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American Journal of Emergency Medicine 38 (2020) 2209-2217

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

journal homepage: www.elsevier.com/locate/ajem

Acute chloroquine and hydroxychloroquine toxicity: A review for
emergency clinicians

Alessandra Della Porta, BS, EMT-B, Kasha Bornstein, MSc Pharm, EMT-P, Austin Coye, BS,
Tim Montrief, MD, MPH, Brit Long, MD *, Mehruba Anwar Parris, MD

* University of Miami Miller School of Medicine, Miami, Florida, USA

> Department of Emergency Medicine, Jackson Memorial Health System, Miami, Florida, USA
© Department of Emergency Medicine, Brooke Army Medical Center, San Antonio, TX, USA

« Emergency Department, Jackson South Medical Center, Miami, Florida, USA

ARTICLE INFO ABSTRACT

Background: Acute chloroquine and hydroxychloroquine toxicity is characterized by a combination of direct car-
diovascular effects and electrolyte derangements with resultant dysrhythmias and is associated with significant
morbidity and mortality.

Objective: This review describes acute chloroquine and hydroxychloroquine toxicity, outlines the complex path-
ophysiologic derangements, and addresses the emergency department (ED) management of this patient popu-
lation.

Article history:

Received 10 June 2020

Received in revised form 11 July 2020
Accepted 11 July 2020

Ke ‘ds: 5 - . . . ar wee . .

Hydronyeh loroquine Discussion: Chloroquine and hydroxychloroquine are aminoquinoline derivatives widely used in the treatment of
Chloroquine rheumatologic diseases including systemic lupus erythematosus and rheumatoid arthritis as well as for malaria
Acute toxicity prophylaxis. In early 2020, anecdotal reports and preliminary data suggested utility of hydroxychloroquine in at-

tenuating viral loads and symptoms in patients with SARS-CoV-2 infection. Aminoquinoline drugs pose unique
and significant toxicological risks, both during their intended use as well as in unsupervised settings by layper-
sons. The therapeutic range for chloroquine is narrow. Acute severe toxicity is associated with 10-30% mortality
owing to a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhyth-
mias. Treatment in the ED is focused on decontamination, stabilization of cardiac dysrhythmias, hemodynamic
support, electrolyte correction, and seizure prevention.

Conclusions: An understanding of the pathophysiology of acute chloroquine and hydroxychloroquine toxicity and
available emergency treatments can assist emergency clinicians in reducing the immediate morbidity and mor-
tality associated with this disease.

Aminoquinoline

Published by Elsevier Inc.

1. Introduction chloroquine and hydroxychloroquine exposures reported to U.S. Poison

Control Centers from January 1, 2020 through April 26, 2020, an in-

Chloroquine and hydroxychloroquine are aminoquinoline deriva-
tives widely used in the treatment of rheumatologic diseases as well
as for malaria prophylaxis [1]. In early 2020, anecdotal reports and pre-
liminary data suggested utility of chloroquine and hydroxychloroquine
for attenuating viral loads and symptoms in patients with severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [2-5]. Clin-
ical trials are underway to determine treatment protocols, efficacy, and
optimal dosing for SARS-CoV-2 infection [6]. Shortly following publica-
tion of initial reports indicating efficacy, cases of acute chloroquine tox-
icity including inadvertent deaths were reported in the United States
(U.S.), African, and European newsmedia [7-9]. There were 283

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, USA.
E-mail addresses: brit.long@yahoo.com (B. Long), mehruba.anwar@jhsmiami.org
(M.A. Parris).

https: //doi.org/10.1016/j.ajem.2020.07.030
0735-6757/Published by Elsevier Inc.

crease of 42% compared to the same time period during the previous
year, with a 93% increase during the month of April 2020 when com-
pared to April 2019 [10]. Aminoquinoline drugs, including chloroquine,
hydroxychloroquine, and amodiaquine, pose unique and significant
toxicological risks, both in therapeutic use as well as in unsupervised
settings by laypersons. For the purposes of this review,
“aminoquinolines” will refer to chloroquine and hydroxychloroquine.
The therapeutic margin for chloroquine toxicity is narrow, and acute
severe toxicity is associated with 10-30% mortality owing to a combina-
tion of direct cardiovascular effects and electrolyte derangements with
resultant dysrhythmias [11]. In typical use, aminoquinoline toxicity is
rarely reported. Fewer than 10 cases of acute severe chloroquine or
hydroxychloroquine overdoses were reported to U.S. Poison Control
Centers from 2012 to 2018, and approximately 70 cases of chloroquine
or hydroxychloroquine overdose were reported in the literature base in


A. Della Porta, K. Bornstein, A. Coye et al.

the past decade [12-18]. While commonly prescribed for rheumatologic
diseases, the novel proposed indication for SARS-CoV-2 infection repre-
sents an unprecedented expansion of aminoquinoline use in a signifi-
cantly wider population [6].

