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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 3  |  Issue : 1  |  Page : 3-7

Use of chloroquine and hydroxychloroquine in COVID-19 patients: A dilemma


1 Department of Periodontology and Implantology, Dasmesh Institute of Research and Dental Sciences, Faridkot, Punjab, India
2 Department of Oral Medicine and Radiology, Dasmesh Institute of Research and Dental Sciences, Punjab, India
3 Department of Oral Medicine and Radiology, RR Dental College and Hospital, Udaipur, Rajasthan, India
4 Department of Conservative and Endodontics, RR Dental College and Hospital, Udaipur, Rajasthan, India

Date of Submission06-Dec-2020
Date of Decision10-Feb-2021
Date of Acceptance20-May-2021
Date of Web Publication03-Mar-2022

Correspondence Address:
Dr. Sandeep Kumar Bains
Department of Oral Medicine and Radiology, Dasmesh Institute of Research and Dental Sciences, Faridkot - 151 203, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jopcs.jopcs_16_20

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  Abstract 


The terror of coronavirus disease 2019 (COVID-19) is present universally. The number of cases is on rise. There is always debate about the use of chloroquine and hydroxychloroquine as a prophylaxis. Healthcare workers being the front-line soldiers need additional protection as compared to general population. This review article highlighted the mechanism of action of both drugs and their role in COVID-19 patients.

Keywords: Chloroquine, coronavirus disease 2019, hydroxychloroquine


How to cite this article:
Bhatia A, Bains SK, Tajinder B, Kuldeep S S, Jaideepa. Use of chloroquine and hydroxychloroquine in COVID-19 patients: A dilemma. J Prim Care Spec 2022;3:3-7

How to cite this URL:
Bhatia A, Bains SK, Tajinder B, Kuldeep S S, Jaideepa. Use of chloroquine and hydroxychloroquine in COVID-19 patients: A dilemma. J Prim Care Spec [serial online] 2022 [cited 2022 Nov 30];3:3-7. Available from: https://www.jpcsonline.org/text.asp?2022/3/1/3/338940




  Introduction Top


In December 2019 in Wuhan city of China, there was sudden outburst of coronavirus disease 2019 (COVID-19) which extended over 90% of countries universally and became health emergency of international concern.[1] A novel coronavirus was affirmed as causative agent of COVID-19 by Chinese center for disease control and prevention on January 8, 2020.[2] The World Health Organization (WHO) on January 30, 2020, confirmed this outbreak as a public health disaster of international status with mortality rate to be 3.4%. Considering its spread all over the world, WHO in March 2020 declared it as pandemic disease.[3]


  Structure Top


Coronaviruses are single-stranded RNA viruses, and the term novel is being used considering it to be new virus to already existing coronavirus family Coronaviridae. The term corona designates to crown shape of the proteins that coat them. This virus is highly infectious and its resemblance to coronavirus species seen in bats, and potentially pangolins have been confirmed in recent research thus it is found to be zoonotic in origin, i.e. animals to humans transmission.[4]

Severe acute respiratory syndrome coronavirus (SARS-CoV) was first recognized in year 2002, and the Middle-East respiratory syndrome coronavirus (MERS-CoV) was first acknowledged in year 2012. COVID-19 is now called as SARS-CoV-2.[5]


  Epidemiology Top


In India, as on 17 September 2020, 08:00 IST (GMT + 5:30), there are total cases of 51, 18, 253, of which, 83198 deaths reported [Table 1].[6] As reported by the WHO, Globally, as of 5:18 pm CEST, August 11, 2020, there have been 19,936,210 confirmed cases of COVID-19, including 732,499 deaths [Table 2].[7]
Table 1: Coronavirus disease 2019 statistics in India

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Table 2: Coronavirus disease 2019 cases worldwide

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Globally, as of 10:53 am CEST, 17 September 2020, there have been 29,679,284 confirmed cases of COVID-19, including 936,521 deaths, reported to the WHO.


