International Journal of Coronaviruses

Current Issue Volume No: 2 Issue No: 2

ISSN: 2692-1537
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Research Article Open Access
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  • Effect of Hydroxychloroquine on Clinical Improvement and Mortality Among Patients with COVID-19 Admitted to Four General Hospitals in Saudi Arabia

    Mohammed Alghamdi 1   Nasser Aljuhani 2   Afrah AL-Somali 3   Saeed Alzahrani 4   Rashed Alotaibi 5   Salma Siddiqua 6   Marwah Naitah 7   Sayda albelewi 8   Ahmed Alghamdi 9   Fayez Alotaibi 10   Abdullmoin AlQarni 11   Khalid Al-Hariqi 12   Manal Al -Gethamy 13  

    1Infectious disease consultant, King Fahad General Hospital

    2Nasser Rajallah Aljuhani, internal medicine and endocrinology Consultant, East Jeddah hospital

    3Afrah A. AL-Somali, Infectious Diseases Department, King Abdullah medical complex , Jeddah, Saudi Arabia

    4Saeed Alzahrani, Consultant Neurologist , King Fahd General Hospital,Jeddah,Saudi Arabia

    5Rashed Hujeel Alotaibi, Internal medicine resident, King Fahad General Hospital, Jeddah, Saudi Arabia

    6Salma Siddiqua, ENT, general physician, Saudi German Hospital, Jeddah, Saudi Arabia.

    7Marwah Tariq Naitah, Medical specialist, Internal medicine , King Fahad general Hospital, Jeddah, Saudi Arabia.

    8Sayda Hamed albelewi, internal medicine S.registrar, East jeddah hospital, Jeddah, Saudi Arabia

    9Ahmed Mashhour Alghamdi, Internal Medicine Resident, East Jeddah Hospital, Jeddah, Saudi Arabia

    10Fayez Omear Alotaibi, Director of pharmacy, Pharmacy, King Fahad general Hospital, Jeddah, Saudi Arabia.

    11Abdullmoin Mohammed AlQarni, infectious Diseases- Internal Medicine Counsultant ,Alnoor Specialist Hospital, Makkah, Saudi Arabia

    12Khalid Waleed Abdullah Al-Hariqi, Internal Medicine Resident, Alnoor Specialist Hospital, Makkah, Saudi Arabia

    13Manal Mansour Mezal Al -Gethamy, Infectious Diseases-Inernal Medicine Consultant, Department of Infection Prevention & Control, Alnoor Specialist Hospital, Makkah, Saudi Arabia

    Abstract

    Background

    The use of hydroxychloroquine in coronavirus disease (COVID-19) pandemic raised significant concerns as regards safety and efficacy in hospitalized patients. The objective was to examine the effect of hydroxychloroquine on clinical improvement and mortality among hospitalized patients with COVID-19.

    Methods

    A prospective cohort study was conducted at four general hospitals in the Western region, Saudi Arabia. Patients who had absolute or relative contraindication for using hydroxychloroquine were excluded. Patients concomitantly receiving other medications including azithromycin, antivirals, and supportive treatment were not excluded.

    Results

    A total 267 patients were included in the current analysis; 185 (69.3%) on hydroxychloroquine and 82 (30.7%) on non-hydroxychloroquine treatments. The average age was 46.0±13.3 years and 78.3% of the patients were males. Approximately 95.9% of the patients were symptomatic with mild (50.6%), moderate (32.6%), severe (8.2%), or ARDS symptoms (4.5%). Compared with no hydroxychloroquine, those on hydroxychloroquine had significantly longer length of stay (11.5±7.1 versus 7.8±4.3 days, p<0.001), more ICU admission (22.7% versus 9.8%, p=0.012), and more intubation (12.4% versus 3.7%, p=0.026). Improvement of symptoms (84.3% versus 81.7%, p=0.595) and hospitalization death (7.0% versus 1.2%, p=0.071) were not significantly different between groups. With exception of length of stay, the association of hydroxychloroquine with the above negative outcomes disappeared after adjustment for several factors including disease severity and concomitant use of azithromycin.