As acute aminoquinoline toxicity is rare, contemporary literature on
management is sparse [19]. Similar to other toxicological emergencies,
randomized controlled trials and systematic reviews analyzing manage-
ment approaches are absent. Prospective clinical trials evaluating treat-
ment are also rare and date back to the 1980s and 1990s [20,21].
Updated treatment recommendations for aminoquinoline toxicity
since the development of rescue modalities including intravenous
lipid emulsion (ILE) and extracorporeal membrane oxygenation
(ECMO) are lacking [22]. This article reviews the pathophysiology of
aminoquinoline toxicity to provide guiding principles for management
of acute complications. Understanding these complications and the ap-
proach to the management of electrolyte imbalances and hemodynamic
instability is essential to optimizing patient care, especially following
acute intoxication that may bring patients to the emergency
department.

2. Methods

This review provides a focused evaluation of emergency
department-based evaluation and treatment of aminoquinoline toxic-
ity. The authors searched PubMed and Google Scholar for articles con-
taining the key words “hydroxychloroquine” OR “aminoquinoline” OR
“chloroquine” OR “quinolone” AND “toxicity” OR “poisoning” OR “ad-
verse effects”. The PubMed search was conducted from database incep-
tion to April 5, 2020, yielding over 6300 articles. The first 200 articles in
Google Scholar were also evaluated for inclusion. The literature search
was restricted to studies published in English, with a focus on emer-
gency medicine and critical care. Authors evaluated case reports and se-
ries, retrospective and prospective studies, systematic reviews and
meta-analyses, and narrative reviews. Authors also reviewed guidelines
and supporting citations of included articles. Articles were chosen based
upon author consensus. When available, systematic reviews and meta-
analyses were preferentially selected. These were followed sequentially
by randomized controlled trials, prospective studies, retrospective stud-
ies, case reports, and other narrative reviews, when alternate data were
not available. A total of 121 articles were selected for inclusion in this
narrative review.

3. Discussion
3.1. Proposed aminoquinoline uses in coronavirus infection

Chloroquine and hydroxychloroquine are derivatives of quinine, de-
rived from the bark of the Peruvian Cinchona tree. Chloroquine was syn-
thesized in 1934 but shelved for years due to concerns for toxicity in
human patients. Hydroxychloroquine sulfate was developed in 1946
in an effort to produce a less toxic chloroquine analog. Animal toxicolog-
ical studies demonstrate hydroxychloroquine to be approximately 40%
less toxic than chloroquine [23]. Initially indicated for antimalarial treat-
ment and prophylaxis, chloroquine and analogs found new anti-
inflammatory use in World War II. As millions of soldiers used it against
malaria, military physicians observed improvement in inflammatory ar-
thritis, leading to trials demonstrating aminoquinoline efficacy for rheu-
matologic conditions [24]. Antimalarial efficacy of chloroquine waned in
the late 20th century, though it is still used for malarial prophylaxis in
regions with susceptible Plasmodium strains. Chloroquine analogues
have also been found to have metabolic, antithrombotic, antineoplastic,
and antiviral effects, and have been hypothesized as targeted agents
against coronavirus infection since the 2003 SARS outbreak [25,26].

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is re-
sponsible for a major international pandemic with significant morbidity
and mortality rates between 1.5 and 9% depending on the population

