Everyday New Yorkers might be struggling from record unemployment or
fearing for the future of their jobs as the coronavirus continues to
ravage the country, but the city’s billionaires are doing just fine.
The numbers represent a 29 percent increase from the approximate date at coronavirus lockdowns started and financial markets plummeted.
Jeff Bezos undoubtedly had the biggest year. Bezos, the chief executive of online retailer Amazon, saw his wealth spike from $73.2 billion to $113 billion [+55%]. Amazon shares gained 40 percent
this year, according to a Business Insider report, as the company
accumulated billions in online orders from consumers confined to their
homes.
US military scientists have been deployed to Georgia for research on bioterrorism agents at the Lugar Center, according to the new data leak. These bio-agents have the potential to be aerosolized and used as bioweapons. Among them anthrax, tularemia, Brucella, Crimean-Congo Hemorrhagic Fever, Hantavirus, Y. pestis (causing the disease plague).
The US military biological research projects in Georgia have been funded by the Defense Threat Reduction Agency (DTRA). According
to internal data, American and Georgian scientists are currently
working on the following DTRA projects in the Lugar Center:
Project 1059: Zoonotic Infections with Fever and Skin Injuries in Georgia
The project includes isolation of new orthopoxviruses in humans, rodents, domestic and wild animals in Georgia, and collection of rodents (as a natural reservoir for this virus) for their further study.
Duration: 01/11/2015-31/10/2018 (extended to 2020)
Funding: $702,343
Project 1060: Characterization of the Georgian National Center for Disease Control (NCDC) Strain Repository by New Generation Sequencing
Description: characterization and genome research on 100 strains from four endemic species: Y. pestis (causing the disease plague), B. anthracis (anthrax), Brucella, and F. tularensis (causing the disease tularemia).
Duration: 01/11/2015-31/10/2018
Funding: $ 518,409
Project 1439: Molecular Virological Research in Georgia
Description and objectives:
Identify and characterize Hantavirus and Crimean-Congo hemorrhagic fever virus (CCHFV) strains by molecular methods;
Characterize and study genetic diversity of Crimean-Congo hemorrhagic fever virus and hantavirus strains isolated from rodents and ectoparasites;
Serological examination of febrile patients with Crimean-Congo hemorrhagic fever and hemorrhagic fever with renal syndrome;
Collection of rodents and ectoparasites (ticks, fleas);
Duration: 16/08/2017-15/08/2021
Funding: $612,614
Project 1497: Molecular Epidemiology and Ecology of Yersinia Species in Georgia and Azerbaijan
Description: 1) Ecological research on rodents in Kerb on the Georgian-Azerbaijani border 2) Isolation of different strains of Yersinia; 3) Molecular screening of collected rodent and flea samples. 4) A comparative analysis of the genomes of Yersinia strains obtained during the fieldwork; 5) Spatial analysis of the distribution of Yersinia strains.
Duration: 01/09/2017-31/08/2018 (extended to 2022)
Funding: $134,090.00
Project 1742: Risks of bat-borne zoonotic diseases in Western Asia
The Pentagon unit USAMRU-Georgia has conducted extensive research on tularemia involving Georgian soldiers, scientific papers reveal.
Tularemia is a rare infectious disease that typically attacks the skin, eyes, lymph nodes and lungs. Tularemia, also called rabbit fever or deer fly fever, is caused by the bacterium Francisella tularensis. It is categorized as a category A bioterrorism agent. Tularemia was weaponized for mass aerosol dissemination by the US Army in the past, according to a recently declassified military report.
Tularemia is one of the bio-weapons that the US Army developed in the past. Source: 1981 US Army Report
900 volunteers (soldiers and civilians) were recruited for the DTRA project GG-19 “Epidemiology and Ecology of Tularemia in Georgia” from 2014 to 2017. Blood samples were collected from those volunteers and tested for tularemia.
According to the study, 10 soldiers (2%) of the 500 solders tested
had antibodies for F. tularensis. The seropositive soldiers were men,
the majority of whom were between 30 and 39 years of age. Seven cases had current residences in known endemic areas (i.e. Kakheti, Samtskhe-Javakheti, Kvemo Kartli, Shida Kartli, and Tbilisi). Three were from areas without previously known F. tularensis transmission (i.e. Imereti).
