Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients

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DOI: 10.1101/2020.05.02.20080036
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Abstract
Background: COVID-19 has rapidly emerged as a pandemic infection that has caused significant mortality and economic losses. Potential therapies and means of prophylaxis against COVID-19 are urgently needed to combat this novel infection. As a result of in vitro evidence suggesting zinc sulfate may be efficacious against COVID-19, our hospitals began using zinc sulfate as add-on therapy to hydroxychloroquine and azithromycin. We performed a retrospective observational study to compare hospital outcomes among patients who received hydroxychloroquine and azithromycin plus zinc versus hydroxychloroquine and azithromycin alone. Methods: Data was collected from electronic medical records for all patients being treated with admission dates ranging from March 2, 2020 through April 5, 2020. Initial clinical characteristics on presentation, medications given during the hospitalization, and hospital outcomes were recorded. Patients in the study were excluded if they were treated with other investigational medications. Results: The addition of zinc sulfate did not impact the length of hospitalization, duration of ventilation, or ICU duration. In univariate analyses, zinc sulfate increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU, and mortality or transfer to hospice for patients who were never admitted to the ICU. After adjusting for the time at which zinc sulfate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95% CI 1.12-2.09) reduction in mortality or transfer to hospice remained significant (OR 0.449, 95% CI 0.271-0.744). Conclusion: This study provides the first in vivo evidence that zinc sulfate in combination with hydroxychloroquine may play a role in therapeutic management for COVID-19.
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1
Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and
azithromycin alone: outcomes in hospitalized COVID-19 patients
Philip M. Carlucci1, Tania Ahuja2, Christopher Petrilli1,3, Harish Rajagopalan3, Simon
Jones4.5, Joseph Rahimian1
1New York University Grossman School of Medicine, Department of Medicine, New
York, NY
2New York University Langone Health, Department of Pharmacy, New York, NY
3NYU Langone Health, New York, NY
4Division of Healthcare Delivery Science, Department of Population Health, NYU
Grossman School of Medicine, New York, NY
5Center for Healthcare Innovation and Delivery Science, NYU Langone Health, New
York, NY
6Division of Infectious Diseases and Immunology, Department of Medicine, NYU
Grossman School of Medicine, New York, NY
Running head: Hydroxychloroquine and azithromycin plus Zinc for COVID
Corresponding author:
Joseph Rahimian, MD
NYU Grossman School of Medicine, Department of Medicine
31 Washington Square West, Floor number 4
New York, NY 10011
Joseph.Rahimian@nyulangone.org
(212) 465-8834
2
ABSTRACT
Background: COVID-19 has rapidly emerged as a pandemic infection that has caused
significant mortality and economic losses. Potential therapies and prophylaxis against
COVID-19 are urgently needed to combat this novel infection. As a result of in vitro
evidence suggesting zinc sulfate may be efficacious against COVID-19, our hospitals
began using zinc sulfate as add-on therapy to hydroxychloroquine and azithromycin.
Methods: This retrospective observational study compared outcomes among
hospitalized COVID-19 patients ordered for zinc sulfate plus hydroxychloroquine and
azithromycin (n=411) to patients ordered to receive hydroxychloroquine and
azithromycin alone (n=521).
Results: The addition of zinc sulfate did not impact the length of hospitalization,
duration of ventilation, or ICU duration. In univariate analyses, zinc sulfate
increased the frequency of patients being discharged home, and decreased the need
for ventilation, admission to the ICU, and mortality or transfer to hospice for patients
who were never admitted to the ICU. After adjusting for the time at which zinc sulfate
was added to our protocol, an increased frequency of being discharged home (OR 1.53,
95% CI 1.12-2.09) and reduction in mortality or transfer to hospice among patients who
did not require ICU level of care remained significant (OR 0.449, 95% CI 0.271-0.744).
Conclusion: This study provides the first in vivo evidence that zinc sulfate may play a
role in therapeutic or prophylactic management for COVID-19.
3
INTRODUCTION
The World Health Organization has declared a pandemic due to spread of the
coronavirus disease of 2019 (COVID-19) caused by the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV2)1,2. Despite limited and conflicting data, the U.S.
Food and Drug Administration authorized the emergency use of hydroxychloroquine for
the treatment of COVID-19 with or without azithromycin. Hydroxychloroquine was
thought to be efficacious partly based on in vitro activity against SARS-CoV-23.
However, clinical data in humans has yielded mixed and disappointing results4-7. In
spite of this, hydroxychloroquine may still have a role to play when combined with zinc
sulfate.
Zinc is an essential trace element that is required for the maintenance of adaptive and
innate immune responses8. The benefits of zinc have previously been recognized for its
therapeutic use against other respiratory viruses including those that cause the common
cold9-11. Zinc has also been observed to improve pneumonia in children and its
deficiency is associated with pneumonia in the elderly9,12,13. Implicating a role for zinc in
COVID-19, zinc inhibits viral RNA dependent RNA polymerase, and has been shown to
do this in vitro against SARS-CoV14. When combined with a zinc ionophore, such as
hydroxychloroquine, cellular uptake is increased making it more likely to achieve
suitably elevated intracellular zinc concentrations for viral inhibition10,15. This
combination is already being tested as a prophylactic regimen in a prospectively
followed cohort (NCT04326725) and in a randomized clinical trial (NCT04377646).