    Conclusions

    Hydroxychloroquine is not associated with better improvement of symptoms compared with other treatments. Moreover, it is associated with longer length of stay but not mortality or ICU admission in adjusted analysis.

    Author Contributions
    Received 07 Dec 2020; Accepted 11 Dec 2020; Published 14 Dec 2020;

    Academic Editor: Jose Luis Turabian, University of Madrid, Toledo, Spain.

    Checked for plagiarism: Yes

    Review by: Single-blind

    Copyright ©  2020 Mohammed Alghamdi, et al.

    License
    Creative Commons License     This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Competing interests

    The authors have declared that no competing interests exist.

    Citation:

    Mohammed Alghamdi, Nasser Aljuhani, Afrah AL-Somali, Saeed Alzahrani, Rashed Alotaibi et al. (2020) Effect of Hydroxychloroquine on Clinical Improvement and Mortality Among Patients with COVID-19 Admitted to Four General Hospitals in Saudi Arabia. International Journal of Coronaviruses - 2(2):13-23.

    Download as RIS, BibTeX, Text (Include abstract )

    DOI 10.14302/issn.2692-1537.ijcv-20-3652

    Introduction

    Since its first appearance in Wuhan (China) in late 2019, more than 30 million patients globally were infected with severe acute respiratory syndrome coronavirus number 2 (SARS-CoV-2) with more than 950 thousands related deaths by mid-September 2020 1, 2. Although the mortality observed in the current coronavirus disease (COVID-19) pandemic (4.1% of closed cases) is much lower than other coronaviruses such as SARS-CoV (10%) and the Middle East Respiratory Syndrome-CoV (MERS-CoV, 35%)3, the rapid and universal spread of COVID-19 caused unprecedented global public health emergency and major healthcare crises 4, 5.

    With the lack of recognized therapeutic medications or effective vaccine, the management of COVID-19 was largely dependent on off-label use of available medications 6, 7. Several medications have been tried during the pandemic including anti-viral drugs, antimalarial drugs, and immunomodulatory agents (such as tocilizumab and interferons) 6, 7.

    Chloroquine and hydroxychloroquine have been used for decades in the prevention and treatment of malaria and then the treatment of some autoimmune diseases 8. Their earlier use in the COVID pandemic was based on pre-pandemic reports that showed their ability to inhibit viral replication of several viruses including SARS and human immunodeficiency virus (HIV) 8, 9. Additionally, in vitro reports published early in the pandemic showing the ability of hydroxychloroquine to inhibit SARS-CoV-2 replication 10. The use of hydroxychloroquine in the COVID pandemic raised significant concerns as regards safety and efficacy, specially among cardiac patients 11. Accumulating evidence and scientific debates forced several international organizations such as the World Health Organization (WHO) and the US Food and Drug Administration (FDA) to limit or halt the use of hydroxychloroquine in the management of patients with COVID-19 11, 12. The objective of the current study was to examine the effect of hydroxychloroquine on clinical improvement and mortality among patients with COVID-19 admitted earlier in the pandemic to general hospitals in Saudi Arabia.

    Methods

    Setting

    The current study was conducted at four general hospitals at Western region, Saudi Arabia. The hospitals included 700-bed King Fahad General Hospital, 500-bed Alnoor Specialist Hospital, 300-bed East Jeddah Hospital, and 300-bed King Abdullah Medical Complex. All were located in Jeddah with exception of Alnoor Specialist Hospital which is located at Mecca. The hospitals were allowed to provide healthcare services for patients with COVID-19 in addition to other types of patients. The hospitals were following the guidelines of Saudi Ministry of Health (MOH) as regards testing, diagnosis, admission, isolation, management, and discharge 13, 14.

    Design

    It was a prospective cohort study conducted between March 1, 2020 and May 30, 2020. The study design obtained all required ethical approvals from the Institutional Review Board (IRB) of the Saudi MOH. Informed consent was obtained from patients or their immediate family members after explaining the objectives of the study.

