

Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering

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

Dipartimento di Medicina Traslazionale

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

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.

Lingua originale	Inglese
Numero di articolo	5556207
Rivista	Journal of Healthcare Engineering
Volume	2021
DOI	https://doi.org/10.1155/2021/5556207
Stato di pubblicazione	Pubblicato - 2021

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10.1155/2021/5556207

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Di Castelnuovo, A., Gialluisi, A., Antinori, A., Berselli, N., Blandi, L., Bonaccio, M., Bruno, R., Cauda, R., Costanzo, S., Guaraldi, G., Menicanti, L., Mennuni, M., My, I., Parruti, G., Patti, G., Perlini, S., Santilli, F., Signorelli, C., Stefanini, G., ... Iacoviello, L. (2021). Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering. Journal of Healthcare Engineering, 2021, Articolo 5556207. https://doi.org/10.1155/2021/5556207

@article{f15846858fc34ce196a1b356ffa68494,

title = "Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering",

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{\textquoteright} 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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2021 Augusto Di Castelnuovo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.",

year = "2021",

doi = "10.1155/2021/5556207",

language = "English",

volume = "2021",

journal = "Journal of Healthcare Engineering",

issn = "2040-2295",

publisher = "John Wiley and Sons Ltd",

}

Di Castelnuovo, A, Gialluisi, A, Antinori, A, Berselli, N, Blandi, L, Bonaccio, M, Bruno, R, Cauda, R, Costanzo, S, Guaraldi, G, Menicanti, L, Mennuni, M, My, I, Parruti, G, Patti, G, Perlini, S, Santilli, F, Signorelli, C, Stefanini, G, Vergori, A, Ageno, W, Agodi, A, Agostoni, P, Aiello, L, Moghazi, SA, Arboretti, R, Aucella, F, Barbieri, G, Barchitta, M, Bonfanti, P, Cacciatore, F, Caiano, L, Cannata, F, Carrozzi, L, Cascio, A, Castiglione, G, Cicullo, A, Cingolani, A, Cipollone, F, Colomba, C, Colombo, C, Crisetti, A, Crosta, F, Danzi, GB, D’Ardes, D, de Gaetano Donati, K, Di Gennaro, F, Di Tano, G, D’Offizi, G, Fusco, FM, Gaudiosi, C, Gentile, I, Gianfagna, F, Giuliano, G, Graziani, E, Guarnieri, G, Langella, V, Larizza, G, Leone, A, Maccagni, G, Magni, F, Maitan, S, Mancarella, S, Manuele, R, Mapelli, M, Maragna, R, Marcucci, R, Maresca, G, Marongiu, S, Marotta, C, Marra, L, Mastroianni, F, Mengozzi, A, Meschiari, M, Milic, J, Minutolo, F, Mussinelli, R, Mussini, C, Musso, M, Odone, A, Olivieri, M, Palimodde, A, Pasi, E, Pesavento, R, Petri, F, Pivato, CA, Poletti, V, Ravaglia, C, Righetti, G, Rognoni, A, Rossato, M, Rossi, I, Rossi, M, Sabena, A, Salinaro, F, Sangiovanni, V, Sanrocco, C, Moriello, NS, Scorzolini, L, Sgariglia, R, Simeone, PG, Spinicci, M, Tamburrini, E, Torti, C, Trecarichi, EM, Vettor, R, Vianello, A, Vinceti, M, Virdis, A, de Caterina, R & Iacoviello, L 2021, 'Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering', Journal of Healthcare Engineering, vol. 2021, 5556207. https://doi.org/10.1155/2021/5556207