4
Other trials are also investigating this regimen for therapeutic efficacy (NCT04370782,
NCT04373733).
As New York became the epicenter of the pandemic, hospitals in the area quickly
adopted investigational therapies, including the use of hydroxychloroquine and
azithromycin. Given this proposed synergistic effect of zinc with hydroxychloroquine,
practices at NYULH changed and the addition of zinc sulfate 220 mg PO BID along with
hydroxcychloroquine 400 mg once followed by 200 mg PO BID with azithromycin 500
mg once daily became part of the treatment approach for patients admitted to the
hospital with COVID-19. This study sought to investigate outcomes among patients who
received hydroxychloroquine and azithromycin alone compared to those who received
triple therapy with zinc sulfate.
5
METHODS
We performed a retrospective analysis of data from patients hospitalized with confirmed
SARS-CoV-2 infection at NYU Langone Health. Data was collected from electronic
medical records (Epic Systems, Verona, WI) for all patients being treated with
admission dates ranging from March 2, 2020 through April 11, 2020. Patients were
admitted to any of four acute care NYU Langone Health hospitals across New York City.
COVID-19 positivity was determined by real-time reverse-transcriptase-polymerase-
chain-reaction (RT-PCR) of nasopharyngeal or oropharyngeal swabs.
Patients were included in the study if they were admitted to the hospital, had at least
one positive test for COVID-19, were ordered to receive hydroxychloroquine and
azithromycin, and had either been discharged from the hospital, transitioned to hospice,
or expired. Patients were excluded from the study if they were never admitted to the
hospital or if there was an order for other investigational therapies for COVID-19,
including tocilizumab, nitazoxanide, rituximab, anakinra, remdesivir, or lopinavir/ritonavir
during the course of their hospitalization to avoid potential confounding effects of these
medications. We collected demographics as reported by the patient and any past
medical history of hypertension, hyperlipidemia, coronary artery disease, heart failure,
chronic obstructive pulmonary disease, asthma, malignancy other than non-melanoma
skin malignancy, and diabetes. We also recorded vital signs on admission, the first set
of laboratory results as continuous variables, and relevant medications as categorical
variables, including NSAIDs, anticoagulants, antihypertensive medications and
corticosteroids ordered at any point during the course of the hospitalization.
6
Statistics
Patients were categorized based on their exposure to hydroxychloroquine (400 mg load
followed by 200 mg twice daily for five days) and azithromycin (500 mg once daily)
alone or with zinc sulfate (220 mg capsule containing 50 mg elemental zinc twice daily
for five days) as treatment in addition to standard supportive care. Descriptive statistics
are presented as mean and standard deviation or mean and interquartile range for
continuous variables and frequencies for categorical variables. Normality of distribution
for continuous variables was assessed by measures of skewness and kurtosis, deeming
the dataset appropriate for parametric or nonparametric analysis. A 2-tailed Student’s t
test was used for parametric analysis, and a Mann Whitney U test was used for
nonparametric data analysis. Pearson’s chi-squared test was used to compare
categorical characteristics between the two groups of patients. Linear regression for
continuous variables or logistic regression for categorical variables was performed with
the presence of zinc as the predictor variable and outcome measures (duration of
hospital stay, duration of mechanical ventilation, maximum oxygen flow rate, average
oxygen flow rate, average FiO2, maximum FiO2, admission to the intensive care unit
(ICU), duration of ICU stay, death/hospice, need for intubation, and discharge
destination), as dependent variables. Data was log transformed where appropriate to
render the distribution normal for linear regression analysis. Multivariate logistic
regression was used to adjust for the timing that our protocol changed to include zinc
therapy using admission before or after March 25th as a categorical variable. P-values
less than 0.05 were considered to be significant. All analyses were performed using
STATA/SE 16.0 software (STATA Corp.).
7
Study approval
The study was approved by the NYU Grossman School of Medicine Institutional Review
Board. A waiver of informed consent and a waiver of the Health Information Portability
Privacy act were granted.
8
RESULTS
Patients taking zinc sulfate in addition to hydroxychloroquine and azithromycin (n=411)
and patients taking hydroxychloroquine and azithromycin alone (n=521) did not differ in
age, race, sex, tobacco use or past medical history (Table 1). On hospital admission,
vital signs differed by respiratory rate and baseline systolic blood pressure. The first
laboratory measurements of inflammatory markers including white blood cell count,
absolute neutrophil count, ferritin, D-dimer, creatine phosphokinase, creatinine, and C-
reactive protein did not differ between groups. Patients treated with zinc sulfate had
higher baseline absolute lymphocyte counts [median (IQR), zinc: 1 (0.7-1.3) vs. no zinc:
0.9 (0.6-1.3), p-value: 0.0180] while patients who did not receive zinc had higher
baseline troponin [0.01 (0.01-0.02) vs. 0.015 (0.01-0.02), p-value: 0.0111] and
procalcitonin [0.12 (0.05-0.25) vs 0.12 (0.06-0.43), p-value: 0.0493) (Table 1).
