Introduction
On December 31st, 2019, severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) was identified
in Wuhan, China. It was responsible for an outbreak of a severe acute respiratory
syndrome that led to a Public Health Emergency of International Concern (PHEIC), and
the World Health Organization (WHO) named it Coronavirus Disease 2019 (COVID-19).
It is considered the third zoonotic human coronavirus of the century, since there
were cases of SARS-CoV in 2002 in China and cases of Middle East Respiratory Syndrome
(MERS-CoV) in 2012 in Saudi Arabia, and it was declared a pandemic by the WHO on March
11th, 2020.[1]
[2]
Since the emergency of COVID-19, many studies have been published trying to clarify
some clinical questions, such as route of transmission, risk factors, natural course,
outcomes, and treatment options. One of the medications that has been used in many
hospitals to manage these patients is chloroquine, a 4-aminoquinoline drug currently
used to treat malaria, rheumatoid arthritis, and systemic erythematosus lupus, reported
as a potential broad-spectrum antiviral drug. Hydroxychloroquine has also been used,
due to its clinical safety profile being better than chloroquine, which allows higher
daily doses with fewer drug interactions.[3]
In his review, Juurlink (2020) has evidenced that the most typical regimen is 5 days
of hydroxychloroquine at daily doses of 400 to 600 mg, which was corroborated by Mehra
et al (2020), and its doses did not exceed 600 mg daily for 5 to 10 days.[4]
[5] On May 20th, 2020, the Brazilian Department of Health expanded the use of hydroxychloroquine
or chloroquine associated with azithromycin during 5 days for patients with mild symptoms
of the disease.[6] However, on the same day, the Brazilian Society of Infectious Diseases pronounced
themselves against the routine use of these drugs, since until this date there are
no randomized clinical trials with a control group that confirm the effectiveness
of these medications in the treatment of patients diagnosed with COVID-19. According
to them, these medications should only be used for scientific purposes and in a clinical
trial.[7]
The most common adverse events related to the use of chloroquine and hydroxychloroquine
are cardiotoxicity and retinal toxicity. However, an important side effect that is
not commonly discussed is the potential ototoxicity of these medications, which is
already known and has been studied for several years. Many reports have described
sensorineural hearing loss after prolonged therapy with chloroquine, but there are
also studies that described cochleovestibular ototoxicity with both acute and chronic
use of chloroquine and hydroxychloroquine. These drugs accumulate and fix selectively
in melanocytes of cochlear sensory hair cells, resulting in variable injuries that
can be irreparable.[3]
[8] There are reports about children with systemic lupus erythematosus who developed
ototoxicity soon after the therapy with hydroxychloroquine was initiated.[9] There are also cases reported in the literature, since 1968, of hearing loss in
newborns of mothers who had malaria and used chloroquine during pregnancy.[10]
[11]
Therefore, the present paper aims to review the literature and describe updated facts
about the ototoxicity of chloroquine and hydroxychloroquine, an important side effect
that can be present in patients with COVID-19 treated with these drugs.
Discussion
The SARS-Cov-2 is a betacoronavirus that uses the angiotensin-converting enzyme 2
receptor for cell entry. The main mode of transmission is person-to-person, especially
via respiratory droplets that can be dispersed in the air for up to two meters and
stay viable in surfaces for a variable amount of time. Thus, the virus is released
not only when an infected person sneezes or talks, but also when a person touches
an infected surface and then touches the eyes, nose, or mouth.[12] According to Park et al (2020), who analyzed 41 epidemiological studies, the mean
incubation period ranges from 4 to 6 days, which is comparable to that of SARS-CoV
(4.4 days) and MERS-CoV (5.5 days worldwide).[13]
Lovato and Filippis (2020) analyzed 5 retrospective cohort studies and described that
fever (85.6%), cough (68.7%), and fatigue (39.4%) were the most commonly observed
symptoms. Among upper airway symptoms, pharyngodynia was present in 12.4% of patients,
rhinorrhea was found in 4%, and nasal congestion in 3.7% of the patients.[2]
Moreover, some cases of smell disorders have been described in patients with COVID-19.
