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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

1
New York University Grossman School of Medicine, Department of Medicine, New

York, NY
2
New York University Langone Health, Department of Pharmacy, New York, NY
3
NYU Langone Health, New York, NY
4
Division of Healthcare Delivery Science, Department of Population Health, NYU

Grossman School of Medicine, New York, NY

5
Center for Healthcare Innovation and Delivery Science, NYU Langone Health, New

York, NY
6
Division of Infectious Diseases and Immunology, Department of Medicine, NYU

Grossman School of Medicine, New York, NY

Corresponding author:
Joseph Rahimian, MD
NYU Grossman School of Medicine, Department of Medicine
31 Washington Square West, Floor number 4
New York, NY 10011
[email protected]
(212) 465-8834

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Key words: COVID-19, Hydroxychloroquine, Azithromycin, Zinc, Mortality

Running head: Hydroxychloroquine and azithromycin plus Zinc

40-word summary: Zinc sulfate added to hydroxychloroquine and azithromycin may

improve outcomes among hospitalized patients.

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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).

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It is made available under a CC-BY-NC 4.0 International license .

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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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]. SARS-CoV2 is a single-strand RNA

coronavirus, which enters human cells mainly by binding the angiotensin converting

enzyme 2 (ACE2)[3]. SARS-CoV2 is primarily transmitted after viral particles are

inhaled and enter the respiratory tract and has the potential to cause a severe systemic

inflammatory response, acute respiratory disease syndrome (ARDS), multi organ

failure, and shock[2, 4]. Laboratory abnormalities found in patients with COVID-19

include lymphopenia, elevation in lactate dehydrogenase, C reactive protein, D-dimer,

ferritin and interleukin-6 (IL-6)[5, 6].

Several medications are under investigation for the treatment of COVID-19. 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. Chloroquine analogues are weak bases that concentrate within acidic

endosomes and lysosomes. Once intracellular, chloroquine analogues become

protonated and increase pH resulting in prevention of endosomal trafficking,

dysfunctional cellular enzymes, and impaired protein synthesis[7]. This inhibits viral

replication through interference with endosome-mediated viral entry or late transport of

the enveloped virus. Further, this results in interference with the terminal glycosylation

of ACE2 receptor expression which prevents SARS-CoV-2 receptor binding and spread

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of infection [8]. Hydroxychloroquine, a hydroxy-derivative of chloroquine, has also been

proposed based on in vitro activity against SARS-CoV-2 with a three-fold higher

cytotoxic potential compared to chloroquine [9]. However, clinical data in humans has

yielded mixed results[10-12]. The anti-viral and anti-inflammatory effects of chloroquine

have been suggested to account for its potential utility in preventing COVID-19-related

pneumonia. Soon current studies will answer whether hydroxychloroquine is effective as

monotherapy or in combination with azithromycin. In the case that hydroxychloroquine

is found to be ineffective, it may still have a role to play when combined with zinc

sulfate. Zinc inhibits RNA dependent RNA polymerase, and has been shown to do this

in vitro against SARS-CoV[13]. However, it is difficult to generate substantial

intracellular concentrations of zinc, therefore prophylactic administration of zinc alone

may not play a role against SarCoV-2[14]. When combined with a zinc ionophore, such

as chloroquine (hydroxychloroquine), cellular uptake is increased making it more likely

to achieve suitably elevated intracellular concentrations[15]. This combination is already

being tested as a prophylactic regimen in a randomized clinical trial.

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

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received hydroxychloroquine and azithromycin alone compared to those who received

triple therapy with zinc sulfate.

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 5, 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. Prior to March 16,

tests were completed by the New York City Department of Health and Mental Hygiene.

After that date, NYU Langone clinical laboratory conducted tests using the Roche

SARS-CoV2 assay in the Cobas 6800 instruments. On March 31, testing was also

conducted using the SARS-CoV2 Xpert Xpress assay in the Cepheid GeneXpert

instruments. After March 16, only pharyngeal samples were tested.

Patients were included in the study if they were admitted to the hospital, had at least

one positive test for COVID-19, received 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

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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.

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

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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.).

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. The protocol was conducted in accordance to Declaration of

Helsinki.

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-

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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

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

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the other associations were no longer significant (Table 4). 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 4).

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 in NEJM, we noticed an increase in the use of hydroxychloroquine

plus azithromycin[16]. 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.

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

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

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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 be reflective of the proposed mechanism

of action of zinc sulfate in COVID-19. Zinc has been shown to reduce SARS-CoV RNA

dependent RNA polymerase activity in vitro [13]. 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 [17]. Our findings suggest a potential

therapeutic synergistic mechanism of zinc sulfate with hydroxychloroquine, if used early

on in presentation with COVID-19. However, our findings do not suggest a prophylactic

benefit of zinc sulfate in the absence of a zinc ionophore, despite interest in this therapy

for prevention. A prophylactic strategy of zinc sulfate should be evaluated to help

answer this question.

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, we only looked at patients taking

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hydroxychloroquine and azithromycin. We do not know whether the observed added

benefit of zinc sulfate to 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. 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. In light of these limitations, this study should not be

used to guide clinical practice. Rather, our observations support the initiation of future

randomized clinical trials investigating zinc sulfate against COVID-19.

ACKNLOWEDGEMENTS

The authors thank 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.

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9. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC 4.0 International license .