In univariate analysis, the addition of zinc sulfate to hydroxychloroquine and
azithromycin was not associated with a decrease in length of hospital stay, duration of
mechanical ventilation, maximum oxygen flow rate, average oxygen flow rate, average
fraction of inspired oxygen, or maximum fraction of inspired oxygen during
hospitalization (Table 2). In bivariate logistic regression analysis, the addition of zinc
sulfate was associated with decreased mortality or transition to hospice (OR 0.511, 95%
CI 0.359-0.726), need for ICU (OR 0.545, 95% CI 0.362-0.821) and need for invasive
ventilation (OR 0.562, 95% CI 0.354-0.891) (Table 3). However, after excluding all non-
critically ill patients admitted to the intensive care unit, zinc sulfate no longer was found
to be associated with a decrease in mortality (Table 3). Thus, this association was
9
driven by patients who did not receive ICU care (OR 0.492, 95% CI 0.303-0.799). We
also found that the addition of zinc sulfate was associated with likelihood of discharge to
home in univariate analysis (OR 1.56, 95% CI 1.16-2.10) (Table 3). We performed a
logistic regression model to account for the time-period when the addition of zinc sulfate
to hydroxychloroquine plus azithromycin became utilized at NYULH. After adjusting for
this date (March 25th), we still found an association for likelihood of discharge to home
(OR 1.53, 95% CI 1.12-2.09) and decreased mortality or transition to hospice however
the other associations were no longer significant (Table 3). The decrease in mortality or
transition to hospice was most striking when considering only patients who were not
admitted to the ICU (OR: 0.449, p-value: 0.002) (Table 3).
10
DISCUSSION
While practicing at the epicenter of the pandemic in the United States, we were faced
with unprecedented challenges of adopting investigational therapies quickly into clinical
practice. Initially, antiviral options at our institution consisted of clinician preference for
either ritonavir/lopinavir or hydroxychloroquine plus azithromycin. After the findings of
ritonavir/lopinavir, we noticed an increase in the use of hydroxychloroquine plus
azithromycin16. Our providers within the infectious diseases division, clinical pharmacy,
and hospitalists discussed the use of zinc sulfate as an addition to hydroxychloroquine,
based on the potential synergistic mechanism, and low risk of harm associated with this
therapy.
There has been significant interest in the use of zinc sulfate to treat and prevent
COVID-19 infection and its use is being considered in several trials (NCT04326725,
NCT04377646, NCT04370782, NCT04373733, NCT04351490)9,17,18. To our
knowledge, we provide the first in vivo evidence on the efficacy of zinc in COVID-19
patients. After adjusting for the timing of zinc sulfate treatment, the negative
associations between zinc and the need for ICU and invasive ventilation were no longer
significant but we did still observe a trend. This observation may be because patients
with COVID-19 were initially sent to the ICU quicker, but as time went on and resources
became more limited, clinicians began treating COVID-19 patients on general medicine
floors for longer periods of time before escalating to the ICU. Future studies are needed
to confirm or refute the hypothesis that the addition of zinc sulfate to a zinc ionophore
11
such as hydroxychloroquine may reduce the need for ICU care in patients with COVID-
19.
The main finding of this study is that after adjusting for the timing of zinc therapy, we
found that the addition of zinc sulfate to hydroxychloroquine and azithromycin was
found to associate with a decrease in mortality or transition to hospice among patients
who did not require ICU level of care, but this association was not significant in patients
who were treated in the ICU. This result may reflect one of the proposed mechanisms
by which zinc sulfate may provide protection against COVID-19. Zinc has been shown
to reduce SARS-CoV RNA dependent RNA polymerase activity in vitro 14. As such, zinc
may have a role in preventing the virus from progressing to severe disease, but once
the aberrant production of systemic immune mediators is initiated, known as the
cytokine storm, the addition of zinc may no longer be effective 19. Our findings suggest a
potential protective effect of zinc, potentially enhanced by a therapeutic synergistic
mechanism of zinc sulfate with hydroxychloroquine, if used early on in presentation with
COVID-19.
This study has several limitations. First, this was an observational retrospective analysis
that could be impacted by confounding variables. This is well demonstrated by the
analyses adjusting for the difference in timing between the patients who did not receive
zinc and those who did. In addition, because no patients at our hospital were taking zinc
sulfate alone, we could only look at patients taking hydroxychloroquine and
azithromycin. We do not know whether the observed added benefit of zinc sulfate to
12
hydroxychloroquine and azithromycin on mortality would have been seen in patients
who took zinc sulfate alone or in combination with just one of those medications since
no patients at our hospitals received zinc sulfate as stand-alone therapy. Given the
added side effects associated with hydroxychloroquine, future studies should examine
whether zinc sulfate would provide benefit as a stand-alone therapy or in combination
with another zinc ionophore. We also do not have data on the time at which the patients
included in the study initiated therapy with hydroxychloroquine, azithromycin, and zinc.
Those drugs would have been started at the same time as a combination therapy, but
the point in clinical disease at which patients received those medications could have
differed between our two groups. Finally, the cohorts were identified based on
medications ordered rather than confirmed administration, which may bias findings
towards favoring equipoise between the two groups.
13
CONCLUSION
Zinc sulfate added to hydroxychloroquine and azithromycin associates with a decrease
in mortality or transfer to hospice among patients who do not require ICU level of care
and an increased likelihood to be discharged directly home from the hospital. In light of
study limitations, this study alone is not sufficient to guide clinical practice. Rather, these
findings suggest a potential role for zinc sulfate in COVID-19 patients and support the
initiation of future randomized clinical trials investigating zinc sulfate against COVID-19.