    Sample Size Calculation

    Assuming an improvement rate of 50% and assuming that hydroxychloroquine is used in the majority of patients, 240 patients (160 use hydroxychloroquine and 80 do not use hydroxychloroquine) would be required to detect 20% difference (60% versus 40%) in improvement using 80% power and 95% level of significance.

    Population

    The study targeted adult patients (age >18 years) with polymerase chain reaction (RT-PCR)-confirmed COVID-19 diagnosis admitted to any of the included four hospitals during the study duration. The patients were divided into two cohorts based on the status of hydroxychloroquine treatment, as per the Saudi MOH guidelines. Patients who had absolute or relative contraindication for using hydroxychloroquine were excluded from the study. These included known hypersensitivity to hydroxychloroquine or similar compounds, Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, decompensated heart failure, prolonged QTc interval, and preexisting retinopathy. Patients concomitantly receiving other medications including azithromycin, antivirals, and supportive treatment were not excluded.

    Recruitment and Data Collection

    Patients were conveniently recruited after obtaining informed consent. Structured study data collection sheet was used to collect the patient information. These included socio-demographic characteristics, exposure history, symptoms, comorbidity, chest imaging findings, relevant laboratory examinations, and outcomes.

    Outcome Definitions

    Clinical improvement was based on comparing the assessments of symptoms, disease severity, and chest imaging before and after the use of treatments. Disease severity was categorized into five groups; asymptomatic, mild (symptomatic without evidence of pneumonia or hypoxia), moderate (clinical signs of pneumonia but no hypoxia), severe (severe pneumonia or hypoxia), and acute respiratory distress syndrome (ARDS) 14, 15. Other outcome measures included length of stay, need for intensive care unit (ICU) admission, need for intubation, need for inotropic support, and hospitalization death.

    Statistical Analysis

    Categorical variables were presented as frequencies and percentage while continuous variables were presented as means and standard deviations (SD) or median and inter-quartile range (IQR), as appropriate. Demographic, clinical, and outcome variables were compared between those who received and those who did not receive hydroxychloroquine. Chi-square or Fisher’s exact test, as appropriate, were used to examine differences in categorical variables while student t-test or Mann–Whitney test, as appropriate, were used to examine differences in continuous variables. To detect independent differences in outcome variables between those who received and those who did not receive hydroxychloroquine, multivariate logistic regression analysis models (for categorical outcomes) and general linear models (for length of stay) were run after adjusting for the variables that were significantly associated with hydroxychloroquine in univariate analysis. All P-values were two-tailed. P-value <0.05 was considered as significant. SPSS software (release 25.0, Armonk, NY: IBM Corp) was used for all statistical analyses.

    Results

    A total 267 patients have been included in the current analysis; 185 (69.3%) on hydroxychloroquine and 82 (30.7%) on non-hydroxychloroquine treatments. As shown in Table 1, the average age was 46.0±13.3 years and 78.3% of the patients were males. More than half (53.6%) of the patients were from Asian countries while Saudi patients represented less than a quarter (23.2%). One-fifth (19.5%) of the patients were currently employed and only 4.5% were healthcare workers (HCWs). Approximately 16.9% of the patients were smokers and only 3.4% of the females were pregnant. Contact with patients with confirmed COVID-19 (37.1%) was much more common than recent travel within 14 days of symptoms (7.9%). Compared with no hydroxychloroquine, those who received hydroxychloroquine were more likely to be between 35 and 54 years and with unknown employment status.