Zinc No Zinc P-value

N=411 N=521
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

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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) 6.9 (5.1-9.3) 0.5994
N=400 N=500
Absolute neutrophil count, 103/ul 5.15 (3.6-7.05) 5.4 (3.8-7.5) 0.0838
N=388 N=488
Absolute lymphocyte count, 103/ul 1 (0.7-1.3) 0.9 (0.6-1.3) 0.0180
N=388 N=482
Ferritin, ng/mL 739 (379-1528) 658 (336.2-1279) 0.1304
N=397 N=473
D-Dimer, ng/mL 341 (214-565) 334 (215-587) 0.7531
N=384 N=435
Troponin, ng/mL 0.01 (0.01-0.02) 0.015 (0.01-0.02) 0.0111
N=389 N=467
Creatine Phosphokinase, U/L 140 (68-330) 151.5 (69.5-398.5) 0.4371
N=343 N=344
Procalcitonin, ng/mL 0.12 (0.05-0.25) 0.12 (0.06-0.43) 0.0493
N=395 N=478

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 medRxiv preprint doi: https://doi.org/10.1101/2020.05.02.20080036.this version posted May 8, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC 4.0 International license .
Creatinine, mg/dL 0.97 (0.8-1.34) 0.99 (0.8-1.27) 0.4140
N=400 N=499
C-Reactive Protein, mg/L 104.95 (51.1-158.69) 108.13 (53-157.11) 0.9586
N=398 N=480
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%

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 medRxiv preprint doi: https://doi.org/10.1101/2020.05.02.20080036.this version posted May 8, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Zinc No Zinc β Coefficient P-value
Length of Hospital stay (in 6 (4-9) 6 (3-9) 0.015 0.646
days)* N=411 N=521

Duration of mechanical* 5 (3-8) 5 (3-9) 0.040 0.667

ventilation (in days) N=33 N=86

It is made available under a CC-BY-NC 4.0 International license .

ICU Duration (in days)* 4.85 (1.97-7.94) 5.54 (2.65-9.32) -0.062 0.504
N=38 N=82

O2 Flow rate max* 6 (3-15) 6 (3-15) -0.015 0.679

N=353 N=426

O2 Flow rate avg* 3.05 (2.1-6.3) 3.5 (2.5-7.5) -0.062 0.082

N=353 N=426

FiO2 AVG 61.52 + 32.03 65.26 + 34.48 -.056 0.402

N=107 N=117

FIO2 MAX 74.94 + 35.75 71.98 + 35.85 0.041 0.538

N=107 N=117

Table 2: Comparisons of continuous hospital outcomes. Data are represented median (IQR) and as mean + SD. Sample size is reported

for each variable tested. β Coefficients and P-values were calculated using linear regression. N was specified for each comparison.

P<.05 was deemed significant. *variables were log transformed for regression analysis

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 medRxiv preprint doi: https://doi.org/10.1101/2020.05.02.20080036.this version posted May 8, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Zinc No Zinc Odds 95% P-value
Ratio Confidence
N=411 N=521 Interval
Discharged home 317 (77.1%) 356 (68.3%) 1.56 1.16-2.10 0.003

Needed ICU 38 (9.2%) 82 (15.7%) 0.545 0.362-0.821 0.004

It is made available under a CC-BY-NC 4.0 International license .

Needed Invasive Ventilation 33 (8.0%) 86 (16.5%) 0.562 0.354-0.891 0.014

Expired/Hospice 54 (13.1%) 119 (22.8%) 0.511 0.359-0.726 <0.0001

Expired/Hospice** 28 (73.6%) 61 (74.4%) 0.964 0.401-2.31 0.934

N=38 N=82
Expired/Hospice*** 26 (6.9%) 58 (13.2%) 0.492 0.303-0.799 0.004
N=373 N=439

Table 3: Comparison of categorical hospital outcomes. Data are represented as N(%). P-values were calculated using logistic

regression. P<.05 was deemed significant. N was specified for subgroup analyses.

**After excluding all non ICU patients

***After excluding all ICU patients

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 medRxiv preprint doi: https://doi.org/10.1101/2020.05.02.20080036.this version posted May 8, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Zinc No Zinc Adjusted Adjusted Adjusted
Odds 95% P-value
N=411 N=521 Ratio Confidence
Interval
Discharged home 317 (77.1%) 356 (68.3%) 1.53 1.12-2.09 0.008

It is made available under a CC-BY-NC 4.0 International license .

Needed ICU 38 (9.2%) 82 (15.7%) 0.733 0.471-1.14 0.168

Needed Invasive Ventilation 33 (8.0%) 86 (16.5%) 0.804 0.487-1.33 0.396

Expired/Hospice 54 (13.1%) 119 (22.8%) 0.559 0.385-0.811 0.002

Expired/Hospice** 28 (73.6%) 61 (74.4%) 1.03 0.404-2.64 0.947

N=38 N=82
Expired/Hospice*** 26 (6.9%) 58 (13.2%) 0.449 0.271-0.744 0.002
N=373 N=439

Table 4: Adjusted comparison of categorical hospital outcomes. Data are represented as N(%). P-values were calculated using

multivariate logistic regression adjusting for patient admission after March 25th as a categorical variable. P<.05 was deemed

significant. N was specified for subgroup analyses.

**After excluding all non ICU patients

***After excluding all ICU patients