Of the 783 residents approached to participate in this study, 35 (5.0%) volunteers had antibodies to F. tularensis.
Interestingly, the Georgian health officials do not ask about any further information or clarificationas to what this new [US] foreign hub is going to do in their own country.Instead,
Georgia’s Ministry of Health has planned the construction of a new
BSL-2 laboratory, conference hall and campus near the Lugar Center with a
loan from the European Investment Bank,according to a letter to the finance minister of Georgia leaked on Raidforums.
Arms Watch could not independently verify the authenticity of this
letter as we did not find it in the leaked files. We have further
analyzed the ministry’s internal data and discovered the following CDC projects in Georgia:
Project 1320: Antimicrobial Resistance Project
Duration: 01/09/2016 -29/09/2020
Funding: $153,492.40
Project 1440: Introducing or Expanding the Use of Influenza Vaccine Outside the United States
Duration: 30/09/2016 – 29/09/2019
Funding: $750,000
Project 1441: Influenza Surveillance Outside the United States
Duration: 30/09 / 16-29 / 09/21
Funding: $250,000
Project 1446: Strengthening New Generation Sequencing Capacities for Hepatitis C Surveillance in Georgia
Duration: 01/07/2017-30 /06/2018
Funding: $22,000
Project 1447: Samples collection under the Hepatitis C Elimination Program in Georgia – Bio-Bank
Objective: The aim of the project is to store samples collected under the Hepatitis C program for future scientific work
*20,000 plasma/serum samples
*6,000 serum samples from the 2015 National Seroprevalence Survey of Hepatitis C and B
*1,000 blood samples from blood banks
*500 blood samples from patients with terminal liver disease
Duration: 01/07/2017-30/06/2018
Project 1456: Strengthening the micronutrient deficit monitoring system in Georgia
Duration: 01/09/2017 – 31/08/2018
Funding: $92,875
Project 1457: Genetic peculiarities of hepatitis C virus in Georgia and its role in the Georgian Hepatitis C elimination program
Objective: Evaluate morbidity and mortality associated with Hepatitis C virus
Duration: 01/09/2017-31/08/2018
Funding: $127,125
Project 1532: Strengthening, detection, response and prevention of diarrhea outbreaks in Georgia
Duration: 30/09/2017 -29/09/2020
Funding: $40,000
Project 1533: Strengthening Immunization and Vaccination Control System
Duration: 30/09/2017 – 29/09/2020
Funding: $67,220.00
Project 1534: Respiratory Disease Surveillance
Duration: 30/09/2017 – 29/09/2020
Funding: $80,000.00
Project 1535: Enterovirus surveillance Georgia
Duration: 30/09/2017 -29/ 09/2020
Funding: $45,000
Project 1536: National Laboratory Quality Control Program in Georgia
Duration: 30/09/2017 -29 /09/2020
Funding: $56,140
Project 1537: South Caucasus Field Epidemiology and Laboratory Training Program
Duration: 30/09/2017 -29 /09/2020
Funding: $150,000
Project 1538: Fever of unknown etiology caused by arboviruses in the Black Sea region – clinical specimens will be shipped to the CDC Laboratory for analyses
Furthermore, why have US scientists working at the Lugar Center been given diplomatic status and immunity to research deadly pathogensand
insects in Georgia? Diplomatic immunity is a principle of international
law by which foreign government officials are not subject to the
jurisdiction of local courts and other authorities for their activities.
Hence, US scientists could even perform illegal experiments in Georgia without being prosecuted as they have diplomatic immunity.”
Added: Why is there a “Lugar Center” in the Republic of Georgia named for former US Senator Richard Lugar? First, because US Senators aren’t actually US Senators, they’re global dignitaries, certainly much too important for the concerns of rubes who elected them. Second, some Senators stay in office for so long that they have buildings named after them. Third, if you’re pathetic Lugar, with help from US Dept. of Defense, you get a building in a foreign country named after you and paid for by hick US taxpayers. Not to worry, there’s also a Lugar Center in Washington, DC.
