key: cord-0965280-7b4nmge9
authors: Marin, Sergio; Val, Alba Martin; Peligero, Maite Bosch; Rodríguez-Bernuz, Cristina; Pérez-Ricart, Ariadna; Vilaró Jaques, Laia; Paredes, Roger; Roca, Josep; Quiñones, Carles
title: Safety of Short-Term Treatments with Oral Chloroquine and Hydroxychloroquine in Patients with and without COVID-19: A Systematic Review
date: 2022-05-21
journal: Pharmaceuticals (Basel)
DOI: 10.3390/ph15050634
sha: e99cbd68a526734ab8e194afafa8e2d480e08e86
doc_id: 965280
cord_uid: 7b4nmge9

Chloroquine (CQ) and hydroxychloroquine (HCQ) have recently become the focus of global attention as possible treatments for Coronavirus Disease 2019 (COVID-19). The current systematic review aims to assess their safety in short treatments (≤14 days), whether used alone or in combination with other drugs. Following the PRISMA and SWiM recommendations, a search was conducted using four health databases for all relevant English-, Chinese-, and Spanish-language studies from inception through 30 July 2021. Patients treated for any condition and with any comparator were included. The outcomes of interest were early drug adverse effects and their frequency. A total of 254 articles met the inclusion criteria, including case and case-control reports as well as cross-sectional, cohort, and randomised studies. The results were summarised either qualitatively in table or narrative form or, when possible (99 studies), quantitatively in terms of adverse event frequencies. Quality evaluation was conducted using the CARE, STROBE, and JADAD tools. This systematic review showed that safety depended on drug indication. In COVID-19 patients, cardiac adverse effects, such as corrected QT interval prolongation, were relatively frequent (0–27.3% and up to 33% if combined with azithromycin), though the risk of torsade de pointes was low. Compared to non-COVID-19 patients, COVID-19 patients experienced a higher frequency of cardiac adverse effects regardless of the regimen used. Dermatological adverse effects affected 0–10% of patients with autoimmune diseases and COVID-19. A broad spectrum of neuropsychiatric adverse effects affected patients treated with CQ for malaria with variable frequencies and some cases were reported in COVID-19 patients. Gastrointestinal adverse effects occurred regardless of drug indication affecting 0–50% of patients. In conclusion, CQ and HCQ are two safe drugs widely used in the treatment of malaria and autoimmune diseases. However, recent findings on their cardiac and neuropsychiatric adverse effects should be considered if these drugs were to be proposed as antivirals again.

Articles identified through the preliminary search were then screened for relevance to our study in two steps. First, the title and abstract of each article were independently checked by two reviewers for at least minimally relevant information on CQ, HCQ, and their safety. The resulting two lists of articles were compared and any differences were resolved by a third reviewer. The second step involved evaluating the full text of each article to confirm its relevance for this review. Articles were only included in the final set if they reported cases of adverse drug reactions to CQ or HCQ, or were case-control, crosssectional, cohort, or randomised studies that reported information on the safety of these drugs for adult patients 18 years or older (it only was admitted if part of the population included adolescents ≥12 years in large cross-sectional, cohort, or randomised studies, not in the cases). Articles were excluded if they reported adverse drug reactions that occurred beyond the first 14 days of treatment; if they were related to intoxications (intakes of more than five times the Defined Daily Dose of 0.5 g of CQ base or 0.516 g of HCQ base) [21] ; if the route of administration was not the oral route; if they were related to work-related exposure; if they were surveys of health professionals; if they assessed the validity of a diagnostic or screening technique; if they contained preclinical data (including in vitro or animal experimentation); if they were protocols, surveys, reviews, systematic reviews, scoping reviews, or meta-analyses; if the adverse drug reaction was associated with a combination of drugs other than those mentioned; if they did not indicate the temporal relationship between drug intake and the appearance of adverse drug reactions; or if they contained duplicate information (the same case or sample of patients reported in separate articles). Two reviewers performed this process independently. Subsequently, the results were compared, and discrepancies were resolved by a third reviewer to produce the final set of articles for synthesis.

Working separately, two reviewers extracted from each of the articles a set of specific data about study design, participants, quality, and the results in a specific datasheet. The two resulting data compilations were compared, and any discrepancies were discussed and resolved with the participation of a third reviewer. We gathered data related to the design, the participants, the quality, and the results of each study. The final data selected for synthesis in this systematic review can be seen in Supplementary Material.