    Table 1. Socio-demographic characteristics and exposure history of patients with confirmed COVID-19 by the treatment status
      Hydroxychloroquine Total P-value
    No Yes
    Age (years)        
    Mean±SD 44.0±14.0 47.0±12.8 46.0±13.3 0.093
    <35 29 (35.8%) 33 (18.6%) 62 (24.0%) 0.017
    35-44 15 (18.5%) 41 (23.2%) 56 (21.7%)  
    45-54 15 (18.5%) 53 (29.9%) 68 (26.4%)  
    ≥55 22 (27.2%) 50 (28.2%) 72 (27.9%)  
    Gender        
    Male 60 (73.2%) 149 (80.5%) 209 (78.3%) 0.178
    Female 22 (26.8%) 36 (19.5%) 58 (21.7%)  
    Nationality        
    Saudi 16 (19.5%) 46 (24.9%) 62 (23.2%) 0.084
    Arab 24 (29.3%) 32 (17.3%) 56 (21.0%)  
    Asia 39 (47.6%) 104 (56.2%) 143 (53.6%)  
    Others 3 (3.7%) 3 (1.6%) 6 (2.2%)  
    Employment        
    Currently employed 20 (24.4%) 32 (17.3%) 52 (19.5%) 0.002
    Not working 21 (25.6%) 31 (16.8%) 52 (19.5%)  
    Retired 0 (0.0%) 2 (1.1%) 2 (0.7%)  
    Umrah 6 (7.3%) 2 (1.1%) 8 (3.0%)  
    Unknown 35 (42.7%) 118 (63.8%) 153 (57.3%)  
    Exposure        
    Recent travel within 14 days of symptoms 10 (12.2%) 11 (5.9%) 21 (7.9%) 0.080
    Contact with patients with confirmed COVID-19 25 (30.5%) 74 (40.0%) 99 (37.1%) 0.138
    Other characteristics        
    Healthcare workers (HCWs) 4 (4.9%) 8 (4.3%) 12 (4.5%) >0.99
    Smoking 9 (11.0%) 36 (19.5%) 45 (16.9%) 0.088
    Pregnancy 2 (9.1%) 0 (0.0%) 2 (3.4%) 0.140

    (Table 2) shows the clinical characteristics of the patients at admission. Approximately 42.7% of the patients had one or more comorbid disease, specially diabetes (30.7%) and hypertension (23.6%). The majority (95.9%) of the patients were symptomatic; with mainly cough (70.0%), fever (65.2%), and shortness of breath (33.3%). The severity ranged between mild (50.6%), moderate (32.6%), severe (8.2%), or ARDS symptoms (4.5%). Approximately two-thirds (67.7%) of chest imaging were abnormal (mainly opacities and consolidations). The average temperature was 37.4±0.7 C°, oxygen saturation was 94.9%±6.0% at room air, and QTc duration was 414.8±40.6. Median C-reactive protein (CRP) was 6.7 (1.5-11.8) mg/dL and ferritin was 517 (254-1031) ug/L. Compared with no hydroxychloroquine, those who received hydroxychloroquine were more likely to be symptomatic and have cough, shortness of breath, severer form of disease, diabetes, abnormal chest imaging, higher temperature, lower oxygen saturation at room air, lower hemoglobin, higher CRP, and higher ferritin at admission.

