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

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.

Full text

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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
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.

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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. 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).

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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.

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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.

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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.).

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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.

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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

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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).

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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

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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 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.

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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.

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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.

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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

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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%

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Zinc
No Zinc
β Coefficient
P-value
Length of Hospital stay (in
days)*
6 (4-9)
N=411
6 (3-9)
N=521
0.015
0.646
Duration of mechanical*
ventilation (in days)
5 (3-8)
N=33
5 (3-9)
N=86
0.040
0.667
ICU Duration (in days)*
4.85 (1.97-7.94)
N=38
5.54 (2.65-9.32)
N=82
-0.062
0.504
Oxygen flow rate maximum*
6 (3-15)
N=353
6 (3-15)
N=426
-0.015
0.679
Oxygen flow rate average*
3.05 (2.1-6.3)
N=353
3.5 (2.5-7.5)
N=426
-0.062
0.082
Fraction of inspired oxygen,
average
61.52 + 32.03
N=107
65.26 + 34.48
N=117
-.056
0.402
Fraction of inspired oxygen,
maximum
74.94 + 35.75
N=107
71.98 + 35.85
N=117
0.041
0.538
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.

21
Discharged
home
Needed ICU
Needed Invasive
Ventilation
Expired/Hospice
Expired/Hospice**
Expired/Hospice***
Zinc
N=411
317 (77.1%)
38 (9.2%)
33 (8.0%)
54 (13.1%)
28 (73.6%)
N=38
26 (6.9%)
N=373
No Zinc
N=521
356 (68.3%)
82 (15.7%)
86 (16.5%)
119 (22.8%)
61 (74.4%)
N=82
58 (13.2%)
N=439
Odds Ratio
1.56
0.545
0.562
0.511
0.964
0.492
95% Confidence Interval
1.16-2.10
0.362-0.821
0.354-0.891
0.359-0.726
0.401-2.31
0.303-0.799
P-value
0.003
0.004
0.014
<0.0001
0.934
0.004
Adjusted Odds Ratio
1.53
0.733
0.804
0.559
1.03
0.449
Adjusted 95% Confidence
Interval
1.12-2.09
0.471-1.14
0.487-1.33
0.385-0.811
0.404-2.64
0.271-0.744
Adjusted P-value
0.008
0.168
0.396
0.002
0.947
0.002
Table 3: Comparison of categorical hospital outcomes. Data are represented as N(%). P-values were calculated using logistic
regression or 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