France first publishedofficial death estimates for people in care homes on the 31st of March. The % of all deaths among care home residents has ranged from 39.2% to 51%.The most recent numbers published by the Ministry of Health on the 16th June reported a total of 29,547deaths as a result of COVID-19, of which 14,341 (49%) were residents in care homes23.
Of these, 10,457 (73%) died in the care home and were mostly “probable
cases” where a doctor confirmed that the symptoms were associated with
COVID-19. The remaining 3,884 (27%) died in hospital and were confirmed
through testing24.”...
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
…….
After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-67; 73% male) received 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). 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=0.12). 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 fewer hospitalizations.
…………
Keywords
SARS-CoV-2
COVID-19
outpatients
zinc
hydroxychloroquine
azithromycin
…………..
1. INTRODUCTION
…………..
In December 2019, the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started as an outbreak in Wuhan, China. This coronavirus has spread rapidly as a pandemic around the world [1],
causing coronavirus disease 19 (COVID-19) pneumonia, acute respiratory
distress syndrome (ARDS), cardiac injury, liver and renal injury,
thrombosis, and death [2].
Due to the lack of vaccines as well as SARS-CoV-2
specific therapies, the proposed use of repurposed antiviral drugs
remains a valid practical consideration [8]. One of the most controversial drugs during the current SARS-CoV-2 pandemic is the well-known
oral antimalarial drug hydroxychloroquine (HCQ), routinely used in the
treatment of autoimmune diseases like rheumatoid arthritis or lupus [9, 10]. HCQ is currently listed as an essential medication for lupus by the World Health Organization (WHO) [11]. With more than 5.6 million prescriptions in the United States, HCQ was the 128th most commonly prescribed medication in 2017[12].
In the meantime, first observational studies concluding beneficial
therapeutic effects of HCQ as monotherapy or in combination with the
antibiotic azithromycin were reported just a few weeks after the start of the SARS-CoV-2 outbreak [13]. All studies that used HCQ with rather contradictory results were done with hospitalized and often sicker patients[13], [14], [15], [16] and one publication was recently withdrawn [17, 18].
Antiviral effects of HCQ are well-documented [19].
It is also known that chloroquine and probably HCQ have zinc ionophore
characteristics, increasing intracellular zinc concentrations [20]. Zinc itself is able to inhibit coronavirus RNA-dependent RNA polymerase activity (RdRp) [21]. It has been hypothesized that zinc may enhance the efficacy of HCQ in treating COVID-19 patients [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[6].
Regardless of the established antiviral effects of zinc and that many
COVID-19 patients are prone to zinc deficiencies, dependent on
comorbidities and drug treatments [22], none of these studies were designed to include zinc supplementation as combination treatment.
This first retrospective case series study with COVID-19 outpatients was done to show whether a) a simple to perform outpatient risk stratification might allow for rapid treatment decision shortly after onset of symptoms, and b) whether the triple 5-day therapy with zinc, low dose HCQ, and azithromycin might result in less hospitalizations and less fatalities compared with relevant public reference data of untreated patients.
2. METHODS
2.1. SETTING
This retrospective case series study analysed data from
COVID-19 outpatients with confirmed severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) infection treated in a community in New York
State, USA between March 18, 2020 and May 14, 2020. Outcome of patients
who were treated with a specific triple therapy was compared to public
reference data of patients in the same community who were not treated
with this therapy.
2.2. CONFIRMATION OF COVID-19 DIAGNOSIS
COVID-19 diagnosis was confirmed if patients were positively tested for SARS-CoV-2 by means of PCR of nasal or pharyngeal swab specimens (majority of tests by Roche, Basel;
99,1% sensitivity and 99,7% specificity; other tests used with lower
frequency included: Diasorin: 500 copies/mL; ThermoFisher: 10 genomic
copy equivalents/reaction; Seegene: 1,250 copies/mL; Hologic: TCID50/mL:
1 × 10-2) or retrospectively by IgG detection tests (DiaSorin: Sensitivity 97.6% (≥ 15 days after diagnosis),
specificity 99.3%; Diazyme: Sensitivity 91.2%, specificity 97.3%). Only
patients who did have a record of a positive test result were included
in the analysis. The PCR assays were authorized by the Food and Drug Administration (FDA) without
clinical sensitivity/specificity data due to the urgent nature of the
pandemic. Only one positive test was necessary for the patient to be
included in the retrospective analysis.