The CARE (CAse REport) Checklist was used to evaluate the quality of reporting in case reports and case series reports [22] . Case-control, cross-sectional, and cohort studies were assessed using the combined STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist [23] . The different items on the checklists mentioned were rated as "Yes" (=1 point), "Partly" (=0.5 point), "No" (=0 points), or "Not applicable". We calculated an overall score for the quality of each study by dividing the total number of points scored per article by the number of items to produce a percentage. A low score indicated low quality, hence a higher risk of bias. We considered studies scoring between 75% and 100% to be of high quality, those between 50% and 74% of moderate quality, and those below 50% of low quality. If more than 50% of the assessed items were rated as "Not applicable", the study was dismissed for quality assessment but not eliminated from our dataset. The quality of randomised studies was judged using the JADAD scale, which assigns a score ranging from 0 to 5 points such that the higher the score, the better the methodological quality [24] 2.5. Data Synthesis and Summary Measures 2.5.1. Case Series, Case Reports, and Case-Control Studies Data from these studies were synthesised in either table or narrative form. Case and case series reports were grouped according to drug or drugs reported (CQ or HCQ alone or in combination), drug indication, and the organ system affected by an adverse effect.

No study was eliminated based on the risk of bias. Case-control studies were presented in a table showing reported adverse drug reactions. Presentation was ordered according to quality evaluation scores, presence of probability scales such as the Naranjo Adverse Drug Reaction Probability Scale for case and case series reports [25] , and relevance of the evidence.

We presented the synthesised evidence following the SWiM (Synthesis Without Metaanalysis) guidelines [26] in table and narrative form. Studies were divided into studies on the safety of CQ or HCQ alone and studies in which CQ and/or HCQ were combined with one of the eligible drugs and also grouped according to drug indication. The rationale for this grouping of studies was our focus on drug safety and the influence of drug combinations and indications on this outcome. Initially, we did not use a standardised metric to present exposure and/or direction effects or p values, so we reported these effects in their original format, namely as mean differences, standardised mean differences, risk ratios, odds ratios, or risk differences. However, whenever possible, we calculated the frequency of each toxicity for each study, and a summary reporting the frequency of adverse events reported as a range of percentages was presented for each group mentioned above. Those studies reporting data on pregnant patients were synthesised using narratives and tables but not included in the quantitative data synthesis. In the case of combinations, only those cases in which more than one study reported enough data were included for quantitative data synthesis. Combinations in which only one study was found were presented separately. Whenever possible, data on adverse drug reactions frequency-adjusted for patient status or comorbidities or any other confounding factors were considered. Due to the heterogeneity of the populations included, drug exposure data, reported adverse drug reactions, and study methodologies, we did not consider a meta-analysis of the outcome effects. Studies were prioritised according to quality evaluation scores, sample size, and relevance of the evidence.

The preliminary online database search yielded a set of 6108 articles, of which 2942 articles were identified through MEDLINE using PubMed, 1977 were identified through Embase using Ovid, 683 were identified through CENTRAL, 232 were identified through LILACS, and 274 more were identified by checking article reference lists. Of this initial set of 6108, 3338 articles were excluded in the title and abstract screening process. Of the remaining 2770 articles, an additional 2516 were excluded for the content eligibility reasons described above (eligibility criteria are summarised in Table S3 of Supplementary Material). The full selection process yielded a final set of 254 studies for this systematic review ( Figure 1 ) . 

A total of 99 articles reporting 123 cases were found . These cases are summarised in Tables 1 and 2 and described more fully in Tables S4-S12 of Supplementary  Material part 2. Case-Control, Cross-Sectional, Cohort, and Randomised Studies Forty-seven articles reported data on the safety of CQ or HCQ when used alone and nine others provided data for when CQ or HCQ were combined with one of the drugs of interest . Tables 3 and 4 show the frequency of adverse drug reactions as reported in these studies. Data from case-control and other observational studies in which the frequency could not be calculated are presented in Table 5 . Full data from these studies can be found in Tables S13-S20 of Supplementary Material part 2.

A total of 26 articles reporting cases related to the safety of HCQ or CQ during treatment for COVID-19 were found . Table 6 synthesises the data from the cases reporting HCQ and CQ adverse drug reactions in COVID-19-affected patients and Table S21 of Supplementary Material part 2 provides full details.

Case-Control, Cross-Sectional, Cohort, and Randomised Studies A total of 74 articles reporting data on the safety of HCQ or CQ in patients treated for COVID-19 were found . Tables 7 and 8 show the frequency of adverse drug reactions as reported in these studies. The full data is provided in Table S22 of the Supplementary Material part 2. Seronegative polyarthritis (2) Suspected Sjögren's like process (1) Resolution (3) Severe pruritus (1) (Gül U et al., 2006) [45] Discoid lupus erythematosus (1) Resolution (1) Pemphigus vulgaris (1) (Ghaffarpour G et al., 2006) [44] Rheumatoid arthritis (1) After 3 w the lesions cleared with only a mild post-inflammatory hyperpigmentation (1) Sweet's syndrome (1) (Manzo C et al., 2019) [63] Sjögren syndrome (1) Resolution (1) Inverse psoriasis (1) [46, 50] Arthritis and related rheumatic disorders (4) Chronic cutaneous lupus (1) Resolution (1) NA (4) Erythema annulare centrifugum (1 (1) Hematologic and metabolic 4 (4)