14
ACKNLOWEDGEMENTS
The authors thank Mark Mulligan, Andrew Admon, Mary Grace Fitzmaurice, Brian
Bosworth, Robert Cerfolio, Steven Chatfield, Thomas Doonan, Fritz Francois, Robert
Grossman, Leora Horwitz, Juan Peralta, Katie Tobin, and Daniel Widawsky for their
operational and technical support. We also thank the thousands of NYU Langone
Health employees who have cared for these patients.
15
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1. Organization WH. Coronavirus Disease 2019 (COVID-19) Situation Report. 2020. 46.
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel
coronavirus in Wuhan, China. The Lancet. 2020;395(10223):497-506.
3. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing
Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020:ciaa237.
4. Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a
treatment of COVID-19: results of an open-label non-randomized clinical trial.
International Journal of Antimicrobial Agents. 2020:105949.
5. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in
United States veterans hospitalized with Covid-19. medRxiv.
2020:2020.2004.2016.20065920.
6. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or
clinical benefit with the combination of hydroxychloroquine and azithromycin in
patients with severe COVID-19 infection. Médecine et Maladies Infectieuses. 2020.
7. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized
Patients with Covid-19. New England Journal of Medicine. 2020.
8. Maares M, Haase H. Zinc and immunity: An essential interrelation. Archives of
Biochemistry and Biophysics. 2016;611:58-65.
9. Skalny AV, Rink L, Ajsuvakova OP, et al. Zinc and respiratory tract infections:
Perspectives for COVID-19. International Journal of Molecular Medicine. 2020.
10. Krenn BM, Gaudernak E, Holzer B, Lanke K, Van Kuppeveld FJM, Seipelt J. Antiviral
activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J
Virol. 2009;83(1):58-64.
11. Hemilä H. Zinc lozenges may shorten the duration of colds: a systematic review. Open
Respir Med J. 2011;5:51-58.
12. Acevedo-Murillo JA, García León ML, Firo-Reyes V, Santiago-Cordova JL, Gonzalez-
Rodriguez AP, Wong-Chew RM. Zinc Supplementation Promotes a Th1 Response and
Improves Clinical Symptoms in Fewer Hours in Children With Pneumonia Younger Than
5 Years Old. A Randomized Controlled Clinical Trial. Frontiers in Pediatrics. 2019;7(431).
13. Barnett JB, Hamer DH, Meydani SN. Low zinc status: a new risk factor for pneumonia in
the elderly? Nutr Rev. 2010;68(1):30-37.
14. te Velthuis AJW, van den Worm SHE, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn2+
Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc
Ionophores Block the Replication of These Viruses in Cell Culture. PLOS Pathogens.
2010;6(11):e1001176.
15. Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding W-Q. Chloroquine is a zinc ionophore.
PloS one. 2014;9(10):e109180-e109180.
16. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with
Severe Covid-19. New England Journal of Medicine. 2020.
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17. Jayawardena R, Sooriyaarachchi P, Chourdakis M, Jeewandara C, Ranasinghe P.
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COVID-19. Journal of Pharmaceutical Analysis. 2020.
17
Zinc
N=411
No Zinc
N=521
P-value
Demographics
Age
63.19 + 15.18
61.83 + 15.97
0.0942
Female Sex
147 (35.7%)
201 (38.6%)
0.378
Race
0.428
African American
68 (16.5%)
81 (15.5%)
White
189 (46.0%
244 (46.8%)
Asian
30 (7.3%)
30 (5.8%)
Other
97 (23.6%)
142 (27.2%)
Multiracial/Unknown
27 (6.6%)
24 (4.6%)
History
Tobacco use
0.142
Never or Unknown
306 (74.5%)
382 (73.3%)
Former
76 (18.5%)
115 (22.1%)
Current
29 (7.1%)
24 (4.6%)
Any cardiovascular condition
182 (44.3%)
248 (47.6%)
0.313
Hypertension
154 (37.5%)
208 (39.9%)
0.445
Hyperlipidemia
99 (24.1%)
148 (28.4%)
0.138
Coronary Artery Disease
36 (8.8%)
41 (7.9%)
0.624
Heart Failure
26 (6.3%)
22 (4.2%)
0.149
18
Asthma or COPD
50 (12.2%)
56 (10.7%)
0.499
Diabetes
105 (25.5%)
130 (25.0%)
0.835
Malignancy
23 (5.6%)
33 (6.3%)
0.638
Transplant
3 (0.7%)
2 (0.4%)
0.473
Chronic Kidney Disease
47 (11.4%)
44 (8.4%)
0.127
BMI kg/m2
29.17 (25.8-33.42)
29.29 (25.77-33.2)
0.8611
Admission Characteristics
Oxygen saturation at presentation
94 (91-96)*
94 (91-96)**
0.1729
Respiratory Rate, respirations per minute
20 (19-24)
20 (18-24)
0.0460
Pulse, beats per minute
97.66 + 18.61
99.40 + 19.82
0.0858
Baseline Systolic BP, mmHg
134.83 + 20.84
132.41 + 21.87
0.0435
Baseline Diastolic BP, mmHg
76.66 + 12.62
76.59 + 14.22
0.4670
Temperature, degrees Celsius
37.65 + 0.82
37.72 + 0.94
0.1354
White blood cell count 103/ul
6.9 (5.1-9.0)
N=400
6.9 (5.1-9.3)
N=500
0.5994
Absolute neutrophil count, 103/ul
5.15 (3.6-7.05)
N=388
5.4 (3.8-7.5)
N=488
0.0838
Absolute lymphocyte count, 103/ul
1 (0.7-1.3)
N=388
0.9 (0.6-1.3)
N=482
0.0180
Ferritin, ng/mL
739 (379-1528)
N=397
658 (336.2-1279)
N=473
0.1304
D-Dimer, ng/mL
341 (214-565)
N=384
334 (215-587)
N=435
0.7531
Troponin, ng/mL
0.01 (0.01-0.02)
N=389
0.015 (0.01-0.02)
N=467
0.0111
Creatine Phosphokinase, U/L
140 (68-330)
N=343
151.5 (69.5-398.5)
N=344
0.4371
Procalcitonin, ng/mL
0.12 (0.05-0.25)
N=395
0.12 (0.06-0.43)
N=478
0.0493
19
Creatinine, mg/dL
0.97 (0.8-1.34)
N=400
0.99 (0.8-1.27)
N=499
0.4140
C-Reactive Protein, mg/L