2.3. PATIENTS
Sequentially consecutive COVID-19 outpatients older than 18 years at diagnosis were included in the analysis as treatment group. All patients were white. Patients received a prescription for the triple therapy only if they met one of the following risk stratification requirements during a medical office-based or telehealth consultation:
Group A: age >60 years; with or without clinical symptoms;
Group B: age ≤60 years and shortness of breath (SOB);
Group C: age ≤60 years, clinically symptomatic and with at least one of the following comorbidities: hypertension, hyperlipidemia, diabetes, obesity (body mass index ≥ 30 kg/m2),
cardiovascular disease, heart failure, history of stroke, history of
deep vein thrombosis or pulmonary embolism, asthma, chronic obstructive
pulmonary disease (COPD), other lung disease, kidney disease, liver
disease, autoimmune disease, or history of cancer. Pregnant women, if any, were to be included in this group as well.
Laboratory confirmed COVID-19 patients of the same
community who were not treated with the described triple therapy and
related outcome data represented the untreated control group which comprised both low risk and high risk patients (public reference data).
2.4. PROCEDURE AND TREATMENT
Data of treated patients were collected from electronic
health records in the year 2020. Demographics, as reported by the
patient, and a current medical history of hypertension, hyperlipidemia,
diabetes, obesity (body mass index ≥ 30 kg/m2),
cardiovascular disease, heart failure, stroke, asthma, COPD, other lung
disease, kidney disease, liver disease, autoimmune disease, history of
cancer, thyroid disease psychiatric disorder, or pregnancy were
collected.
The presence of the following clinical symptoms of treated patients were documented: cough/dry cough, fever, SOB,
changes of or no smell or taste, sore throat, headache, runny
nose/clear rhinorrea, sinus congestion, diarrhea/vomiting, cold
symptoms, feeling sick, weakness, and low back pain. If reported, number of days since onset of symptoms was documented.
The following vital signs,
if available, were collected and documented: heart rate (beats per
minute), breaths per minute (BPM), systolic and diastolic blood pressure
(mmHg), body temperature (°C), oxygen saturation measured by pulse
oximetry (O2 %), body weight (kg), and/or body mass index (BMI).
Main co-medications were characterised based on primary care prescriptions active at the time of diagnosis, were documented
as categorical variables and included: beta-blockers,
angiotensin-converting enzyme inhibitors, angiotensin-2 antagonists,
calcium channel blockers, hydrochlorothiazide, statins, bronchodilators,
antidiabetics, and insulin.
Only diagnosed COVID-19 patients who met the
defined risk stratification requirements of group A, B, or C got a
prescription for the following triple therapy for 5 consecutive days in
addition to standard supportive care: zinc sulfate (220 mg capsule once
daily, containing 50 mg elemental zinc), HCQ (200 mg twice daily), and
azithromycin (500 mg once daily). No loading dose was used. Patients
who did not meet the risk stratification requirements received standard
of care to treat common upper respiratory infection. Patients were not treated with HCQ if they had known contraindications, including QT prolongation, retinopathy, or glucose-6-phosphate dehydrogenase (G6PD) deficiency.
As usual and following best practice patients were informed about
possible drug related side effects. Reported events, if any, were
documented as required.
The selection of the used zinc supplement and drugs, dosages and the combination thereof, were based on treatment guidelines, positive reports from other countries like South Korea, emerging first clinical evidence, and based on the discretion of the treating physicians.
2.5. OUTCOME
Two outcomes were studied: COVID-19 related hospital admission and all-cause death during time of follow up of at least 28 days in the treatment group and
in the untreated control group (public reference). The outcome of
COVID-19 patients in the untreated control group was reported by the
responsible health department.