Hypoglycaemic coma (1) (Shojania K et al., 1999) [101] Rheumatoid polyarthritis (1) Resolution (1) Hypoglycaemia (1) (Winter EM et al., 2011) [102] Osteoarthritis (1) Resolution (1) Thrombocytopaenia (1) (Demir D et al., 2014) [104] Used erroneously as a pain killer (1) Resolution (1) Thrombotic thrombocytopaenic purpura (1 [199] Resolved with prednisone after 38 days AGEP (1) (Delaleu J, 2020) [198] NA Erythema multiforme (1) (Monte-Serrano J, 2020) [197] NA Urticaria with maculopapular rash, palmoplantar itching (1) (Sardana K, 2020) [196] NA Urticaria (1) (Sardana K, 2020) [196] NA Purpuric erythematous rash with non-follicular pustules, on the trunk and limps, with intense involvement of armpits and scalp (1) (Abadías-Granado I, 2021) [201] No Purpuric erythematous rash with non-follicular pustules and targetoid lesions on the back (1) (Abadías-Granado I, 2021) [201] No Hematologic, muscular and metabolic 6

Worsening of haemolysis (1 

For case series and case reports, overall CARE Checklist scores ranged from 34% to 100%. Only two studies could not be assessed because more than 50% of the checklist items were judged "Not applicable", one of them reporting a case of acute psychosis after CQ administration and the other reporting a case of acute generalised exanthematous pustulosis with HCQ [47, 66] . A total of 73 studies were rated as high quality, 40 as moderate quality, and 11 as low quality. Although 11 articles were rated as having low reporting quality, the adverse effects were clearly described in all cases, so this did not affect their inclusion in the qualitative synthesis of the results. A total of 84 observational studies were assessed using the combined STROBE checklist. A total of 47 studies were rated as high quality, 29 as moderate quality, and 6 as low quality. The quality of 2 other studies could not be assessed because more than 50% of the checklist items were "Not applicable". In the case of the randomised studies, 46 articles including 49 clinical trials were assessed using the JADAD scale. A total of 16 studies received scores less than 3, whereas 33 studies received scores greater than or equal to 3.

The study data on the frequency of adverse events was quantitatively synthesised and is reported as a range of percentages ordered by indication and drug combination in Table 9 . Table 5 shows the adverse effects reported in the case-control studies as well as those that could not be added to the data synthesis.

Of the 47 studies reporting data on CQ or HCQ alone, 31 provided data that could be added to the quantitative data synthesis , but in the case of 15 others, the frequency could not be calculated so they were not included [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] . The data from one additional study reported data from pregnant patients and was likewise excluded from the quantitative synthesis [172] . Of the nine studies reporting data on CQ or HCQ combined with other drugs, three reported data that could be added to the quantitative data synthesis [146, 173, 174] , whereas four others did not report adverse event frequency [175] [176] [177] [178] , and two reported data from pregnant patients [179, 180] . One article reported data that could be added to our synthesis both for CQ alone and for CQ plus AZM [146] .

Out of a total of 74 studies, 66 provided data that could be added to the quantitative synthesis . Seven of these studies contained data on COVID-19 prophylactic treatments [266] [267] [268] [269] [270] [271] [272] . The remaining studies lacked information about these drug combinations (e.g., they were the only studies reporting data in this specific combination) or reported data with which the frequency could not be calculated and were therefore not included in the quantitative synthesis [273] [274] [275] [276] [277] [278] [279] [280] . 

Cases of a complete heart block, an implanted pacemaker failure, and a QTinterval prolongation were described in patients treated with HCQ for autoimmune conditions [97, 98, 100] , and cases of cardiovascular collapse, non-specified cardiac arrhythmia, and syncopal attacks with torsade de pointes were described in patients treated with CQ for malaria, amoebiasis, and a dermatological problem [95, 96, 99] . In patients being treated for COVID-19, six cases of cardiac adverse effects with QT interval prolongation were described, consisting of a case of QT interval prolongation and recurrent torsade de pointes with CQ [188] , a case of right bundle branch block and critical QT interval prolongation with HCQ [181] , a case of torsade de pointes in a patient treated with HCQ plus dexamethasone [190] , a case of suspected HCQ-induced sinus bradycardia and QT interval prolongation [191] , a case of QT prolongation in a patient treated with HCQ plus AZM [192] , and a case of death due to progressive metabolic acidosis and multiple organ system failure in a patient being treated with HCQ plus AZM [186] . Additionally, a case of death from cardiac arrest in a patient who developed wide complex tachycardia during CQ plus AZM treatment [189] , and a case of sinus bradycardia with HCQ plus AZM were reported [192] .

