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SCIENCE CHINA Life Sciences, Volume 63 , Issue 10 : 1515-1521(2020) https://doi.org/10.1007/s11427-020-1732-2

Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19

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  • ReceivedApr 23, 2020
  • AcceptedMay 12, 2020
  • PublishedMay 15, 2020

Abstract

Coronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high fatality. The most urgent need is to find effective treatments. We sought to determine whether hydroxychloroquine (HCQ) application may reduce the death risk of critically ill COVID-19 patients. In this retrospective study, we included 550 critically ill COVID-19 patients who need mechanical ventilation in Tongji Hospital, Wuhan, from February 1, 2020 to April 4, 2020. All 550 patients received comparable basic treatments including antiviral drugs and antibiotics, and 48 of them were treated with oral HCQ treatment (200 mg twice a day for 7–10 days) in addition to the basic treatments. Primary endpoint is fatality of patients, and inflammatory cytokine levels were compared between HCQ and non-hydroxychloroquine (NHCQ) treatments. We found that fatalities are 18.8% (9/48) in HCQ group, which is significantly lower than 47.4% (238/502) in the NHCQ group (P<0.001). The time of hospital stay before patient death is 15 (10–21) days and 8 (4–14) days for the HCQ and NHCQ groups, respectively (P<0.05). The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2 (8.3–118.9) pg mL–1 at the beginning of the treatment to 5.2 (3.0–23.4) pg mL–1 (P<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group. These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives.


Funded by

projects from Ministry of Science and Technology of China(2020YFC0844500)

the National Natural Science Foundation of China(31130031)

Emergency Project Fund of Chinese Academy of Sciences(2020YJFK0105)

Chinese Academy of Engineering and Ma Yun Foundation(2020-CMKYGG-05)


Acknowledgment

This work was supported in part by projects from Ministry of Science and Technology of China (2020YFC0844500), the National Natural Science Foundation of China (31130031), Emergency Project Fund of Chinese Academy of Sciences (2020YJFK0105) and Chinese Academy of Engineering and Ma Yun Foundation (2020-CMKYGG-05). We thank all our colleagues from the Department of Internal Medicine, Tongji Hospital, as well as all the medical staff fighting against COVID-19, for their tremendous efforts. We also thank Professor H. Eric Xu in Shanghai Institute of Materia Medica, Chinese Academy of Sciences for his great help in writing this paper.


Interest statement

The author(s) declare that they have no conflict of interest. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


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  • Figure 1

    Kaplan-Meier curve of COVID-19 patients treated with or without HCQ. HCQ treatment significantly reduced the fatality of critically ill COVID-19 patients compared with NHCQ treated patients (*P<0.001).

  • Figure 2

    Effects of HCQ treatment on plasma levels of IL-6. HCQ treatment significantly decreased the levels of IL-6 in about 5 (4–8) days, *P<0.05 (A). The levels of IL-6 were not significantly decreased in NHCQ treatment group at the same observation time (B). Data are presented as medians and interquartile range (Q1–Q3).

  • Figure 3

    Continuous curves of plasma levels of IL-6 showing that the consistency of HCQ treatment period with lowering IL-6 levels, *P<0.05. Data are presented as medians and interquartile range (Q1–Q3).

  • Table 1   Baseline characteristics of critically ill COVID-19 patientsa)

    All patients (n=550)

    HCQ (n=48)

    NHCQ (n=502)

    P

    Age, years

    68 (59–77)

    68 (60–75)

    68 (59–77)

    0.619

    Age range, years

     

    ≤60 (%)

    139 (25.3)

    11 (22.9)

    128 (25.5)

    0.694

    >60 (%)

    411 (74.7)

    37 (77.1)

    374 (71.9)

    0.694

    Gender, male (%)

    344 (62.5)

    32 (66.7)

    312 (62.2)

    0.537

    Original comorbidities

     

    Hypertension (%)

    252 (45.8)

    23 (47.9)

    229 (45.6)

    0.760

    Coronary heart disease (%)

    59 (10.7)

    2 (4.2)

    57 (11.4)

    0.147

    COPD (%)

    16 (2.9)

    0 (0)

    16 (3.2)

    0.383

    Diabetes (%)

    94 (17.1)

    12 (25.0)

    82 (16.3)

    0.128

    Vital signs

     

    Body temperature, °C

    36.6 (36.3–37.0)

    36.7 (36.2–37.3)

    36.7 (36.3–37.3)

    0.704

    Pulse, beats min–1

    89 (80–102)

    91 (80–103)

    92 (81–107)