2.6. STATISTICAL ANALYSES
Only patients in the treatment group who met the defined risk stratification requirements
and who received at least a prescription for HCQ, with or without zinc,
for 5 days, were included in the retrospective analysis and were
categorized accordingly. If the patient’s electronic health record did
not include information on a clinical characteristic, it was assumed
that the characteristic was not present. In the group of the public
reference data only confirmed COVID-19 patients who were not treated in
the respective general practice with the triple therapy were included in
the analysis. For this untreated control group only outcome data for
hospitalization and all-cause death was available and used for the
statistical comparison with the treatment group.
No sample-size calculations were performed. Descriptive
statistics are presented as median and interquartile range (IQR) for
continuous variables and frequencies for categorical variables. For
comparison with results of other studies means and standard deviations
were calculated as needed. Normality of distribution for continuous variables was assessed by the Shapiro-Wilk-Test.
A 2-tailed Student’s t-test was used for parametric analysis, and a
Wilcoxon Signed-Rank test was used for nonparametric data analysis. For
calculation of correlation the point biserial correlation coefficient
was applied if one variable was dichotomous. Associations between two
categorical variables were calculated with the Chi-Square test. Odds
ratio (OR) were calculated for comparison of the outcome of the
treatment group with the untreated control group. The α: 0.05 was
considered as a significance level. The data were analysed using Microsoft Excel for Microsoft 365 MSO (32-Bit), the Excel add-on Real Statistics, SigmaStat 4, and Sigma Plot 14.0.
2.7. STUDY APPROVAL
The study was approved by the Western Institutional Review Board and
it was exempt under 45 CFR § 46.104(d)(4). Reference number:
D4-Excemption-Zelenko (06-16-2020). The analysis was conducted with
de-identified patient data, according to the USA Health Insurance Portability and Accountability Act (HIPAA), Safe Harbor. For that reason exact dates and locations are not mentioned in this study.
3. RESULTS
3.1. PATIENTS
In accordance with available public reference
data, 712 confirmed SARS-CoV-2 PCR positively tested COVID-19 patients
were reported for the respective community at the defined time point of the analysis. Of these 712 patients, 335 presented as outpatients at a general practice
and 127 were treated with the triple combination therapy. Of these 127
patients, 104 met the risk stratification criteria and were included in
the analysis (table 1). 208
patients of the 335 did not meet the defined risk stratification
criteria were treated with standard of care and recovered at home.
The SARS-CoV-2 infection of 37 additional patients who were clinically
diagnosed with COVID-19, who met the risk stratification criteria and
who were also treated with the triple therapy, was later confirmed by
IgG tests (table 1). These patients were included additionally in the analysis resulting in a total number of 141 patients,
all with a confirmed SARS-CoV-2 infection by PCR or IgG tests. None of
these patients were lost to follow-up for the defined outcome. The
outcome of the remaining N=377 positively tested but not treated
COVID-19 patients, e.g. from other practices of the community, served as
public reference (fig 1). Analysis of the 141 patients in the treatment group showed that all of these patients (100%) got a prescription of HCQ,136 (96.5%) of zinc sulfate, and 133 (94.3%) of azithromycin, while 1 patient (0.7%) got doxycycline instead. Instead of the triple therapy, 1 (0.7 %) patient in the treatment group got HCQ only, 7 (5%) patients got HCQ and zinc, and 4 (2.8%) patients got HCQ and azithromycin.
Table 1. COVID-19 Diagnostics by PCR and IgG tests of Patients in the Treatment Group
Figure 1. Study population. N=141 COVID-19 patients, all with a laboratory-confirmed SARS-CoV-2 infection,
were included in the analysis as treated group. N=377 positively tested
COVID-19 patients of the public reference were included in the analysis
as untreated group.