Studies including patients treated with CQ or HCQ for malaria, autoimmune conditions, or porphyria cutanea tarda (PCT) did not report any cases of cardiac adverse effects. One retrospective cohort study assessing cases of cardiac symptoms, cardiac arrest, and ventricular arrhythmias in patients treated with CQ plus AZM for autoimmune diseases did not find significant differences in these events in comparison with amoxicillin treatment [177] . One study assessing cases of torsade de pointes, QT prolongation, and death in patients treated with CQ or HCQ plus AZM for diverse pathologies did not find any potential safety concerns for HCQ or CQ alone. Conversely, this study found a significant safety risk for torsade de pointes and QT prolongation when AZM was used alone [178] . In two randomised studies on the combination of CQ plus AZM for malaria, only three cases of palpitations were identified after evaluating 227 patients [173] . However, this was not observed in four other studies, which did not describe electrocardiographic evaluations [146, 174, 179, 180] . In subjects with COVID-19, cardiac adverse drug reactions were the most common adverse drug reactions reported. Prolongation of the corrected QT interval ≥500 ms was observed in 0-25% of subjects treated with HCQ or CQ alone [207, 212, 215, 219, 220, 240, 241, 246] , 0-33% of subjects treated with HCQ or CQ plus AZM [207, 209, 210, [214] [215] [216] 221, 226, 238, 241, 245, 246, 248, 249, 251, 254, 262, 263] , 18.2% of subjects treated with HCQ plus LPVr [208] , and 6.1% of subjects treated with HCQ plus AZM plus LPVr [254] . Prolongation of the corrected QT interval ≥60 ms was observed in 0-8% of subjects treated with HCQ alone [215, 226, 240, 241] , in 0-18% of subjects treated with HCQ plus AZM [210, [214] [215] [216] 221, 226, 228, 241, 254] , and in 18.4% of subjects treated with HCQ plus AZM plus LPVr [254] . Torsade de pointes was only observed in 5 out of 15,039 patients in CQ or HCQ plus AZM COVID-19 studies [207, 209, 212, 215, 216, 219, 220, 226, 228, 230, 235, 236, 245, 249, 250, 253, 255, 256, 258, 260, 261, 264, 265] . No subjects in studies on HCQ plus LPVr or DRVr, or HCQ plus AZM plus LPVr or DRVr developed torsade de pointes [207, 208, 215, 219, 220, 229, 255] . Arrhythmogenic deaths were not reported in any study. The discontinuation of CQ or HCQ due to cardiac adverse drug reactions was observed in 2.4% of patients treated with HCQ or CQ alone [219] , in 0-9.5% of patients treated with CQ or HCQ plus AZM [212, 214, 216, 217, 219] , and in 0-36.4% of patients treated with HCQ plus LPVr [208, 212] .

A total of 41 cases of mild to severe dermatological adverse effects, including 2 cases of fatal toxic epidermal necrolysis, were described in patients treated with HCQ for autoimmune diseases [31, [34] [35] [36] 38, [40] [41] [42] [43] [44] [45] [46] [47] [48] [50] [51] [52] [53] [54] [55] [56] [57] 59, 60, [62] [63] [64] [65] . A smaller number of cases were reported in patients treated with CQ for autoimmune conditions or malaria although one fatal case was reported [27] [28] [29] [30] 32, 33, 37, 39, 49, 54, 58, 61] . In connection with treatment for COVID-19, 12 cases were reported in patients treated with HCQ including cases of psoriasis exacerbation, rash, acute generalised exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS), urticaria, palmoplantar itching, and purpuric erythematous rashes [185, 187, [196] [197] [198] [199] [200] [201] [202] .

Observational and Randomised Studies Pruritus has been described as occurring with high frequency (2-64.5%) in black African patients treated with CQ (with or without AZM) for malaria [138] [139] [140] 170, 171] . Two studies revealed a favourable effect of prednisolone to prevent pruritus without reporting other adverse effects [160, 176] . Severe reactions were less often described in patients treated with CQ for malaria or autoimmune conditions. Erythema, exanthema, and maculopapular and vesiculopapular rashes in patients treated with CQ for malaria [140] ; cutaneous drug eruptions, erythema, urticaria, and macular and papular exanthemas in patients treated with CQ or HCQ for SLE; and cutaneous lupus erythematosus (CLE) and dermatomyositis [132] [133] [134] , and a generalised maculopapular rash in one patient treated with CQ for pulmonary sarcoidosis were described [145] , with frequencies ranging from 0% to 6.4%. In COVID-19-affected patients, moderate to severe skin reactions were described in 0% to 10.0% of subjects although the highest frequency corresponded to a study that only included 10 patients [216, 222, 223, 232, 239, 240, 248, 252, 257] . We did not find increases in skin adverse effects when HCQ or CQ were combined with AZM, DRVr, or LPVr [239, 242] . In the majority of the studies included that referred to patients with malaria, PCT, or COVID-19, there was no reference at all to dermatological toxicities.