On March 22nd, 2020, the Brazilian Academy of Otorhinolaryngology and Head and Neck Surgery warned
physicians about the possibility of hyposmia and anosmia being a symptom of COVID-19.[14] The European Rhinology Society reported that up to 60% of patients appear to have
some loss of smell that can be presented before other common symptoms, like fever
and cough.[15] Giacomelli et al (2020) analyzed 59 hospitalized patients with COVID-19 in Milan,
Italy. Of these, 20 (33.9%) reported at least one taste or olfactory disorder, and
11 (18.6%) reported both. It is known that a wide range of viral infections can lead
to taste and smell disorders. According to a mice model, SARS-CoV-2 has a transneural
penetration through the olfactory bulb, and the angiotensin converting enzyme 2 receptor
is widely expressed on the epithelial cells of the mucosa of the oral cavity. Thereby,
the mechanism of taste and smell disorders in SARS-CoV-2 infection could be explained
by these findings.[16]
Hearing loss can also be a manifestation of several viral infections, and there are
findings suggesting that SARS-CoV-2 might be one of these agents. The mechanisms involved
in hearing loss are variable, ranging from direct damage to inner ear structures,
such as hair cells and organ of Corti, and induction of inflammatory and immune-mediated
responses to increasing susceptibility of bacterial and fungal infection. Typically,
this type of hearing loss is sensorineural and, occasionally, hearing recovery can
occur spontaneously.[17] Mustafa (2020) performed an audiological evaluation of 20 patients with COVID-19
who did not have the classic symptoms and compared with a group of 20 people who were
asymptomatic and tested negative for the disease. On the pure-tone audiometry, there
was a significant difference between the groups at the frequencies of 4,000, 6,000,
and 8,000 Hz (p < 0.05), and the transient evoked otoacoustic emissions exhibited a highly significant
difference between both groups.[17]
Due to the significant global health threat of COVID-19, there is an urgent need for
effective treatment that can not only reduce patient's symptoms, but also decrease
the duration of virus carriage to limit the transmission in the community.[18] Perhaps, the treatment is the point that leads to more anxiety and doubts, since
much has been speculated about it, but there is still controversial data about the
safety and efficacy of some drugs, and it is not possible yet to define a therapeutic
management that is known to be effective.[12]
Hydroxychloroquine and chloroquine are being widely prescribed for treatment of COVID-19.[5] Chloroquine can block virus infection by increasing the endosomal pH required for
virus/cell fusion, as well as interfering with the glycosylation of cellular receptors
of SARS-CoV-2 even before cell exposure to the virus, suggesting a prophylactic effect
of the drug.[19] Chloroquine also has an immunomodulatory effect, which may synergistically increase
its antiviral effect in vivo.[20] Despite its in vitro action, there are still no meta-analyses of multicenter, controlled,
blind and randomized clinical trials to prove the benefit of this drug in the treatment
of COVID-19.[6]
A recent study developed in a tertiary hospital in France showed efficiency in clearing
viral nasopharyngeal carriage of SARS-CoV-2 in COVID-19 patients after 3 to 6 days
of treatment (p = 0.001).[18] However, a meta-analysis by Chacko et al (2020), which included 11 studies among
randomized controlled trials and observational studies with a control group, outlined
that there were no statistically significant differences between patients who received
hydroxychloroquine compared with the control group regarding mortality (p = 0.28), clinical worsening or lack of symptomatic improvement (p = 0.76), and viral clearance (p = 0.87). Furthermore, patients who received hydroxychloroquine had a significantly
higher incidence of adverse events than those who did not receive the medication (p = 0.009).[21]
The efficacy of chloroquine or hydroxychloroquine to prevent or to treat patients
with COVID-19 is not well established yet. However, the potential side effects and
harms of these medications, which are widely used to treat other diseases, are known.