  Clinical Symptoms Top


Patient present with prodromal symptoms such as cold- or flu-like symptoms usually appears 2–4 days after a coronavirus infection. However, there can be variations in symptoms from person-to-person. The most common symptoms are high-grade fever, dry cough, shortness of breath or dyspnea, and fatigue or tiredness.[8] Some patients may experience myalgia or muscle pain, headache, sore throat, vomiting, and diarrhea. There can be diminished sense of smell (hyposmia) and abnormal taste sensation (dysguesia).[9] Computed tomographic scan shows ground-glass opacities, bilateral patchy shadows, and bilateral pneumonia in the chest. Severe patients may develop arrhythmia and shock which need ventilatory support.[10]


  Management Top


The management of positive cases is by supportive therapy only. Many clinical trials are being conducted worldwide but till date no vaccine has been invented. According to the Center of Disease control so far, there are no US Food and Drug Administration-approved drugs for the management of COVID-19 infected patients.[11] The treatment is focused on the prevention of infection by adhering to universal WHO recommended safety measures which includes proper handwashing with soap for at least 20 s, disinfection of frequently touched surfaces, maintaining physical distance of 3 meters or 6 feet, usage of mask and preventing social gathering.[12] Supportive care comprises the use of hydration, antipyretics, analgesics, and antitussives. Asymptomatic patients are advised to self-isolate for at least 7 days after a positive test result. Symptomatic positive COVID-19 patients are hospitalized where they remain under close observations for 21 days and are managed based on symptoms.[13] There oxygen level is maintained via high-flow oxygen or noninvasive positive pressure ventilators. In severe cases, patient may develop acute respiratory distress syndrome which requires intubation with mechanical ventilation in an intensive care unit setting.[14]

Many antiviral drugs such as remdesivir, favipiravir, chloroquine (CQ)/hydroxychloroquine (HCQ), convalescent plasma, interleukin-6 (IL-6) inhibitors, and lopinavir-ritonavir have been proposed in the treatment of COVID-19 time to time.[15] Their effectiveness is being assessed and they are under clinical trials.


  Chloroquine/Hydroxychloroquine Top


CQ was first synthesized in 1934 and is the main drug for the prevention and treatment of malaria. They are routinely used in autoimmune conditions including systemic lupus erythematosus, porphyria cutanea tarda, rheumatoid arthritis, and Q fever and also act as immunomodulating agent.[16] Later on in year 1955, HCQ, a derivative of CQ became available in the market. It proved to be better with additional outcomes and less side effects.[17] They are lipophilic weak bases that quickly pass across cell membranes and gather in acidic organelles, such as lysosomes, Golgi, and endoplasmic reticulum. These drugs are active against Plasmodium parasites, the causative agent of malaria which acts by interacting with parasites DNA causing inhibition of the polymerization of heme.[18]

HCQ shows its anti-inflammatory properties by increasing the pH within intracellular vacuoles and endosomes, thus interferes with antigen processing in macrophages and antigen-presenting cells.[19] CQ/HCQ shows antibacterial, antiviral, and antifungal activities. It is found to be active against HIV, poliovirus, rabies virus, herpes simplex virus, and hepatitis B virus. CQ is available for oral administration in tablet form as CQ phosphate 500 mg and HCQ sulfate 200 mg. A maximum dose of 2000 CQ and HCQ are used in active malarial cases. The mean half-life of CQ is 22 days and for HCQ is 20–60 days. The peak plasma concentration of CQ found to be 30 min and that of HCQ is 3–4 h.[20]

Nausea, vomiting, and diarrhea are frequent side effects of these drugs. Arnaout et al.[21] assessed the use of CQ and observed nausea and abdominal cramps in 24% and diarrhea in 17% of breast cancer patients. Furst et al.[22] found GIT side effects with dose of 800 mg HCQ in patients of rheumatoid arthritis [Table 3].
Table 3: Studies of hydroxychloroquine compared to placebo in patients with coronavirus disease 2019

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  Mechanism of Action Top


The mechanism of action of HCQ/CQ against COVID-19 is still to be fully explained. CQ was first studied in SARS-CoV for the SARS coronavirus epidemic in year 2002–2003. There is 79% of genetic sequence similarity of SARS-CoV and SARS-CoV-2.[23]


  Hindrance of Cell Membrane Fusion Top


Various cellular proteases such as trypsin, elastase, and cathepsin L actively participate in cell membrane fusion of SARS-COV-2 by after causing endocytosis in the presence of triggering factors such as proteolytic activation.[24] CQ/HCQ may involve the interference of the endosome acidification process, which might inactivate lysosomal proteases, thus interfering with the fusion of virus and host membranes.[25]