104.95 (51.1-158.69)
N=398
108.13 (53-157.11)
N=480
0.9586
Medications recorded during
hospitalization
NSAID
53 (12.9%)
74 (14.2%)
0.563
Anticoagulant
402 (97.8%)
511 (98.1%)
0.772
ACE inhibitor or ARB
138 (33.6%
175 (33.7%)
0.997
Beta Blocker
91 (22.1%)
132 (25.3%)
0.256
Calcium Channel Blocker
89 (21.7%)
104 (20.0%)
0.527
Corticosteroid
40 (9.7%)
47 (9.0%)
0.711
Table 1: Comparisons of baseline characteristics and hospital medications. Data are
represented as median (IQR) or mean + SD. Sample size is reported where it differed due to lab
results not tested. P-values were calculated using 2-sided t-test for parametric variables and
Mann Whitney U test for nonparametric continuous variables. Pearson χ2 test was used for
categorical comparisons. P < .05 was deemed significant. Laboratory results represent the first
measured value while hospitalized.
*measured on supplemental oxygen for 86.4%
**measured on supplemental oxygen for 83.1%
  • ... Nine studies were retrieved from the search of pre-print repositories. These included one RCT [35] and eight non-randomized studies [36][37][38][39][40][41][42][43]. The studies evaluated a total of 7702 hospitalized patients with COVID-19. ...
    ... Details regarding downgrading are provided in Figure 1, and the weighted risk of bias is presented as a plot in Figure S1 (Supplementary Material 4) Fourteen [12,14,38,39,41,42,15,17,23,28,33,34,36,37] nonrandomized studies were evaluated using the ROBINS-I tool [7]. The most frequent domain causing downgrading was confounding. ...
    Article
    Purpose To assess efficacy and safety of chloroquine (CQ)/hydroxychloroquine (HCQ) for treatment or prophylaxis of COVID-19 in adult humans. Materials and methods MEDLINE, PubMed, EMBASE and two pre-print repositories (bioRxiv, medRxiv) were searched from inception to 8th June 2020 for RCTs and nonrandomized studies (retrospective and prospective, including single-arm, studies) addressing the use of CQ/HCQ in any dose or combination for COVID-19. Results Thirty-two studies were included (6 RCTs, 26 nonrandomized, 29,192 participants). Two RCTs had high risk, two ‘some concerns’ and two low risk of bias (Rob2). Among nonrandomized studies with comparators, nine had high risk and five moderate risk of bias (ROBINS-I). Data synthesis was not possible. Low and moderate risk of bias studies suggest that treatment of hospitalized COVID-19 with CQ/HCQ may not reduce risk of death, compared to standard care. High dose regimens or combination with macrolides may be associated with harm. Postexposure prophylaxis may not reduce the rate of infection but the quality of the evidence is low. Conclusions Patients with COVID-19 should be treated with CQ/HCQ only if monitored and within the context of high quality RCTs. High quality data about efficacy/safety are urgently needed.
  • ... 22 The first clinical trial results confirming this hypothesis were recently published as preprint. 23 Nevertheless, many studies with HCQ in monotherapy or in combination with the antibiotic azithromycin have been inconclusive so far. [13][14][15][16] In all of these studies, HCQ was used later than 5 days after onset of symptoms when hospitalized patients most likely had already progressed to stage II or III of the disease. ...
    ... 22 This hypothesis was recently confirmed by a study using a similar triple therapy and treatment duration. 23 Zinc added to HCQ and azithromycin resulted in a significantly increased number of patients being discharged, a reduction in mortality, or transfer to hospice. In another study, when a lower dose of 200 mg HCQ twice daily was added to basic treatment, mortality of even critically ill patients was significantly reduced. ...
    Preprint
    Objective: To describe outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low dose hydroxychloroquine, and azithromycin (the triple therapy) dependent on risk stratification. Design: Retrospective case series study. Setting: General practice. Participants: 141 COVID-19 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the year 2020. Main Outcome Measures: Risk-stratified treatment decision, rate of hospitalization and all-cause death. Results: Of 335 positively PCR-tested COVID-19 patients, 127 were treated with the triple therapy. 104 of 127 met the defined risk stratification criteria and were included in the analysis. In addition, 37 treated and eligible patients who were confirmed by IgG tests were included in the treatment group (total N=141). 208 of the 335 patients did not meet the risk stratification criteria and were not treated. After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-60; 73% male) got a prescription for the triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control. 4 of 141 treated patients (2.8%) were hospitalized, which was significantly less (p<0.001) compared with 58 of 377 untreated patients (15.4%) (odds ratio 0.16, 95% CI 0.06-0.5). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated group. One patient (0.7%) died in the treatment group versus 13 patients (3.5%) in the untreated group (odds ratio 0.2, 95% CI 0.03-1.5; p=0.16). There were no cardiac side effects. Conclusions: Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalizations and 5 times less all-cause deaths.