3.2. BASELINE CHARACTERISTICS OF THE PATIENTS
Table 2 shows the baseline demographics and clinical characteristics of all 141
patients in the treatment group and for the risk stratification groups
A, B, and C. 69 patients (49%) belonged to group A, 48 (34%) to group B,
and 24 (17%) to group C. Age ranged from 18 to 80 years and the median
age was 58 years with an interquartile range (IQR) of 40-67. The median age of group A, B, and C was 67, 39, and 45 years. A total of 103 patients (73.1%) were male with a male-to-female ratio of 2.71. Most common comorbidities included hypertension (28%), obesity (28%), hyperlipidemia (23%), and diabetes (18%),
whilst least common ones were liver disease (2%), heart failure (1%),
and stroke (1%). One patient was pregnant (1%) at initiation of
treatment. There was a positive and significant correlation between age and hypertension
(r=0.3309, p=0.001), hyperlipidemia (r=0.26306, p<0.001), and
cardiovascular disease (r=0.16757, p<0.05), while asthma was
negatively correlated with age (r=-0.30867, p<0.001).
Table 2. Baseline Demographics and Clinical Characteristics of Patients in the Treatment Group*
Characteristics
Risk Stratified Group A (N=69)
Risk Stratified Group B (N=48)
Risk Stratified Group C (N=24)
All Patients Treatment Group (N=141)
Median age (IQR) ̶ years
67 (64-69)
39 (24-47)
45 (36-50)
58 (40-67)
Male sex ̶ no. (%)
46 (67)
40 (83)
17 (71)
103 (73)
Coexisting conditions ̶ no. (%)
Any condition
44 (64)
31 (65)
24 (100)
99 (70)
Hypertension
27 (39)
4 (8)
8 (33)
39 (28)
Hyperlipidemia
21 (30)
7 (15)
5 (21)
33 (23)
Diabetes
16 (23)
4 (8)
5 (21)
25 (18)
Obesity
20 (29)
10 (21)
10 (42)
40 (28)
Cardiovascular Disease
9 (13)
1 (2)
3 (13)
13 (9)
Heart Failure
2 (3)
0 (0)
0 (0)
2 (1)
Stroke
1 (2)
0 (0)
0 (0)
1 (1)
Asthma
2 (3)
9 (19)
2 (8)
13 (9)
COPD
0 (0)
0 (0)
0 (0)
0 (0)
Other Lung Disease
6 (9)
5 (10)
4 (17)
15 (11)
Kidney Disease
1 (2)
3 (6)
2 (8)
6 (4)
Liver Disease
1 (2)
2 (4)
0 (0)
3 (2)
Autoimmune Disease
2 (3)
4 (8)
4 (17)
10 (7)
History of Cancer
6 (9)
2 (4)
1 (4)
9 (6)
Thyroid Disease
7 (10)
4 (8)
2(8)
13 (9)
Psychiatric Disorder
7 (10)
4 (8)
5 (21)
16 (11)
Pregnancy
–
–
1 (4)
1 (1)
⁎IQR interquartile range
Median time between onset of clinical symptoms and medical consultation was 4 days (IQR 3-6; available for 66/141 patients, mean 4.8 days ± 2.7) (table 3).
There was no significant correlation between age and days of onset of
clinical symptoms to consultation (p>0.05). Days from onset of
symptoms to consultation were not significantly different between groups
(p>0.05).
Table 3. Patients with Reported Days Since Onset of Symptoms in the Treatment Group
Characteristics
Risk Stratified Group A (N=69)
Risk Stratified Group B (N=48)
Risk Stratified Group C (N=24)
All Patients Treatment Group (N=141)
Patients with reported days ̶ no. (%)
32 (46)
25 (48)
9 (38)
66 (47)
Median days since onset of symptoms ̶ (IQR)
4 (3-6)
3 (3-6.5)
4 (3-5.5)
4 (3-6)
Most common clinical symptoms included cough (87.2%), fever (77.3%), SOB (46.1%), and changes of or no smell or taste (30%), whilst least common ones were sinus congestion (16%), diarrhea/vomiting (5%), and low back pain (3%). Table 4
shows symptoms of all patients and stratified by groups A, B, and C.
There was a significant negative correlation between age and changes of
smell or taste (r=-0.43, p<0.001). No patient had a clinical diagnosis of pneumonia.