A broad spectrum of neurological and psychiatric events was described in patients treated with CQ for malaria, amoebiasis, arthritis, acute myocardial infarction, erythema nodosum leprosum, or COVID-19 125, 193, 195] . Nevertheless, in the case of treatment with HCQ, only one case of psychomotor agitation in a patient with RA and one case of psychosis in a patient with SLE were reported [74, 93] .

Anxiety was reported in one patient treated with CQ in a study on pulmonary sarcoidosis [145] , and anxiety and nervousness in patients treated with HCQ for COVID-19 prophylaxis [272] . Insomnia was reported in 0.18% of patients with HCQ plus AZM for COVID-19 [216] , and sleep disturbances were reported in patients treated with HCQ for COVID-19 prophylaxis [266, 272] . Dizziness was reported in 3.2% of patients with SLE treated with HCQ [133] , 0.3-19% of patients with malaria treated with CQ [126, 146, 171] , 0-15.9% of patients treated with CQ plus AZM for malaria [140, 173] , 1.5-3.6% of patients treated for COVID-19 prophylaxis [266, 269, 270, 272] , 9.4% of patients treated with HCQ for COVID-19 [252] , and 0-0.3% of patients treated with HCQ plus AZM for COVID-19. Headache was reported in 0.3-25% of patients with malaria treated with CQ [126, 138, 140, 142, 171] , 0-17.7% of patients treated with CQ plus AZM for malaria [173, 174] , 25% of patients with PCT treated with HCQ [135] , 0-3.2% of patients treated with CQ or HCQ [222, 223, 227, 252] , and 0.28% for patients treated with HCQ plus AZM for COVID-19 [216] , but was not reported in patients with autoimmune conditions. Paraesthesia was reported in 0-3% of patients treated with CQ plus AZM for malaria [174] and 2% of patients treated with HCQ for COVID-19 prophylaxis [270] , but not reported in other conditions. One study assessing cases of depression as well as accidents/injuries in patients treated with CQ or HCQ plus AZM for diverse pathologies did not find potentially meaningful pharmacovigilance signs for CQ or HCQ, either alone or in combination with AZM [178] . However, a pharmacovigilance analysis suggested that COVID-19 patients exposed to HCQ could suffer psychiatric disorders and that HCQ was associated with an increased risk of reporting psychiatric disorders compared with other treatments [280] . Psychosis was not observed in patients treated with CQ for malaria nor in patients with COVID-19 [126, 223] and was not reported in the rest of the studies.

Prior to COVID-19, five cases of liver injury were reported, one involving treatment with CQ and four involving HCQ, including one fatal case [111] [112] [113] [114] [115] . One case of hepatotoxicity in a COVID-19-affected patient treated with HCQ was also reported [182] .

Nausea and vomiting affected 0-11.5% of patients treated with CQ for malaria [130, 138, 140, 141, 146, 171, 172] , 12.5-20.8% of patients treated with CQ or HCQ for PCT [135] , 0-30% of patients treated with CQ plus AZM for malaria [146, 173, 174] , 40-50% of patients treated with CQ for COVID-19 (data from a small study of 10 patients) [223] , 0-31.3% of patients treated with HCQ for COVID-19 [239, 252, 257] , 0-19% of patients treated with HCQ plus AZM for COVID-19 [213, 216, 231, 239, 248, 257] , 4.5-9.5% of patients treated with HCQ plus LPVr for COVID-19 [239, 242] , and 0-14.2% of patients treated with HCQ plus AZM plus LPVr for COVID-19 [239] , Diarrhea was reported in 3.8-8.3% of patients treated for malaria with CQ [138, 146, 171] , 6.4% of patients treated with HCQ for autoimmune conditions [133] , and 0-12% of patients treated with CQ plus AZM for malaria [133, 146, 173, 174, 179, 180] [239] , and 10% of patients treated with HCQ plus standard of care (SOC) including antiviral agents, antibiotics, or systemic glucocorticoids [211] . Abdominal discomfort or pain or other gastrointestinal discomforts were reported in 4.7-30.0% of patients treated with CQ for malaria [126, 138, 142, 171] , 3.2-4.3% of patients treated with CQ or HCQ for autoimmune conditions [133, 145] , 20.0% of patients treated with HCQ for PCT [135] , 0-11.5% of patients treated with CQ plus AZM for malaria [173, 174] , 10% of patients with COVID-19 treated with CQ [223] , 0-24% of patients treated with HCQ [239, 247] , 0.3-25% of patients treated with HCQ plus AZM [216, 239, 247] , and 4.5-16.7% of patients treated with HCQ plus LPVr [212, 239] . Dyspepsia and gastritis affected 3.6% of patients treated with HCQ for RA [143] and 1-4% of patients treated with CQ plus AZM for malaria [174] . Transaminase increase and other hepatic disorders were reported in the majority of patients treated with CQ or HCQ and affected by PCT but observed less often in patients treated for other conditions such as malaria, autoimmune conditions, or COVID-19 [135, 136] .