    Table 2. Clinical characteristics at admission among patients with confirmed COVID-19 by the treatment status
      Hydroxychloroquine Total P-value
    No Yes
    Comorbidity        
    None 54 (65.9%) 99 (53.5%) 153 (57.3%) 0.081
    One 17 (20.7%) 40 (21.6%) 57 (21.3%)  
    Two or more 11 (13.4%) 46 (24.9%) 57 (21.3%)  
    Type of comorbidity        
    Hypertension 14 (17.1%) 49 (26.5%) 63 (23.6%) 0.095
    Diabetes 16 (19.5%) 66 (35.7%) 82 (30.7%) 0.008
    Chronic lung disease 0 (0.0%) 6 (3.2%) 6 (2.2%) 0.182
    Heart disease 4 (4.9%) 9 (4.9%) 13 (4.9%) >0.99
    Symptoms        
    Asymptomatic 9 (11.0%) 2 (1.1%) 11 (4.1%) 0.001
    Symptomatic 73 (89.0%) 183 (98.9%) 256 (95.9%)  
    Type of symptoms        
    Fever 51 (62.2%) 123 (66.5%) 174 (65.2%) 0.497
    Cough 43 (52.4%) 144 (77.8%) 187 (70.0%) <0.001
    Shortness of breath 13 (15.9%) 76 (41.1%) 89 (33.3%) <0.001
    Chest pain 2 (2.4%) 2 (1.1%) 4 (1.5%) 0.589
    Nausea or vomiting 8 (9.8%) 11 (5.9%) 19 (7.1%) 0.264
    Diarrhea 6 (7.3%) 9 (4.9%) 15 (5.6%) 0.404
    Severity of symptoms        
    Asymptomatic 9 (11.0%) 2 (1.1%) 11 (4.1%) <0.001
    Mild 50 (61.0%) 85 (45.9%) 135 (50.6%)  
    Moderate 21 (25.6%) 66 (35.7%) 87 (32.6%)  
    Severe 2 (2.4%) 20 (10.8%) 22 (8.2%)  
    ARDS 0 (0.0%) 12 (6.5%) 12 (4.5%)  
    Chest imaging findings        
    Unremarkable 49 (59.8%) 37 (20.1%) 86 (32.3%) <0.001
    Findings detected 33 (40.2%) 147 (79.9%) 180 (67.7%)  
    Other related examinations        
    Systolic BP (mm Hg) 124.6±13.3 125.6±13.2 125.3±13.2 0.546
    Diastolic BP (mm Hg) 77.0±8.3 76.5±9.6 76.7±9.2 0.728
    Temperature (C°) 37.2±0.7 37.4±0.7 37.4±0.7 0.035
    Oxygen saturation at room air 97.0±3.2 94.0±6.7 94.9±6.0 <0.001
    Hemoglobin (g/dl) 13.6±2.3 12.7±2.1 13.0±2.2 0.009
    White blood cell count (x10 ^9/L) 6.7±3.2 7.3±3.4 7.1±3.3 0.163
    Absolute lymphocyte count (x10 ^9/L) 2.0±1.3 1.7±1.4 1.8±1.4 0.186
    Platelet count (x10 ^9/L) 248.7±124.3 251.0±112.3 250.3±115.8 0.884
    C-reactive protein (mg/dL) 1.6 (0.4-9.1) 7.5 (3.0-13.2) 6.7 (1.5-11.8) 0.001
    Creatinine (mg/dL) 0.9 (0.7-1.1) 0.9 (0.8-1.1) 0.9 (0.8-1.1) 0.053
    D.dimer (mg/L) 0.6 (0.3-1.3) 0.9 (0.5-1.5) 0.8 (0.5-1.4) 0.076
    Ferritin (ug/L) 311(102-668) 634(334-1159) 517(254-1031) 0.001
    QTc duration (ms) 406.5±27.7 417.7±44.0 414.8±40.6 0.121

    ARDS, acute respiratory distress syndrome

    Irrespective of hydroxychloroquine, patients included in the study were receiving azithromycin (73.0%), supportive treatment (48.7%), antivirals (17.6%), and zinc (9.0%). Table 3 shows the clinical characteristics of the patients after receiving hydroxychloroquine or non-hydroxychloroquine treatments. Approximately 58.8% of the patients were still symptomatic. Approximately 10.9% of the patients still had severe disease or ARDS. Approximately 60.0% of chest imaging was still abnormal. The average temperature slightly decreased to 37.1±0.4 C° and oxygen saturation slightly increased to 96.5%±3.3% at room air. Compared with no hydroxychloroquine, those who received hydroxychloroquine were more likely to use azithromycin, still symptomatic with more fever, cough, and shortness of breath, have severer form of disease, abnormal chest imaging, lower levels of oxygen saturation at room air and hemoglobin, and higher levels of white blood cell (WBC) count, platelet count, creatinine, D-dimer, and ferritin after receiving hydroxychloroquine.