    0.594

    Respiratory rate, breaths min–1

    20 (20–22)

    25 (20–30)

    21 (20–26)

    0.052

    Systolic blood pressure, mmHg

    130 (119–144)

    131 (117–149)

    133 (118–148)

    0.789

    Diastolic blood pressure, mmHg

    80 (72–89)

    79 (70–90)

    80 (71–88)

    0.608

    SpO2 on admission (%)

    97 (95–98)

    95 (90–96)

    96 (88–98)

    0.216

    Symptoms, number/total number (%)

     

    Fever

    354/458 (77.3)

    29/43 (67.4)

    325/415 (78.3)

    0.105

    Cough

    312/458 (68.1)

    29/43 (67.4)

    283/415 (68.2)

    0.920

    Sputum production

    223/458 (48.7)

    26/43 (60.5)

    197/415 (47.5)

    0.105

    Chest tightness

    65/458 (14.2)

    7/43 (16.3)

    58/415 (14.0)

    0.680

    Shortness of breath

    221/458 (48.3)

    30/43 (69.8)

    191/415 (46.0)

    0.003

    Nasal congestion

    4/458 (0.9)

    0/43 (0)

    4/415 (1.0)

    1

    Nausea

    18/458 (3.9)

    1/43 (2.3)

    17/415 (4.1)

    1

    Diarrhea

    100/458 (21.8)

    9/43 (20.9)

    91/415 (21.9)

    0.880

    Muscle aches

    32/458 (0.7)

    1/43 (2.3)

    31/415 (7.5)

    0.344

    Pharynx discomfort

    16/458 (3.5)

    2/43 (4.7)

    14/415 (3.4)

    0.655

    Fatigue

    87/458 (19.0)

    8/43 (18.6)

    79/415 (19.0)

    0.945

    Laboratory parameters,

     

    White-cell count, ×109 L–1

    7.7 (5.5–11.4)

    7.3 (5.3–12.1)

    7.7 (5.5–11.4)

    0.923

    Lymphocyte count, ×109 L–1

    0.7 (0.5–1.0)

    0.7 (0.5–1.0)

    0.7 (0.5–1.0)

    0.923

    Neutrophil count, ×109 L–1

    6.2 (4.2–10.1)

    6.3 (4.2–9.5)

    6.2 (4.2–10.2)

    0.909

    Platelet count, ×109 L–1

    182.0 (129.8–255.0)

    189.0 (137.0–257.0)

    182.0 (128.5–255.0)

    0.879

    Hemoglobin, g L–1

    125.0 (109.0–139.0)

    121.0 (107.5–134.5)

    125.0 (110.0–139.0)

    0.424

    Alanine aminotransferase, U L–1

    26.0 (16.0–41.0)

    30.0 (22.0–52.0)

    25.0 (16.0–40.0)

    0.009

    Aspartate aminotransferase, U L–1

    35.0 (23.0–53.0)

    42.0 (20.0–60.0)

    34.0 (24.0–52.0)

    0.468

    Total bilirubin, μmol L–1

    10.8 (7.8–15.7)

    11.0 (8.2–15.5)

    10.7 (7.7–15.8)

    0.938

    Albumin, g L–1

    31.4 (28.7–34.5)

    31.1 (29.6–33.6)

    31.5 (28.7–34.6)

    0.527

    Lactate dehydrogenase, U L–1

    395.5 (293.0–536.0)

    401.0 (311.5–493.0)

    395.0 (291.5–541.0)

    0.949

    Creatinine, μmol L–1

    81.0 (62.0–103.0)

    86.0 (63.0–110.5)

    79.0 (62.0–103.0)

    0.440

    Blood urea nitrogen, mmol L–1

    6.4 (4.4–10.4)

    5.9 (4.1–9.6)

    6.5 (4.5–10.7)

    0.392

    International normalized ratio

    1.1 (1.1–1.3)

    1.1 (1.1–1.2)

    1.2 (1.1–1.3)

    0.034

    D-dimer, mg L–1

    2.3 (1.1–9.6)

    2.6 (1.0–10.1)

    2.3 (1.1–9.7)

    0.895

    APTT, s

    40.3 (36.6–45.4)

    39.0 (36.2–50.7)

    40.4 (36.6–44.9)

    0.962

    C-reactive protein, mg L–1

    75.7 (36.3–128.9)

    84.1 (27.5–117.4)

    75.6(37.1–131.5)

    0.789

    NT-ProBNP, pg mL–1

    598.5 (223.5–1814.3)

    600.5 (191.8–1926.5)