Qaseem et al (2020) plead against the use of hydroxychloroquine as both prophylaxis
and treatment for COVID-19, due to known harms and absence of evidence of benefits
of the medication.[22]
Furthermore, Mehra et al (2020) published an analysis made of 96,032 hospitalized
patients from 671 hospitals who were diagnosed with COVID-19. Of these, 81,144 patients
were in the control group and the other 14,888 patients were in the treatment groups
(1,868 received chloroquine, 3,783 received chloroquine with a macrolide, 3,016 received
hydroxychloroquine, and 6,221 received hydroxychloroquine with a macrolide). In this
large multinational analysis, there were no benefits on in-hospital outcomes with
the use of chloroquine or hydroxychloroquine (with or without a macrolide), but, instead,
its use was associated with a higher risk of ventricular arrhythmias and, hence, increased
the chances of in-hospital death.[5] These data were corroborated by a cohort study done by Rosenburg et al (2020) in
the state of New York, which is the largest disease and mortality burden of the US.
The study compared the effects of the treatment with hydroxychloroquine and/or azithromycin.
They concluded that following the adjustment for illness severity, preexisting conditions,
and demographics characteristics, there were no significant differences in mortality
rates between the groups, but cardiac arrest was more frequent in patients who received
hydroxychloroquine.[23]
The ototoxicity related to chloroquine is known, but it is not widely studied. In
the literature, there have been cases reported since 1968. The oldest one described
hearing loss in a child whose mother used chloroquine during pregnancy.[11] Drug ototoxicity can be defined as a transient or definitive disturbance of auditory
and/or vestibular function, induced by therapeutic substances.[24] There is no current available therapy to reverse the damage that can be caused by
ototoxic drugs, such as balance disorders and permanent hearing loss.[25] The patient's main symptoms are tinnitus, vertigo, and sensorineural hearing loss,
which is usually irreversible, although there have been reported exceptions.[10]
A study published in 1975 demonstrated a high concentration of chloroquine in the
vascular stria, modiolus, planum semilunatum, sac and utricle walls, and semicircular
canals, which are inner ear tissues that contain melanin. This protein is present
in highly vascularized areas in the inner ear, and the melanocytes usually are arranged
around the blood vessels.[26] In this context, it is believed that the buildup of chloroquine is responsible for
a vascular injury and degenerative changes in the planum semilunatum and stria vascularis.[24] Thus, the high demand for oxygen from the vascular stria and external hair cells
may be responsible for their sensitivity to quinine, a natural alkaloid present in
chloroquine and hydroxychloroquine.[27]
Castoldi et al (2001) described that chloroquine may induce ototoxicity by mechanisms
other than the one described in the 1975 study by Dencker and Lindquist26. The increased glutamate concentration in the extracellular environment induced by
the drug can favor neuronal excitotoxicity in the inner ear. Thus, chloroquine causes
an overproduction of reactive oxygen species (ROS), which is another important mediator
of toxicity on glial cells of the inner ear.[28] The authors also implied a possible therapeutic target for this drug-induced ototoxicity.
Antioxidants, such as ascorbic acid, are effective against cell death induction by
overproduction of ROS. Thereby, the protective effect in glial cells observed with
this essential vitamin can contribute to the treatment against ototoxicity induced
by the use of chloroquine.[29]
There is a predominance of adverse events related to chloroquine toxicity, but ototoxicity
is also related to the use of hydroxychloroquine, which is theoretically known to
be less toxic. Most of these cases are reported with chronic use of chloroquine, and
it may be explained by a long-term retention and accumulation of the drug in the melanocytes
in the inner ear cells, resulting in variable injuries to the cochlear sensory hair
cells and decreasing neuronal population. Nevertheless, cochleovestibular ototoxicity
has also been related to acute use of the drug.[3]
Khalili et al (2014) reported the case of a 54-year-old-man with bilateral hearing
loss that initiated 1 month after receiving hydroxychloroquine for treatment of rheumatoid
arthritis. Pure-tone and speech audiometry presented with moderate-to-severe sensorineural
hearing loss and reduced speech recognition in both ears. Hydroxychloroquine-induced
hearing loss was suspected to be the cause. The drug was discontinued and, 2 months
later, his audiometric findings improved, with pure-tone and speech audiometry revealing
mild-to-moderate hearing loss and slightly-to-mild disability in speech recognition.