    Table 3. Clinical characteristics after using hydroxychloroquine among patients with confirmed COVID-19 by the treatment status
      Hydroxychloroquine Total P-value
    No Yes
    Other medication        
    Azithromycin 45 (54.9%) 150 (81.1%) 195 (73.0%) <0.001
    Lopinavir/ritonavir (Kaletra) 16 (19.5%) 27 (14.6%) 43 (16.1%) 0.313
    Oseltamivir (Tamiflu) 2 (2.4%) 2 (1.1%) 4 (1.5%) 0.589
    Zinc 8 (9.8%) 16 (8.6%) 24 (9.0%) 0.770
    Supportive treatment 45 (54.9%) 85 (45.9%) 130 (48.7%) 0.178
    Symptoms        
    Asymptomatic 43 (52.4%) 67 (36.2%) 110 (41.2%) 0.013
    Symptomatic 39 (47.6%) 118 (63.8%) 157 (58.8%)  
    Type of symptoms        
    Fever 1 (1.2%) 17 (9.2%) 18 (6.7%) 0.017
    Cough 3 (3.7%) 32 (17.3%) 35 (13.1%) 0.002
    Shortness of breath 4 (4.9%) 32 (17.3%) 36 (13.5%) 0.006
    Nausea or vomiting 0 (0.0%) 1 (0.5%) 1 (0.4%) >0.99
    Diarrhea 0 (0.0%) 2 (1.1%) 2 (0.7%) >0.99
    Severity of symptoms        
    Asymptomatic 43 (52.4%) 67 (36.2%) 110 (41.2%) 0.033
    Mild 29 (35.4%) 69 (37.3%) 98 (36.7%)  
    Moderate 7 (8.5%) 23 (12.4%) 30 (11.2%)  
    Severe 2 (2.4%) 10 (5.4%) 12 (4.5%)  
    ARDS 1 (1.2%) 16 (8.6%) 17 (6.4%)  
    Chest imaging findings        
    Unremarkable 39 (79.6%) 33 (25.2%) 72 (40.0%) <0.001
    Findings detected 10 (20.3%) 98 (74.8%) 108 (60.0%)  
    Other related examinations        
    Systolic BP (mm Hg) 121.9±7.6 121.2±8.8 121.4±8.5 0.595
    Diastolic BP (mm Hg) 75.1±7.6 74.9±8.8 74.9±8.5 0.863
    Temperature (C°) 37.0±0.3 37.1±0.5 37.1±0.4 0.144
    Oxygen saturation at room air (%) 97.5±2.4 96.1±3.5 96.5±3.3 0.010
    Hemoglobin (g/dl) 13.6±2.3 12.7±2.1 13.0±2.2 0.009
    White blood cell count (x10 ^9/L) 6.7±3.4 8.7±5.6 8.1±5.1 0.011
    Absolute lymphocyte count (x10 ^9/L) 2.4±1.7 2.1±1.8 2.2±1.8 0.478
    Platelet count (x10 ^9/L) 288.1±150.8 354.4±149.9 335.0±152.8 0.005
    C-reactive protein (CRP, mg/dL) 2.5 (0.9-11.9) 6.2 (2.4-11.8) 5.3 (1.5-11.6) 0.118
    Creatinine (mg/dL) 0.8 (0.7-1.0) 0.9 (0.8-1.1) 0.9 (0.7-1.1) 0.018
    D.dimer (mg/L) 0.8 (0.2-1.2) 1.2 (0.7-4.3) 1.0 (0.6-3.1) 0.018
    Ferritin (ug/L) 346(178-769) 771(370-1248) 691(301-1140) 0.021

    ARDS, acute respiratory distress syndrome

    As shown in Table 4, patients experienced clinical improvement mainly in symptoms (83.5%), disease severity (47.9%), and to less extent chest imaging (10.6%) after receiving hydroxychloroquine or non-hydroxychloroquine treatments. The average length of stay was 10.4±6.6 days. Approximately 18.7% of the patients required ICU admission, 9.7% required intubation, 2.6% required inotropic support, and 5.2% died during admission. Compared with no hydroxychloroquine, those on hydroxychloroquine had significantly longer length of stay (11.5±7.1 versus 7.8±4.3 days, p<0.001), more ICU admission (22.7% versus 9.8%, p=0.012), and more intubation (12.4% versus 3.7%, p=0.026). The difference in ICU admission and intubation but not length of stay disappeared after stratification by disease severity and to less extent by the presence of comorbidity (data not shown).