  • ... Other antiviral compounds, including remdesivir and hyperimmune gamma globulins [29], may have antiviral activity at an early stage of the disease, although there is to date no convincing published report, comparable to that of oseltamivir at the early stage of influenza [30]. Taking into account the association between low blood zinc levels and poor clinical outcomes, zinc supplementation should be 15 also considered, as recently reported [31]. However, the choice of the best treatment should be made according to its safety profile, which is much better for HCQ-AZ than for remdesivir (adverse events leading to cessation of treatment in 0.3% in our study vs. 12% for remdesivir [12]). ...
    Article
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    Background In our institute in Marseille, France, we initiated early and massive screening for coronavirus disease 2019 (COVID-19). Hospitalization and early treatment with hydroxychloroquine and azithromycin (HCQ-AZ) was proposed for the positive cases. Methods We retrospectively report the clinical management of 3,737 screened patients, including 3,119 (83.5%) treated with HCQ-AZ (200 mg of oral HCQ, three times daily for ten days and 500 mg of oral AZ on day 1 followed by 250 mg daily for the next four days, respectively) for at least three days and 618 (16.5%) patients treated with other regimen (“others”). Outcomes were death, transfer to the intensive care unit (ICU), ≥10 days of hospitalization and viral shedding. Results The patients’ mean age was 45 (sd 17) years, 45% were male, and the case fatality rate was 0.9%. We performed 2,065 low-dose computed tomography (CT) scans highlighting lung lesions in 592 of the 991 (59.7%) patients with minimal clinical symptoms (NEWS score = 0). A discrepancy between spontaneous dyspnoea, hypoxemia and lung lesions was observed. Clinical factors (age, comorbidities, NEWS-2 score), biological factors (lymphocytopenia; eosinopenia; decrease in blood zinc; and increase in D-dimers, lactate dehydrogenase, creatinine phosphokinase, and C-reactive protein) and moderate and severe lesions detected in low-dose CT scans were associated with poor clinical outcome. Treatment with HCQ-AZ was associated with a decreased risk of transfer to ICU or death (Hazard ratio (HR) 0.18 0.11–0.27), decreased risk of hospitalization ≥10 days (odds ratios 95% CI 0.38 0.27–0.54) and shorter duration of viral shedding (time to negative PCR: HR 1.29 1.17–1.42). QTc prolongation (>60 ms) was observed in 25 patients (0.67%) leading to the cessation of treatment in 12 cases including 3 cases with QTc> 500 ms. No cases of torsade de pointe or sudden death were observed. Conclusion Although this is a retrospective analysis, results suggest that early diagnosis, early isolation and early treatment of COVID-19 patients, with at least 3 days of HCQ-AZ lead to a significantly better clinical outcome and a faster viral load reduction than other treatments.
  • ... In a retrospective comparison study at NYU Langone Health for all patients admitted between March 2 and April 5, 2020 (35), there were a large number of patients treated with HCQ plus AZT. During the one month period, there was a move to add zinc 100 mg daily to the HCQ plus AZT regimen. ...
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    Background. The spread of COVID-19 from Wuhan in China throughout the world has been alamingly rapid. Epidemiologic techniques succeeded in containing the disease in China, but efforts were not as successful in the rest of the world, particularly the United States where there have been 1,592, 599 cases with 95,863 deaths as of May 25, 2020. Projections are for continued new infections and deaths if no effective treatments can be activated over the next six months.. We performed a systematic review to determine the potential time course of development of treatments and vaccines focusing on availability in the last half of 2020. Methods. Our search was performed during the week of May 17, 2020. Publications: We reviewed up to date information from several sources to identify potential treatments for COVID-19: We used the Reagan-Udall Expanded Access Navigator COVID-19 Treatment Hub to track the efforts of companies to develop treatments. We then used the results to search for publications on pubmed.gov and on MedRxiv, the preprint server. We further used a targeted Google search to find announcements of trial results. Clinical Trials: We searched for all investigational trials involving potential treatments using several different sources: (A) covid-trials.org, then validated results on (B) clinicaltrials.gov and the (C) World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP). We focused on trials which were completed or currently recruiting for patients, reasoning that the timeline to arrive at treatments by the end of the year would require completion within the next 6 months. We excluded studies which were clearly observational, with no randomization, control or comparison group. We furtherset a cutoff of 100 for numbers of subjects since smaller trial size could lack statistical power to establish superiority of the intervention over the control condition. Results. Published Data: We found 19 publications reporting findings on 6 classes of agents. There were 9 publications related to hydroxychloroquine (HCQ), three on lopanovir/ritonavir (LPV/R) (one of which was combined with interferon beta-1),three on remdesivir, two on favipiravir, one on mepaluzamab, and one on tocilizumab. Ten publications reported randomized controlled trials, the rest were retrospective observational. Only one publication touched on outpatient management, the rest on hospitalized patients. Clinical Trials: We found 409 trials meeting our minimum requirement of 100 subjects which were