2210

American Journal of Emergency Medicine 38 (2020) 2209-2217

investigated [27,28]. The pathophysiology of SARS-CoV-2 includes but
is not limited to cytokine dysregulation, direct cytopathic effects on re-
spiratory tract epitheliocytes, and down-regulation of lung protective
angiotensin converting enzyme resulting in diffuse alveolar damage
and hypercoagulability [29,30]. Viral entry is facilitated by cellular
protease-primed spike protein binding to angiotensin-converting en-
zyme 2 (ACE2) receptors [31]. Efforts to repurpose or develop targeted
therapeutics for SARS-CoV-2 infection have included assessment of
anti-inflammatory drugs such as corticosteroids and interleukin inhibi-
tors, macrolide antibiotics such as azithromycin, and direct-acting anti-
virals such as protease inhibitors and adenosine analogs [6]. The utility
of aminoquinolines in attenuating infection severity is hypothesized to
derive from preventing SARS-CoV-2 binding to target receptors and
inhibiting viral cell entry [6]. Chloroquine and hydroxychloroquine are
concentrated within the endosome, where they are thought to modu-
late organelle pH, inhibiting autophagosome formation and impairing
cleavage of the SARS-CoV-2 spike protein [32]. Additional hypothesized
immunomodulatory effects in SARS-CoV-2 infection include downregu-
lation of T-cell response and inflammatory cytokine storm that play a
role in organ injury and acute respiratory distress syndrome [32,33].
Preliminary in-vitro data and clinical trials in China and France in
early 2020 using chloroquine and hydroxychloroquine suggested anti-
SARS-CoV-2 activity [2,34]. These clinical trials utilized chloroquine at
dosages and treatment courses greater than those prescribed for anti-
malarial and rheumatologic indications, raising concern for toxicologi-
cal implications in susceptible patients. Following the United States
Food and Drug Administration emergency use authorization for chloro-
quine and hydroxychloroquine in the treatment of SARS-CoV-2, many
additional clinical trials with randomization, blinding, and larger sample
sizes were initiated to determine the benefit and risks. The largest of
these studies, enrolling over 96,000 patients, initially demonstrated in-
creased in-hospital mortality rates in patients treated with chloroquine
or hydroxychloroquine [35]. However, that study has since been
retracted due to concerns regarding veracity of the data and analyses
conducted and inability to conduct an independent and private peer re-
view [36]. Additional studies have demonstrated similar findings of in-
creased mortality or did not find any evidence of prevention of
primary endpoints, such as need for mechanical ventilation or death
in patients treated with aminoquinolines [37-39]. As of June 2020,
there are over 40 ongoing clinical trials actively assessing the efficacy
of chloroquine or hydroxychloroquine, demonstrating continued inter-
est in its role as a therapeutic agent for COVID-19. Furthermore, addi-
tional trials targeting frontline healthcare workers are underway to
assess for the possible preventative action of these agents. The use of
chloroquine or hydroxychloroquine sulfate in combination with other
novel antiviral agents has been discouraged by the United States Food
and Drug Administration, as recent in-vitro data demonstrating increas-
ing concentrations of chloroquine phosphate reduced formation of acti-
vated remdesivir triphosphate in human bronchial epithelial cells,
raising concerns that it may reduce the antiviral activity of this medica-
tion [40]. Widespread non-prescription use of aminoquinolines for ei-
ther prophylaxis or treatment by laypersons in response to fears of
COVID-19 raises significant and continued concern for unintended tox-
icity from overdose and/or drug-drug interactions.

3.2. Chloroquine and hydroxychloroquine toxicology

3.2.1. Metabolism and pharmacokinetics

Despite slight differences in chemical structure, chloroquine and
hydroxychloroquine are similar in regard to both metabolism and toxic-
ity [41,42]. Both molecules are highly lipophilic, have a high volume of
distribution, and have mild-to-moderate protein binding [43,44]. Fol-
lowing ingestion, the drugs are rapidly absorbed from the upper gastro-
intestinal (GI) tract and slowly redistribute to other compartments,
eventually accumulating in erythrocytes, liver, lung, kidney, heart, mus-
cle, and retinal tissue [43]. The combination of rapid absorption, high


Aspirin is most of the time an innocuous drug. There are 2 cats in the kitchen. But it can have deleterious effect if it is administered with a dosage of more than 1000 mg. Some adverse effects are exacerbated for some patients. For instance, if they are more than 70 years old, effects will be more pronounced.
Some studies have proven the impact of cytoxin on young female patients. Indeed, it can cause nose bleeding when 500mg or more if taken by the patient. This a test sentence.
In this paper we try to prove how chloroquine can generate negative effects on elderly people. It can in particular causes stomach pain when the maximum 1000mg dosage is not respected. Finally we show that it has no or little effect on younger patients even when they take more than 1000mg.
Patients with hemoglobin E beta-thalassemia, a severe form of the disease, were found to have impaired hepcidin function and higher TfR1 levels as a result of an increased erythropoietic drive stemming from the continuously failing erythropoiesis that is caused by improper hemoglobin production [56].
Another study observed a 3-year disease free survival rate of 80 percent, and an overall survival rate of 82 percent in cervical cancer patients.
A study reported that individuals with hereditary hemochromatosis exhibit an increased risk for developing cancer, particularly in the liver and primarily hepatocellular carcinoma as opposed to biliary tract related cancers.
Due to oxygen's atomic nature, its reduction must proceed in a stepwise fashion of individual electron additions and reactive intermediates.
Chloroquine was syn-thesized in 1934 but shelved for years due to concerns for toxicity in human patients.