Cases of hypoglycaemia (including a case of hypoglycaemic coma) [99] [100] [101] [102] , thrombocytopaenia [104] , thrombotic thrombocytopaenic purpura [105, 203] , methaemoglobinaemia, sense organ adverse effects (including cases of severe positional vertigo [107] , severe vestibular toxicity [108] , loss of hearing [109] , complete ageusia [110] , diplopia and blurred vision) [106] , porphyria variegata [116] , severe myopathies [118, 119] , myasthenic syndrome [194] , anaphylaxis [121] , urinary incontinence [122] , diffuse interstitial lung disease [123] , and acute eosinophilic pneumonias [120] , were described in connection with short-term CQ and HCQ treatments.

Various cases of haemolysis and methaemoglobinaemia were described in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency treated with HCQ or CQ for COVID-19 [183, 184, [204] [205] [206] .

The evidence collected does not show that COVID-19 patients treated with CQ or HCQ alone or in combination with studied drugs suffered a greater proportion of dermatologic, gastrointestinal, hepatic, metabolic, or haematological adverse effects compared with subjects receiving these drugs for indications other than COVID-19. However, no clinical benefits were found when those drugs were used to treat or prevent COVID-19 [281] [282] [283] .

Although the ocular toxicity of CQ and HCQ is extremely important in long-term regimens with these drugs [284] , it was rarely mentioned in connection with short-term regimens or in the first weeks of long-term regimens. The cases of patients with G6PD deficiency are of special interest because the related toxicity has been shown in such patients with and without COVID-19, and CQ and HCQ treatment must therefore be avoided in these patients [183, 184] . During the first days of treatment, gastrointestinal adverse effects should be considered as they were reported in most indications. In the case of cardiac events, it is noteworthy that in more than 70 years of use, only a few cases of early cardiac adverse effects were found [94] [95] [96] [97] [98] [99] . In contrast, in the much shorter period that has elapsed since the start of the COVID-19 pandemic, a greater number of cardiac cases have been reported involving COVID-19-affected patients regardless of the drug regimen used. In addition, the concomitant use of other drugs such as AZM should be considered. This systematic review shows that cardiac adverse effects such as QTc prolongation were frequent in COVID-19-affected-patients treated with CQ or HCQ (0-27.3%, and up to 33% if combined with AZM), though the risk of torsade de pointes was low. These data were extracted from 55 observational and 18 randomised studies with an overall favourable quality assessment. In 52 of these studies, at least some electrocardiographic changes were reported in patients treated with HCQ or CQ and a consistent and large effect was found. The results of this systematic review coincide with those of the previous one (that only included COVID-19 studies) that showed a significantly higher rate of adverse events with CQ or HCQ treatment but no significant differences in the case of serious adverse events (including cardiac arrhythmias and life-threatening events) [285] . A recent systematic review that focused on the cardiac safety of CQ and HCQ in COVID-19-affected patients has also shown an important association between CQ and HCQ use and the risk of drug-induced QT prolongation with a relatively higher incidence of torsade de pointes, ventricular tachycardia, or cardiac arrest [286] . Beyond the medication effects, several cardiac manifestations have been described in patients with COVID-19 including acute myopericarditis, acute coronary syndrome, congested heart failure, cardiogenic shock, and cardiac arrhythmias as a result of the injuries caused by the virus and systemic inflammation [287] . These cardiac manifestations were not only shown with CQ or HCQ use, but also with other drugs used in the treatment of COVID-19 such as corticosteroids, rivabirin, LPVr, and AZM [288] [289] [290] [291] . This suggests that COVID-19 could have a role in these cardiac safety reports. Nevertheless, publication or measurement bias cannot be ruled out in pre-COVID-19 published data since these cardiac effects were rarely assessed or mentioned.

The cardiac abnormalities found in this study could be explained by CQ and HCQ electrophysiological effects, AZM combination, and COVID-19 concurrence. CQ and HCQ can cause acute cardiac functional changes by inhibition of ion channels with membranestabilizing effects that can lead to conduction disturbances [14] . Laboratory electrophysiological studies revealed CQ blocked the inward sodium current, the l-type calcium current, and the potassium currents such as the rapid delayed rectifier outward currents explaining prolongations and reductions in maximum velocity of cardiac action potentials and QT interval prolongation [292, 293] . Moreover, synergistic effects of HCQ and AZM on the electrophysiological and contractile functions of human-induced pluripotent stem cellderived cardiomyocytes have been observed in the short-term [294] . Furthermore, AZM might act as a weak CYP3A4 inhibitor involved in the metabolism of these drugs [295] . In addition to CQ, HCQ, and AZM effects, some common clinical concerns in elderly patients with COVID-19, such as dyselectrolythemia or dehydration, could increase the risk of arrhythmias [296, 297] . In the case of neuropsychiatric symptoms associated with HCQ and CQ, different pharmacological mechanisms have been proposed such as serotonin or cholinergic imbalances induction or lysosomal dysfunction, although this has not been elucidated to date [280, 298] .