    Table 4. Study outcomes among patients with confirmed COVID-19 by treatment status
      Hydroxychloroquine Total P-value
    No Yes
    Improved symptoms 67 (81.7%) 156 (84.3%) 223 (83.5%) 0.595
    Reduced severity 42 (51.2%) 86 (46.5%) 128 (47.9%) 0.475
    Improved chest imaging 8 (16.3%) 11 (8.5%) 19 (10.6%) 0.128
    Length of stay (days) 7.8±4.3 11.5±7.1 10.4±6.6 <0.001
    Length of stay (days) 7 (5-9) 10 (7-14) 9 (6-13) <0.001
    ICU admission 8 (9.8%) 42 (22.7%) 50 (18.7%) 0.012
    Intubation 3 (3.7%) 23 (12.4%) 26 (9.7%) 0.026
    Inotropic support 0 (0.0%) 7 (3.8%) 7 (2.6%) 0.104
    Death 1 (1.2%) 13 (7.0%) 14 (5.2%) 0.071

    (Table 5) shows the results of multivariate analysis of study outcomes. With two exceptions, patients who received hydroxychloroquine had generally similar outcomes compared with those who received non-hydroxychloroquine treatments after adjusting for several factors that were significantly different between the two groups in univariate analysis (Table 1 through Table 4. Nevertheless, the length of stay was significantly longer (9.8±2.4 versus 7.6±2.0, p=0.006) and the improvement in chest imaging was significantly lower (odds ratio was 0.02, 95% CI 0.001-0.20, p=0.001) among patients who received hydroxychloroquine compared with those who received non-hydroxychloroquine treatments.

    Table 5. Adjusted outcomes* (multivariate analysis) among patients with confirmed COVID-19 who received hydroxychloroquine compared with those who received non-hydroxychloroquine treatments
      Odds ratio (OR) 95% confidence interval of OR P-value Adjusted R-square
    Lower Upper
    Improved symptoms 1.14 0.42 3.10 0.797 0.280
    Reduced severity 0.58 0.27 1.21 0.146 0.305
    Improved chest imaging 0.02 0.001 0.20 0.001 0.499
    ICU admission 1.02 0.39 2.69 0.967 0.215
    Intubation 1.76 0.37 8.49 0.480 0.351
    Inotropic support >10 0.00 . 0.996 0.325
    Death 1.04 0.07 15.66 0.978 0.575
      Hydroxychloroquine Total P-value
    No Yes
    Length of stay (days) 7.6±2.0 9.8±2.4 8.6±2.5 0.006

    * Adjusted for age, employment status, diabetes, symptoms (cough and shortness of breath), temperature, severity of disease, oxygen saturation at room air, chest imaging findings, use of azithromycin, and levels of hemoglobin and creatinine.

    Discussion

    The current study examined the efficacy and safety of hydroxychloroquine among admitted patients with COVID-19 of different disease severity. The findings showed that hydroxychloroquine was the second most commonly used single medication (69.3%) after azithromycin (73.0%). It was used approximately four-folds higher than all antiviral medications. The heavy use of hydroxychloroquine is probably reflecting the MOH guidelines at the time of study (March through May) which placed hydroxychloroquine as a first-line drug for all patients (mild to ARDS) while adding antivirals for severe and critical patients 14. The high use of hydroxychloroquine underscores the importance of reviewing local efficacy and safety data.

    The patients in the current study experienced a significant clinical improvement specially in symptoms and disease severity after treatment. However, hydroxychloroquine was not associated with better clinical improvement (including symptoms and severity) than non-hydroxychloroquine treatments in both univariate and multivariate analysis. On the other hand, improvement of chest imaging was significantly slower among those receiving hydroxychloroquine. Consistent with current findings, meta-analysis studies could not detect significant clinical improvement (mainly symptoms) in patients receiving hydroxychloroquine [16-18]. However, the results of these studies were conflicting as regards the ability of hydroxychloroquine to limit the radiologic progression [17-19]. Variability may be related to the difference in disease severity and time of re-assessment of chest imaging in different study designs.