recruiting or completed. The WHO has launched the Solidarity megatrial performed in over 100 countries actively comparing HCQ, lopanovir/ritonavir (LPV/R) alone and in combination with interferon beta-1, and remdesivir. That trial is scheduled to complete enrollment in the first quarter of 2021. In addition, we found 46 trials of HCQ, 11 trials of LPV/R and 8 trials of interferons. There were 18 ongoing trials of antiviral agents, 24 immune modulator trials, 9 vaccine trials, and 62 trials of other agents.We excluded a large number of trials of Chinese traditional medications, reasoning that there was insufficient clinical experience with these agents outside China to offer these treatments to the rest of the world. Forty four trials were hoping to complete enrollment by the end of the second quarter of 2020. Of these, only 9 were conducted on outpatients. A few vaccine trials are hoping to complete Phase 3 enrollment by the end of the third quarter, but a prolonged follow-up of patients will likely be required. Conclusion. Several treatments for severe disease in hospitalized patients have now been granted emergency authorization. However, the disease is propagated primarily by infected ambulatory individuals. There are only a few randomized controlled studies in outpatients which can be expected to yield results in time to impact on the continuing spread of the epidemic in 2020. It will be necessary for public health authorities to make hard decisions with limited data. The choices will be hardest in dealing with potential early release of vaccines. Keywords: Coronavirus, COVID-19, SARS-Cov-2, remdesivir, hydroxychloroquine
  • Article
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    Coronavirus 2019 (COVID-19) is a pandemic with substantial mortality and no accepted therapy. We report here on four consecutive outpatients with clinical characteristics (CDC case definition) of and/or laboratory-confirmed COVID-19 who were treated with high dose zinc salt oral lozenges. All four patients experienced significant improvement in objective and symptomatic disease measures after one day of high dose therapy suggesting that zinc therapy was playing a role in clinical recovery. A mechanism for zinc’s effects is proposed based on previously published studies on SARS- CoV-1, and randomized controlled trials assessing zinc shortening of common cold duration. The limited sample size and study design preclude a definitive statement about the effectiveness of zinc as a treatment for COVID-19 but suggest the variables to be addressed to confirm these initial findings in future trials.
  • Article
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    Background: Axillary lymph node sampling is considered as one of the most pivotal investigations in determining the lymph node status in management of carcinoma breast. The present study attempts to assess sensitivity, specificity and positive predictive value of axillary four node sampling (FNS) in management of carcinoma of breast, and its efficacy in downstaged patients.Methods: A total of 35 patients, node negative operable cases of carcinoma breast and locally advanced breast cancer (LABC) patients downstaged after 3 cycles of neoadjuvant chemotherapy, were enrolled. Lymph node mapping was done by injecting 3 - 5 ml of methylene blue dye, just before surgery. Level 1 lymph nodes stained by methylene blue were sampled and axillary dissection was carried out, level 3 lymph nodes were identified and sampled, rest of the axillary dissection specimen was sent as a separate sample for histopathological examination , node positivity was compared in level 1 and level 3 , and conclusions were drawn.Results: The sensitivity, specificity for FNS in node negative operable cases were found to be 83.33% and 91.3% respectively. The negative and positive predictive value were found to be 95.40% and 71.42% respectively. Specificity of FNS in LABC downstaged patients was found to be 40%.Conclusions: Targeted four node sampling using methylene blue dye can be considered as an alternative method for sentinel lymph node. Further study should be conducted to establish it as a reliable method for axillary lymph node staging.
  • Article
    Background Despite limited and conflicting evidence, hydroxychloroquine, alone or in combination with azithromycin, is widely used in COVID-19 therapy. Methods We performed a retrospective study of electronic health records of patients hospitalized with confirmed SARS-CoV-2 infection in United States Veterans Health Administration medical centers between March 9, 2020 and April 29, 2020. Patients hospitalized within 24 hours of diagnosis were classified based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) or no HC as treatments. The primary outcomes were mortality and use of mechanical ventilation. Findings A total of 807 patients were evaluated. Compared to the no HC group, after propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HC group (adjusted hazard ratio (aHR), 1.83; 95% CI, 1.16 to 2.89; P=0.009) but not in the HC+AZ group (aHR, 1.31; 95% CI, 0.80 to 2.15; P=0.28). Both the propensity score-adjusted risks of mechanical ventilation and death after mechanical ventilation were not significantly different in the HC group (aHR, 1.19; 95% CI, 0.78 to 1.82; P=0.42 and aHR, 2.11; 95% CI, 0.96 to 4.62; P=0.06, respectively) or in the HC+AZ group (aHR, 1.09; 95% CI, 0.72 to 1.66; P=0.69 and aHR, 1.25; 95% CI, 0.59 to 2.68; P=0.56, respectively), compared to the no HC group. Conclusions Among patients hospitalized with COVID-19, this retrospective study did not identify any significant reduction in mortality or in the need for mechanical ventilation with hydroxychloroquine treatment with or without azithromycin. Funding University of Virginia Strategic Investment Fund.