  Inhibition of Receptor Recognition Process Top


SARS-COV-2 virus has its S protein which when enters in host body is broken down into two subunits such as S1 and S2. SARS-COV-2 attaches to the angiotensin-converting enzyme 2 receptors whereas S2 binds with cell membrane. CQ and HCQ may inhibit terminal glycosylation by preventing virus attachment to receptors.[26]

de Wilde et al.[27] assessed the efficacy of CQ against MERS-CoV and HCoV-229E in the human hepatoma cell line (Huh-7) and found that CQ was effective in hindering replication cycle of MERS-CoV. There was 3.0 μM concentration of CQ and 3.3 μM of HCQ. Study provided that the selectivity indexes of CQ were 19.4 and for HCQ were more than 15. It was found that addition of 16 μm of CQ 1 h before MERS-CoV infection decreased the production of virus by 1-log and with 32 μM concentrations of CQ by 2-logs. Cortegiani et al.[28] in their in vitro study evaluated the role of HCQ on Vero E6 cells infected with SARSCoV-2 found significant reduction in viral replication with an effective concentration 90 of 6.90 μM.


  Inhibition of T Cell Activation and Cytokine Production Top


CQ/HCQ prevents T cell activation and obstructs expression of CD154 on the surface of CD4 + T cells. They cause change in pH of endosomes, thus decrease cytokines production such as IL-1, IL-6, and tumor necrosis factor-α from T cells and B cells.[29] Huang et al.[30] and Chen et al.[31] in their studies have observed increased level of cytokines and pro-inflammatory factors such as IL-6 and IL-10 in SARS-CoV-2 patients, concluding that cytokine release syndrome is associated with disease severity.


  Alteration of Cell Signaling Pathway and Host Defense Mechanism Top


It is established that there is transmission of signals from the surface of cell to its nucleus such as SARS-CoV through mitogen-activated protein kinase (MAPK) pathway delivers.[32] HCQ could lead to the formation of cellular reactive oxygen species, which are necessary for activation of innate immunity. Thus, CQ/HCQ can both suppress the activation of p38 MAPK pathway and affect the host defense mechanism.[10]

Gao et al.[33] conducted a clinical study in >10 Chinese hospitals to assess the efficacy of CQ on pneumonia associated in COVID-19 positive patients. They recommended 500 mg of CQ per day for 10 days to their patients. They suggested that CQ is efficacious in treating pneumonia in COVID-19 positive patients because of its anti-viral and anti-inflammatory properties.

Yao et al.[15] in their vitro study evaluated pharmacological properties of CQ and HCQ on SARS-CoV-2 infected Vero cells. It was found that CQ was highly efficient in controlling 2019-nCoV infection. HCQ was more potent than CQ in inhibiting SARS-CoV-2 in vitro.

It is not very clear whether to consume or not to consume CQ or HCQ as a precautionary measure or to treat COVID-19 in malaria-endemic areas. It may have impact on local malaria prevalence. Subjects consuming CQ or HCQ by its own without medical consultation would become plasmodium asymptomatic carriers.[34] This may lead to decrease or inhibition of parasite count and mostly if CQ-sensitive strains supplants CQ-resistant strains. After stopping of drugs, there are chances that malaria would rebound itself because of deficiency of control measures. In addition, as CQ-resistant strains are still circulating, CQ intake could result in selection of resistant strains bearing mutations on some Plasmodium genes involved in drug resistance. Coppee et al.[35] assessed possible association between some Plasmodium genes and altered activity of other antimalarials such as artemisinin-based combination therapy. Author suggested that long use of CQ or HCQ may lead to emergence of malarial resistant strains. Singh et al.[36] in their meta-analysis of 3 studies on assessing the efficacy of HCQ on control as well as on COVID-19 subjects which focused on viral clearance measured by reverse transcriptase-polymerase chain reaction (RT-PCR) found no benefit on COVID-19 subjects. There were more deaths with the use of HCQ as compared to control. Authors found increase mortality rate with HCQ.[37]


  Conclusion Top


CQ and HCQ are relatively cheap, readily available and have few side effects. There are few clinical trials that warned the use of CQ/HCQ in COVID-19 patients due to high mortality rates compared to control whereas other found good results too. There is insufficient evidence that strongly recommend these drugs in the management of COVID-19-positive patients. The present study has not sufficient data to support the use of CQ/HCQ in COVID-19 patients and increasing care should be taken about the application of CQ/HCQ in COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Structure
Epidemiology
Clinical Symptoms
Management
Chloroquine/Hydr...
Mechanism of Action
Hindrance of Cel...
Inhibition of Re...
Inhibition of T ...
Alteration of Ce...
Conclusion
References
Article Tables

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