    Hydroxychloroquine in the current study was associated with longer length of stay in both univariate and multivariate analysis. Similarly, hydroxychloroquine with or without azithromycin was associated with longer length of stay in both univariate and multivariate analysis in a retrospective cohort design 20. However, most of the previous studies either did not focus on the length of stay as an outcome or could not find benefit of hydroxychloroquine on the length of stay 21, 22. It should be mentioned that the length of stay may be easily affected by the hospital capacity and discharge polices 20.

    The patients in the current study who were receiving hydroxychloroquine experienced negative outcomes including ICU admission and intubation, which largely disappeared in multivariate analysis adjusted for several factors including disease severity and concomitant use of azithromycin. This finding may indicate that the above negative outcomes were not caused by hydroxychloroquine itself but rather by the difference between treatment groups as regards clinical picture, severity, and other received treatments. Similarly, previous studies could not detect any significant increase in ICU admission or intubation in patients receiving hydroxychloroquine 19, 21, 23.

    The current study showed that hydroxychloroquine was associated with an insignificant increase in mortality that completely disappeared in multivariate analysis. Previous studies examining the impact of hydroxychloroquine on all-cause mortality were conflicting and probably changing overtime. For example, earlier meta-analysis reports that included few studies published before the end of April 2020 showed a significant increase in mortality among patients receiving hydroxychloroquine, with risk ratios above two 19, 24. However, the majority of include studies were observation with high level of heterogeneity due to variable doses, disease severity, and concomitant treatments. Later meta-analysis reports that included more recent studies published up to June or July 2020 found no significant increase in mortality among patients receiving hydroxychloroquine 16, 17, 25, 26. A recent local prospective cohort study (pre-review publication) showed that hydroxychloroquine was associated with lower hospital admission and mortality among outpatients with mild-moderate COVID-19 symptoms 27. The apparently conflicting finding may underscore the variability of the outcome by the type of patient and severity of the disease. Interestingly, a two recent report showed a significant increase in mortality only among patients who were receiving both hydroxychloroquine and azithromycin 25, 26. Consistently, a sub-analysis of the current data showed that this group had the worst outcome in univariate analysis, probably because physicians were reserving hydroxychloroquine/azithromycin combination for severe/critical patients (data not shown). Additionally, adjustment for concomitant azithromycin use was a major factor that pushed the adjusted odds ratio for mortality towards null.

    The current study is considered the first study in Saudi Arabia to comprehensively examine the efficacy and safety of hydroxychloroquine in admitted patients. The study used a prospective multi-hospital design, included patients with different severity, and reported both univariate and multivariate analysis. Nevertheless, we acknowledge a number of limitations. The lack of randomization may have introduced selection bias. However, the observational design allowed for evaluation of actual treatment practices while adjusting for group differences at admission in multivariate analysis. The concomitant use of other types of treatments represented an important confounding factor for the current outcomes. However, it is probably unethical to deprive patients from other potential treatments at the time of pandemic with limited therapeutic information. Additionally, this has been adjusted for in multivariate analysis.

    In conclusion, hydroxychloroquine have been heavily used to treat patients with COVID-19 admitted to general hospitals in Saudi Arabia during the time of the study. Hydroxychloroquine was not associated with better clinical improvement and it was associated with longer length of stay. The observed univariate associations between hydroxychloroquine and negative outcomes such as ICU admission, intubation, and may be mortality can be can be largely explained by the differences between treatment groups in clinical severity and other received treatments. The current findings represent a significant addition to the debate about hydroxychloroquine use in COVID-19 pandemic.

    Acknowledgments

    Thanks for all staff at four hospitals who assisted in data collection and other study logistics

    Funding

    None received

    Disclosures

    The authors report no conflicts of interest in this work

    Statement

    All authors have been acknowledged as contributors of submitted work and fulfill the standard criteria for authorship. All authors have read and approved the submission of the current version of the manuscript. The material included in this manuscript is original and it has been neither published elsewhere nor submitted for publication simultaneously.

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