  • Article
    Background Hydroxychloroquine has been widely administered to patients with Covid-19 without robust evidence supporting its use. Methods We examined the association between hydroxychloroquine use and intubation or death at a large medical center in New York City. Data were obtained regarding consecutive patients hospitalized with Covid-19, excluding those who were intubated, died, or discharged within 24 hours after presentation to the emergency department (study baseline). The primary end point was a composite of intubation or death in a time-to-event analysis. We compared outcomes in patients who received hydroxychloroquine with those in patients who did not, using a multivariable Cox model with inverse probability weighting according to the propensity score. Results Of 1446 consecutive patients, 70 patients were intubated, died, or discharged within 24 hours after presentation and were excluded from the analysis. Of the remaining 1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days); 45.8% of the patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses. Conclusions In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed. (Funded by the National Institutes of Health.)
  • Article
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    Background and aims Balanced nutrition which can help in maintaining immunity is essential for prevention and management of viral infections. While data regarding nutrition in coronavirus infection (COVID-19) are not available, in this review, we aimed to evaluated evidence from previous clinical trials that evaluated nutrition-based interventions for viral diseases (with special emphasis on respiratory infections), and summaries our observations. Methods A systematic search strategy was employed using keywords to search the literature in 3 key medical databases: PubMed®, Web of Science® and SciVerse Scopus®. Studies were considered eligible if they were controlled trials in humans, measuring immunological parameters, on viral and respiratory infections. Clinical trials on vitamins, minerals, nutraceuticals and probiotics were included. Results total of 640 records were identified initially and 22 studies were included from other sources. After excluding duplicates and articles that did not meet the inclusion criteria, 43 studies were obtained (vitamins: 13; minerals: 8; nutraceuticals: 18 and probiotics: 4). Among vitamins, A and D showed a potential benefit, especially in deficient populations. Among trace elements, selenium and zinc have also shown favourable immune-modulatory effects in viral respiratory infections. Several nutraceuticals and probiotics may have some role in enhancing immune functions. Micronutrients may be beneficial in nutritionally depleted elderly population. Conclusions We summaries possible benefits of some vitamins, trace elements, nutraceuticals and and probiotics. Nutrition principles based on these data could be useful in possible prevention and management of COVID-19
  • Article
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    In view of the emerging COVID‑19 pandemic caused by SARS‑CoV‑2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID‑19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‑CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin‑converting enzyme 2 (ACE2), known to be the receptor for SARS‑CoV‑2. Improved antiviral immunity by zinc may also occur through up‑regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti‑inflammatory activity by inhibiting NF‑κB signaling and modulation of regulatory T‑cell functions that may limit the cytokine storm in COVID‑19. Improved Zn status may also reduce the risk of bacterial co‑infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID‑19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID‑19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator‑induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.
  • Article
    Background: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. Results: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Conclusions: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
  • Article
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    Background: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. Methods: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug's safety profile. Results: Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Conclusions: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
  • Article
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    Coronavirus disease 2019 (COVID-19) is a kind of viral pneumonia with an unusual outbreak in Wuhan, China, in December 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The emergence of SARS-CoV-2 has been marked as the third introduction of a highly pathogenic coronavirus into the human population after the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) in the twenty-first century. In this minireview, we provide a brief introduction of the general features of SARS-CoV-2 and discuss current knowledge of molecular immune pathogenesis, diagnosis and treatment of COVID-19 on the base of the present understanding of SARS-CoV and MERS-CoV infections, which may be helpful in offering novel insights and potential therapeutic targets for combating the SARS-CoV-2 infection.
  • Article
    An outbreak of a novel coronavirus (COVID‐19 or 2019‐CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA virus infection and we have found that general treatments, coronavirus‐specific treatments, and antiviral treatments should be useful in fighting COVID‐19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers. In addition, convalescent plasma should be given to COVID‐19 patients if it is available. In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID‐19 if the infection is uncontrollable. This article is protected by copyright. All rights reserved.
  • Article
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    Background: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods: All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings: By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation: The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding: Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
  • Article
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    Background: Pneumonia caused 704,000 deaths in children younger than 5 years in 2015. Zinc is an important micronutrient due to its role in immune function. Since 2004, WHO recommends zinc supplementation for children with diarrhea to shorten the duration and decrease severity. Zinc supplementation for children with pneumonia is controversial. Methods: A randomized controlled clinical trial was conducted, and 103 children 1 month to 5 years old with pneumonia were included. Zinc or placebo was given during hospitalization. Clinical symptoms were recorded, and a blood draw was obtained to determine serum zinc levels, lymphoproliferation, and cytokines at hospitalization and at discharge of the patient; a nasal wash was obtained to detect viral or bacterial pathogens by multiplex RT-PCR. Results: Zinc supplementation improved in fewer hours the clinical status (76 ± 7 vs. 105 ± 8, p = 0.01), the respiratory rate (37 ± 6 vs. 57 ± 7, p = 0.04), and the oxygen saturation (53 ± 7 vs. 87 ± 9, p = 0.007) compared to the placebo group. An increase in IFNγ and IL-2 after treatment in the zinc group was observed. Conclusions: Zinc supplementation improved some clinical symptoms in children with pneumonia in fewer hours and induced a cellular immune response. Clinical Trial Registration: The trial was retrospectively registered in ClinicalTrials.gov, identifier NCT03690583, URL https://clinicaltrials.gov/ct2/show/NCT03690583?term=zinc+children&cond=Pneumonia&draw=2&rank=1.