TY - JOUR

T1 - Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering

AU - Di Castelnuovo, Augusto

AU - Gialluisi, Alessandro

AU - Antinori, Andrea

AU - Berselli, Nausicaa

AU - Blandi, Lorenzo

AU - Bonaccio, Marialaura

AU - Bruno, Raffaele

AU - Cauda, Roberto

AU - Costanzo, Simona

AU - Guaraldi, Giovanni

AU - Menicanti, Lorenzo

AU - Mennuni, Marco

AU - My, Ilaria

AU - Parruti, Giustino

AU - Patti, Giuseppe

AU - Perlini, Stefano

AU - Santilli, Francesca

AU - Signorelli, Carlo

AU - Stefanini, Giulio

AU - Vergori, Alessandra

AU - Ageno, Walter

AU - Agodi, Antonella

AU - Agostoni, Piergiuseppe

AU - Aiello, Luca

AU - Moghazi, Samir Al

AU - Arboretti, Rosa

AU - Aucella, Filippo

AU - Barbieri, Greta

AU - Barchitta, Martina

AU - Bonfanti, Paolo

AU - Cacciatore, Francesco

AU - Caiano, Lucia

AU - Cannata, Francesco

AU - Carrozzi, Laura

AU - Cascio, Antonio

AU - Castiglione, Giacomo

AU - Cicullo, Arturo

AU - Cingolani, Antonella

AU - Cipollone, Francesco

AU - Colomba, Claudia

AU - Colombo, Crizia

AU - Crisetti, Annalisa

AU - Crosta, Francesca

AU - Danzi, Gian Battista

AU - D’Ardes, Damiano

AU - de Gaetano Donati, Katleen

AU - Di Gennaro, Francesco

AU - Di Tano, Giuseppe

AU - D’Offizi, Gianpiero

AU - Fusco, Francesco Maria

AU - Gaudiosi, Carlo

AU - Gentile, Ivan

AU - Gianfagna, Francesco

AU - Giuliano, Gabriele

AU - Graziani, Emauele

AU - Guarnieri, Gabriella

AU - Langella, Valerio

AU - Larizza, Giovanni

AU - Leone, Armando

AU - Maccagni, Gloria

AU - Magni, Federica

AU - Maitan, Stefano

AU - Mancarella, Sandro

AU - Manuele, Rosa

AU - Mapelli, Massimo

AU - Maragna, Riccardo

AU - Marcucci, Rossella

AU - Maresca, Giulio

AU - Marongiu, Silvia

AU - Marotta, Claudia

AU - Marra, Lorenzo

AU - Mastroianni, Franco

AU - Mengozzi, Alessandro

AU - Meschiari, Marianna

AU - Milic, Jovana

AU - Minutolo, Filippo

AU - Mussinelli, Roberta

AU - Mussini, Cristina

AU - Musso, Maria

AU - Odone, Anna

AU - Olivieri, Marco

AU - Palimodde, Antonella

AU - Pasi, Emanuela

AU - Pesavento, Raffaele

AU - Petri, Francesco

AU - Pivato, Carlo A.

AU - Poletti, Venerino

AU - Ravaglia, Claudia

AU - Righetti, Giulia

AU - Rognoni, Andrea

AU - Rossato, Marco

AU - Rossi, Ilaria

AU - Rossi, Marianna

AU - Sabena, Anna

AU - Salinaro, Francesco

AU - Sangiovanni, Vincenzo

AU - Sanrocco, Carlo

AU - Moriello, Nicola Schiano

AU - Scorzolini, Laura

AU - Sgariglia, Raffaella

AU - Simeone, Paola Giustina

AU - Spinicci, Michele

AU - Tamburrini, Enrica

AU - Torti, Carlo

AU - Trecarichi, Enrico Maria

AU - Vettor, Roberto

AU - Vianello, Andrea

AU - Vinceti, Marco

AU - Virdis, Agostino

AU - de Caterina, Raffaele

AU - Iacoviello, Licia

N1 - Publisher Copyright: Copyright © 2021 Augusto Di Castelnuovo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85110514370&partnerID=8YFLogxK

U2 - 10.1155/2021/5556207

DO - 10.1155/2021/5556207

M3 - Article

SN - 2040-2295

VL - 2021

JO - Journal of Healthcare Engineering

JF - Journal of Healthcare Engineering

M1 - 5556207

ER -

Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering

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