    598.5 (224.5–1829.8)

    0.803

    cTnI, pg mL–1

    15.9 (6.2–59.5)

    12.1 (6.5–47.2)

    16.3 (6.2–60.7)

    0.582

    IL-6, pg mL–1

    37.4 (14.0–96.1)

    25.3 (12.0–111.1)

    31.6 (14.0–95.9)

    0.593

    IL-10, pg mL–1

    6.5 (5.0–12.7)

    6.8 (5.0–9.3)

    6.5 (5.0–13.5)

    0.706

    IL-8, pg mL–1

    22.4 (12.0–43.8)

    23.1 (10.4–30.8)

    22.2 (12.1–47.5)

    0.471

    TNF-α, pg mL–1

    10.6 (8.2–14.6)

    11.0 (9.1–13.7)

    10.4 (8.2–14.8)

    0.596

    IL-1β, pg mL–1

    5.0 (5.0–5.0)

    5.0 (5.0–5.3)

    5.0 (5.0–5.0)

    0.524

    IL-2R, U mL–1

    1026.0 (679.0–1501.0)

    977.5 (749.0–1544.8)

    1026.0 (672.0–1490.5)

    0.592

    Oxygen therapy, number (%)

    545 (99.1)

    47 (97.9)

    498 (99.2)

    0.368

    Mechanical ventilation, number (%)

    349 (63.5)

    28 (58.3)

    321 (63.9)

    0.441

    Mechanical ventilation contained non-invasive ventilation and invasive ventilation. Data are presented as medians and interquartile range (Q1–Q3). HCQ, hydroxychloroquine treatment; NHCQ, non-hydroxychloroquine treatment; COPD, chronic obstructive pulmonary disease; APTT, activated partial thromboplastin time; NT-proBNP, N-terminal pro-B-type natriuretic peptide; cTnI, cardiac troponin I; IL, interleukin; TNF-α, tumor necrosis factor-α; SpO2, percutaneous oxygen saturation.

  • Table 2   Comparison of clinical outcomes between HCQ-treated and NHCQ-treated patientsa)

    HCQ

    NHCQ

    P

    Total patients, n

    48

    502

     

    Dead patients, n (%)

    9 (18.8)

    238 (47.4)

    <0.001

    Hospital stay time before death (d)

    15 (10–21)

    8 (4–14)

    0.027

    Data are presented as medians and interquartile range (Q1–Q3). HCQ, hydroxychloroquine treatment; NHCQ, non-hydroxychloroquine treatment.

  • Table 3   Univariable and multivariable cox proportional hazards model for 60-day fatality after HCQ treatmenta)

    Crude HR (95% CI), P

    Adjusted HR (95% CI), P*

    HCQ-treated

    0.31 (0.16–0.61), 0.001

    0.36 (0.18–0.75), 0.006

    Age

    1.02 (1.01–1.03), <0.001

    1.02 (1.01–1.03), 0.004

    Gender

    1.45 (1.11–1.9), 0.006

    1.64 (1.18–2.29), 0.003

    Hypertension

    0.73 (0.57–0.94), 0.017

    0.77 (0.56–1.05), 0.093

    Coronary heart disease

    1.21 (0.84–1.76), 0.313

    1.11 (0.71–1.72), 0.656

    COPD

    1.12 (0.55–2.26), 0.761

    0.77 (0.31–1.93), 0.583

    Diabetes

    0.64 (0.45–0.93), 0.018

    0.57 (0.35–0.92), 0.023

    Body temperature

    1.34 (1.16–1.56), <0.001

    1.3 (1.09–1.54), 0.003

    Pulse

    1 (1–1), 0.526

    Respiratory rate

    1 (1–1.01), 0.349

    Systolic blood pressure

    1 (0.99–1), 0.401

    Diastolic blood pressure

    1 (0.99–1), 0.104

    SpO2 on admission

    0.96 (0.95–0.97), <0.001

    0.97 (0.96–0.99), <0.001

    Fever

    0.87 (0.63–1.19), 0.384

    Cough

    0.79 (0.6–1.06), 0.118

    Shortness of breath

    1.05 (0.8–1.39), 0.709

    Oxygen therapy

    0.93 (0.23–3.73), 0.915

    0.14 (0.03–0.63), 0.01

    Mechanical ventilation

    7.4 (4.88–11.2), <0.001

    8.07 (4.83–13.47), <0.001

    *, The variables with a P value less than 0.01 in the univariable Cox models, and those representing the history of diseases were included into the multivariable analysis. HCQ, hydroxychloroquine treatment.

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