This systematic review only partially fulfils the proposed objectives. In patients not affected by COVID-19, only the combinations with AZM and glucocorticoids could be assessed, whereas in the case of patients affected by COVID-19, quantitative data synthesis could only be performed in combinations with AZM, LPVr, and boosted DRV but there were no sufficient studies reporting on the other possible combinations. The studies examined here were performed in very different settings and the methodologies used for the assessment of drug safety were very different, thus limiting our ability to compare the results reported. Furthermore, some adverse effects were not monitored with the same intensity in different contexts, so the question remains as to whether they did not occur or were simply not measured. Data synthesis was performed according to drug indication and whether CQ or HCQ were used alone or in combination with a second drug, but not according to how the dose regimen used could have influenced the adverse effects (e.g., drug regimens used in COVID-19 were generally longer than those used in malaria and in higher daily doses than those used in autoimmune diseases). Moreover, this systematic review was not focused on finding differences between CQ and HCQ safety. Despite these limitations, this systematic review clearly suggests that the use of CQ or HCQ tended to increase the cardiac risks for patients being treated for COVID-19, although these rarely resulted in severe consequences and the risk of torsade de pointes was low. Taking into account these considerations, in the future great caution should be exercised when testing potentially arrhythmogenic drugs in patients affected by severe acute viral or inflammatory pathologies.

Early adverse effects of CQ and HCQ may manifest as cardiac, dermatologic, neuropsychiatric, gastrointestinal, hepatic, metabolic, or haematological events. In the evidence reviewed, the occurrence and frequency of these toxicities were variable depending on the drug indication and the characteristics of the population being treated. Unlike pre-COVID-19 patients who received CQ or HCQ treatment, cardiac adverse drug effects occurred often in COVID-19 patients. Although severe consequences were rarely reported, this data must be considered, especially if CQ or HCQ are combined with other drugs such as AZM. This systematic review provides a comprehensive synthesis of the reported evidence on the short-term safety of CQ and HCQ treatment and provides important data for further research on the use of these drugs.

The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/ph15050634/s1, Table S1 search terms and MeSH terms used in the bibliographic search on the safety of chloroquine and hydroxychloroquine alone; Table S2 : search terms and MeSH terms used in the bibliographic search on the safety of chloroquine and hydroxychloroquine in combination with other drugs used for the treatment of COVID-19 disease; Table S3 : articles exclusion according to eligibility criteria; Table S4 : total of adverse effects related to CQ/HCQ: case reports and case series; Table S5 : characteristics of included studies: case reports and case series related to dermatological adverse events; Table S6 : characteristics of included studies: case reports and case series related to psychiatric adverse events; Table S7 : characteristics of included studies: case reports and case series related to neurologic adverse events; Table S8 : characteristics of included studies: case reports and case series related to cardiac adverse events; Table S9 : characteristics of included studies: case reports and case series related to hematologic and metabolic adverse events; Table S10 : characteristics of included studies: case reports and case series related to sense organs adverse events; Table S11 : characteristics of included studies: case reports and case series related to hepatic adverse events; Table S12 : characteristics of included studies: case reports and case series related to other adverse events; Table S13 : characteristics of included studies: observational studies, patients affected by malaria or who received prophylactic treatment; Table S14 : characteristics of included studies: observational studies, patients affected by cutaneous and/or systemic lupus erythematosus and dermatomyositis; Table S15 : characteristics of included studies: observational studies, patients affected by porphyria cutanea tarda; Table S16 : characteristics of included studies: observational studies, patients affected by diverse pathologies; Table S17 : characteristics of included studies: clinical trials, patients affected by malaria or who received prophylactic treatment; Table S18 : characteristics of included studies: clinical trials, patients affected by rheumatoid arthritis; Table S19 : characteristics of included studies: clinical trials, patients affected by other pathologies; Table S20 : characteristics of included studies: clinical trials and observational studies, patients affected by malaria or who received prophylactic treatment with CQ or HCQ in combination with other drugs; Table S21 : characteristics of included studies: case reports and case series in patients with COVID-19; Table S22 : characteristics of included studies: observational studies and clinical trials (COVID-19 treatment and prophylaxis). 

The authors declare no conflict of interest.