As it was described before, the hearing loss is usually irreversible, but there are
some exceptions reported in the literature.[30]
Furthermore, there are reports of children with systemic erythematosus lupus who developed
ototoxicity soon after the therapy with hydroxychloroquine was initialized. Lim and
Tang (2011) reported an 11-year-old girl treated with hydroxychloroquine, and, 2 months
later, she complained of reduced hearing in both ears. Audiological tests confirmed
the complaint and outlined a bilateral sensorineural loss, predominantly affecting
the low-frequency range. They also suggested in their report that ototoxicity in children
might occur with low doses and in short-term use.[9] There are also case reports of hearing loss in newborns of mothers who had malaria
and used chloroquine during pregnancy.[8]
[11] The occurrence of malaria in this period and its treatment, especially in the third
trimester, can have implications for fetal or neonatal development.[31]
Ototoxicity has a high prevalence in the developing countries of Africa. Kokong (2014)
analyzed 156 patients in Nigeria who had drug-induced ototoxicity over a period of
3 years, confirmed by audiometric findings. The injection of an unknown agent was
the most common cause of hearing loss (n = 55 [35.3%]). Among the known agents, chloramphenicol was the main drug involved
(n = 25 [16.0%]), followed by chloroquine (n = 22 [14.1%]) and gentamicin (n = 20 [12.8%]). Kokong also reports a pregnant woman that received intramuscular chloroquine
and had a miscarriage 4 months after the drug use. Regarding the audiometric patterns,
profound sensorineural hearing loss was identified in 155 ears (49.7%), and mixed
hearing loss in 90 ears (28.8%).[25]
Considering the current scenario, COVID-19 turned out to be the major public health
emergency of this century. Thus, it is plausible and essential that researchers focus
unprecedented attention in analyzing the virus and understanding the disease.[18] The evidence on suppression of activity of SARS-CoV-2 and other coronavirus strains
from in vitro studies increased the interest in the use of hydroxychloroquine and
chloroquine with or without azithromycin for the treatment of COVID-19, raising hopes
but also doubts of a possible reduction in disease morbidity and mortality.[23]
However, research has been limited by the outcomes assessed, small sample size, types
of patients studied and short follow-up. There are no randomized clinical trials that
can prove so far the efficacy of chloroquine or hydroxychloroquine, and few studies
have evaluated adverse events potentially linked to their use in patients with COVID-19,
although, as described, these drugs have known harms reported in several patients
when used to treat other diseases.[23]
In the current unusual context, authorities such as the United States Food and Drug
Administration and the Brazilian Department of Health recently authorized the emergency
use of chloroquine and hydroxychloroquine and obscured the negative aspects of these
drugs. People have been self-treating in Nigeria for apparent COVID-19, and many deaths
were reported there due to chloroquine overdoses.[32] Still, it is hard not to try the use of these drugs that, despite their unclear
benefits, are speculated to have potential advantage in the treatment of this pandemic
disease. Thereby, with so many uncertainties, the only reliable information are that
the use of chloroquine or hydroxychloroquine alone or in combination with azithromycin
to prevent or treat COVID-19 is not well established, and that these 4-aminoquinolines
have known side effects, especially cardiotoxicity, retinopathy, and ototoxicity,
that might be irreversible.[22]
Despite the fact that there is no concrete evidence on the incidence of ototoxicity
when using chloroquine in the short term, we need to consider that, as a pandemic
disease, millions of patients with COVID-19 may receive this treatment. Moreover,
the margin between the therapeutic and toxic dose is narrow, and chloroquine poisoning
has been associated with cardiovascular disorders that can be life threatening.[33]
Since there are no convincing evidence from well-designed clinical trials that support
the use of chloroquine or hydroxychloroquine with good efficacy and safety for the
treatment of COVID-19, and considering their known adverse effects, especially concerning
ototoxicity, we should ask ourselves: should it be used in the current scenario? Can
this ototoxicity worsen the potential audiological symptoms that the disease itself
may cause and turn it to be irreversible? It is important to notice that most of those
infected are elderly, which already have some kind of hearing loss that can also be
worsened by the use of these drugs. Future randomized and well-designed clinical trials
are needed to answer these questions.
