Introduction

In December 2019, unexplained pneumonia cases were reported in Wuhan, China, which was later confirmed to be caused by a novel coronavirus identified as SARS-CoV-2. The clinical symptoms caused by this novel coronavirus were named as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO). SARS-CoV-2 is a β-coronavirus and its genomic sequence is 96.2% identical to that of Bat-SARSs-CoV RaTG13 and 79.5% identical to that of SARS-CoV. Based on the sequencing results and evolutionary analysis of the viral genome, bats are suspected to be the natural hosts of SARS-CoV-2, while the intermediate host is unknown. Previous studies have shown that SARS-CoV-2, like SARS-CoV, can infect human cells that express angiotensin-converting enzyme 2 (ACE2) (Guo et al. 2020).

The most common symptoms of COVID-19 patients include fever, cough, fatigue, and myalgia. However, the disease can evolve in some cases and patients begin to experience dyspnea, shock, multiple organ damage and may even die (Huang et al. 2020). Studies estimate that the basic reproduction number (R0) of SARS-CoV-2 is about 2.2, but it can vary from 1.4 to 6.5 (Adhikari et al. 2020; Guo et al. 2020; Imai et al. 2020; Shen et al. 2015; Srinivasa et al. 2017).

On the other hand, patients who took these drugs for long periods experienced toxic effects, such as retinopathy, circular defects (or bull’s eye maculopathy), and retinal diameter defects, which are generally irreversible, mainly due to drug accumulation in the eye (Schrezenmeier and Dörner 2020). Among toxic effects, retinopathy is the more serious clinical problem that can cause irreversible damage to vision, and even blindness. The American Academy of Ophthalmology determined the risk factors for retinopathy due to HCQ use, which include a time of use greater than 5 years, a high daily drug dosage (HCQ > 5.0 mg/kg lean body mass; CQ > 2.3 mg/kg lean body mass), renal or liver disease patient, high body fat levels, use of concomitant drugs similar to tamoxifen, macular disease and age over 60 years (Marmor et al. 2016). Remarkably, the daily dose and duration of use are the main risk factors. When the HCQ daily dose exceeds 20 mg/kg, the incidence of retinopathy is a 25 to 40% within 1 to 2 years (Marmor et al. 2016). Although the use duration of HCQ and CQ in COVID-19 patients is generally very short, it is still necessary to be aware of their retinal toxicity. Retinal degeneration caused by HCQ and CQ can continue to develop even after treatment is stopped.

The CQ and HCQ side effects in the heart are mainly conduction disorders and cardiomyopathy, which are usually irreversible and fatal (Frisk-Holmberg et al. 1983; Tönnesmann et al. 2013). The cardiotoxicity of these drugs may be related to the their long-term use, which causes acquired lysosomal accumulation disorder. This eventually leads to drug-induced cardiomyopathy, or in the case of excessive doses ingestion, acute poisoning (Yogasundaram et al. 2014). There is a case report of an elderly woman with lupus patient who used HCQ for a long time was diagnosed with refractory ventricular arrhythmia due to a prolonged QT interval. After excluding other causes, she was diagnosed with cardiac conduction abnormalities caused by chronic HCQ poisoning (Chen et al. 2006).

Because CQ and HCQ affect the cardiac conduction system, their use should be avoided in combination with other drugs that block cardiac conduction to prevent fatal arrhythmia. Among them, digitalis drugs (digoxin, desacetylgoxin, digitoxin, and trichoside K), antiarrhythmic drugs class Ia (quinidine and procainamide), antiarrhythmic drugs class III (amiodarone, sotalol, ibutilide, and dronedarone), benpredil, hydrochlorothiazide, and indapamide. In addition, the CQ/HCQ combination with antibiotics, such as quinolones and macrolides, should be prohibited to avoid the risk of promoting the QT interval prolongation and leading to tip torsion. In addition, it is worth mentioning that the interval between the therapeutic and toxic doses of CQ and HCQ is narrow, and acute CQ poisoning is associated with a potential life-threatening cardiovascular disease (Touret and de Lamballerie 2020).

Regarding the nervous system, currently there is no experimental evidence that CQ, HCQ and their metabolites can affect its conduction properties. It is only known that quinine is neurotoxic to dopaminergic neurons in the limbic system (Zou et al. 2018). Further studies are needed to investigate the CQ and HCQ effects on the central and peripheral nervous systems. Therefore, the CQ and HCQ use should follow strict rules and self-medication is not recommended. Moreover, for patients using these drugs, ECG and echocardiographic monitoring should be performed regularly to early detect potential cardiac toxicity early (Yogasundaram et al. 2014).

Over the years, researchers have measured the correlation between CQ/HCQ and toxicity. Their toxicological properties are concentration-dependent. The concentration that causes mild side effects, such as dizziness, diplopia, and fatigue, is about 0.5 to 1.2 × 10–6 mol/L. According to previous reports, about 80% of patients with side effects have CQ/HCQ plasma concentration higher than 2.5 × 10–6 mol/L. On the other hand, no toxic reaction has been reported when their plasma concentration is below 1.25 × 10–6 mol/L. Finally, the critical plasma concentration of cardiovascular toxicity caused by CQ is about 1000 μg/L (3 × 10−6 mol/L) (Ducharme and Farinotti 1996).

Conclusion and suggestions

In summary, HCQ and CQ were found to have exert anti-SARS-CoV-2 effects both in vitro and in vivo, and represent potential treatment options for COVID-19 (Fig. 1). However, the clinical evidence of their effects is from some single-center clinical trials. Evidence from multi-center clinical trials is still lacking. In accordance with the pharmacological and toxicological effects of CQ and HCQ discussed here, the authors of this review recommend the following: (1) Multicenter randomized controlled clinical trials are needed to clarify the CQ and HCQ efficiency and safety in the COVID-19 treatment; (2) Considering their ocular, cardiac and neuro toxicities, CQ and HCQ should not be recommended as preventive drugs for the COVID-19 pandemic; (3) Follow-up of patients who received CQ or HCQ treatment is necessary to access their long-term effects and side effects; (4) The CQ and HCQ dosage and their combination regimen with other drugs in clinical trials should be appropriately adjusted.

Fig. 1
figure 1

Anti-SARS-CoV-2 effects of HCQ and CQ exert both in vitro and in vivo. Descriptive graphic shown the process of SARS-CoV-2 infection and replication, and the anti-SARS-CoV-2 effects of HCQ and CQ in it. (1) CQ and HCQ can glycosylate SARS-CoV-2 itself and its receptor. (2) CQ and HCQ can inhibit cell autophagy, which was involve in virus infection process. (3) CQ and HCQ can directly inhibit the replication of RNA viruses. (4) CQ and HCQ can directly inhibit the expression of SARS-CoV viral gene. (5) After CQ and HCQ directly enter the cell body, the intracellular pH rises and inhibits a series of viral replication and recombination processes

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