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Chloroquine-related depression

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Chloroquine Induced Mania

Serious psychiatric symptoms after chloroquine treatment following experi-mental malaria infection

Chloroquine-Induced Recurrent Psychosis

Challenge and Rechallenge Episodes of Chloroquine-Induced Psychotic Mania in a Patient with Rheumatoid Arthritis

Exacerbations of bipolar disorder triggered by chloroquine in systemic lupus erythematosus-A case report

Chloroquine-induced subacute paranoid-like disorder as a complication of dermatological treatment

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Chloroquine induced involuntary movements

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Syncope in a patient being treated for hepatic and intestinal amoebiasis

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Hypoglycemia: An unusual adverse reaction to chloroquine

Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis

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Acute life-threatening methaemoglobinaemia following ingestion of chloroquine

A case of thrombocytopenia associated with the use of hydroxychloroquine following open heart surgery

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Chloroquine causing vestibular toxicity

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Hydroxychloroquine and azithromycin tolerance in haemodialysis patients during COVID-19 infection

Hydroxychloroquine use in hospitalised patients with COVID-19: An observational matched cohort study

Safety, tolerability, and clinical outcomes of hydroxychloroquine for hospitalized patients with coronavirus 2019 disease

Effects on QT interval of hydroxychloroquine associated with ritonavir/darunavir or azithromycin in patients with SARS-CoV-2 infection

Hydroxychloroquine in Nonhospitalized Adults with Early COVID-19: A Randomized Trial

QT prolongation in a diverse, urban population of COVID-19 patients treated with hydroxychloroquine, chloroquine, or azithromycin

Absence of relevant QT interval prolongation in not critically ill COVID-19 patients

Hydroxychloroquine/azithromycin treatment, QT interval and ventricular arrhythmias in hospitalised patients with COVID-19

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

The effect of favipiravir on QTc interval in patients hospitalized with coronavirus disease 2019

Effect of Combination Therapy of Hydroxychloroquine and Azithromycin on Mortality in Patients with COVID-19

Hydroxychloroquine plus azithromycin and early hospital admission are benefi-cial in COVID-19 patients: Turkish experience with real-life data

Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19

QT Interval Prolongation Under Hydroxychloroquine/Azithromycin Association for Inpa-tients with SARS-CoV-2 Lower Respiratory Tract Infection

Incidence and determinants of QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin

Experience with Hydroxychloroquine and Azithromycin in the Coronavirus Dis-ease 2019 Pandemic: Implications for QT Interval Monitoring

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter

Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19

Safety of hydroxychloroquine in healthcare workers for COVID-19 prophylaxis

A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19

Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Randomized Trial

Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

HyPE study: Hydroxychloroquine prophylaxis-related adverse events' analysis among healthcare workers during COVID-19 pandemic: A rising public health concern

Clinical efficacy and safety of different antiviral regimens in patients with coronavirus disease 2019

A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tol-erability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19)

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients with COVID-19: A Randomized Clinical Trial

Clinical outcomes and adverse events in patients hospitalised with COVID-19, treated with off-label hydroxychloroquine and azithromycin

Bari-citinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: An observational cohort study

Hydroxychloroquine and tocilizumab therapy in COVID-19 patients-An observational study

Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial

Psychiatric Disorders and Hydroxychloroquine for Coronavirus Disease 2019 (COVID-19): A VigiBase Study

The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis: A systematic review and meta-analysis of randomized trials

Hydroxychloroquine for treatment of nonsevere COVID-19 patients: Systematic review and meta-analysis of controlled clinical trials

Safety of hydroxychloroquine in COVID-19 and other diseases: A systematic review and meta-analysis of 53 randomized trials

Ocular toxicity of hydroxychloroquine

Efficacy and safety of hydroxychloroquine/chloroquine against SARS-CoV-2 infection: A systematic review and meta-analysis

Cardiac Toxicity of Chloroquine or Hydroxychloroquine in Patients with COVID-19: A Systematic Review and Meta-regression Analysis

Coronavirus disease-19 and cardiovascular disease: A risk factor or a risk marker?

Perspective: Cardiovascular disease and the Covid-19 pandemic

Azithromycin and the Risk of Cardiovascular Death

Prescribing practices of lopinavir/ritonavir, hydroxychloroquine and azithromycin during the COVID-19 epidemic crisis and pharmaceutical interventions in a French teaching hospital

Benefit versus toxicity risk of digoxin in patients with COVID-19

Cardiotoxicity of antimalarial drugs

Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel

Synergistic Adverse Effects of Azithromycin and Hydroxychloroquine on Human Cardio-myocytes at a Clinically Relevant Treatment Duratio n

Serious Cardiovascular Adverse Events Associated with Hydroxychloroquine/Chloroquine Alone or with Azithromycin in Patients with COVID-19: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS)

SARS-CoV-2 Treatment: Current Therapeutic Options and the Pursuit of Tailored Therapy

COVID-SAFER: Deprescribing Guidance for Hydroxychloroquine Drug Interactions in Older Adults

Psychosis Likely Induced by Hydroxychloroquine in a Patient with Chronic Q Fever: A Case Report and Clinically Relevant Review of Pharmacology