Table 4. COVID-19 Diagnostics and Baseline Reported Clinical Symptoms of Patients in the Treatment Group
Clinical Symptoms ̶ no. (%)
Risk Stratified Group A (N=69)
Risk Stratified Group B (N=48)
Risk Stratified Group C (N=24)
All Patients Treatment Group (N=141)
Cough/Dry Cough
60 (87)
39 (81)
24 (100)
123 (87)
Fever
53 (77)
38 (79)
18 (75)
109 (77)
Shortness of Breath (SOB)
17 (25)
48 (100)
0 (0)
65 (46)
Changes of or no smell or taste
21 (30)
19 (40)
2 (8)
42 (30)
Sore Throat
19 (28)
8 (17)
7 (29)
34 (24)
Headache
19 (28)
6 (13)
7 (29)
32 (23)
Runny Nose/Clear Rhinorrhea
16 (23)
8 (17)
4 (17)
28 (20)
Sinus Congestion
10 (15)
9 (19)
4 (17)
23 (16)
Diarrhea/Vomiting
1 (2)
5 (10)
1 (4)
7 (5)
Cold Symptoms
31 (45)
16 (33)
12 (50)
59 (42)
Feels Sick
40 (58)
38 (79)
17 (71)
95 (67)
Weakness
44 (64)
22 (46)
11 (46)
77 (55)
Low Back Pain
3 (4)
0 (0)
1 (4)
4 (3)
Table 5 shows vital signs, as they were available, for all patients and by group A, B, and C.
Many patients consulted the general practice during the COVID-19 crisis
via telehealth so vital signs were not available for all of these
patients. The highest proportion of patients had available measurements
for heart rate (63%) and pulse oximetry (60%). Vital signs were not
significantly different between risk stratification groups (p>0.05)
except for systolic blood pressure of group A and B (p<0.05).
Table 5. Physical Examination – Vital Signs of Patients in the Treatment Group
Parameter
Patients with available Parameters ̶ no. (%) of N=141
Median Heart Rate ̶ beats per minute ̶ (IQR)
86 (80-94)
89 (63)
Median Breaths per Minute [BPM] ̶ (IQR)
16 (15-18)
43 (31)
Median Systolic Blood Pressure [mmHg] ̶ (IQR)
126 (120-139)
66 (47)
Median Diastolic Blood Pressure [mmHg] ̶ (IQR)
80 (74-85.5)
66 (47)
Median Body Temperature [°C] ̶ (IQR)
37.2 (37-37.8)
79 (56)
Median Pulse Oximetry [O2 %] ̶ (IQR)
97 (96-98)
85 (60)
Median Body Weight [kg] ̶ (IQR)
88 (72.6-98.4)
43 (31)
Median Body Mass Index [kg/m2] ̶ (IQR)
32.2 (28.5-36.3)
30 (21)
Table 6
summarizes most important co-medications. 16% of patients were taking
angiotensin-converting enzyme inhibitors, angiotensin-2-antagonists,
hydrochlorothiazide or a combination thereof. The most common long-term
therapies at the time of COVID-19 diagnosis were statins (20%),
beta-blockers (12%), and insulin (18%). A few patients had chronic
prescriptions for oral corticosteroids (9%), because of co-morbidities
like asthma or autoimmune diseases and 3 patients (2%) got an additional
antibiotic (levofloxacin) because of superinfections.
Table 6. Co-Medications of Patients in the Treatment Group
Drug Class
Patients ̶ no. (%) of N=141
Betablockers
17 (12)
Angiotensin-converting enzyme inhibitors
8 (6)
Angiotensin-2 Antagonists
13 (9)
Calcium channel blockers
8 (6)
Hydrochlorothiazide
6 (4)
Statins
28 (20)
Bronchodilators
10 (7)
Antidiabetics
11 (8)
Insulin
26 (18)
Oral Corticosteroids
13 (9)
Antibiotics
3 (2)
3.3. HOSPITALIZATIONS AND ALL-CAUSE DEATH
In the treatment group 4 of 141 patients were hospitalized, which was significantly less than in the untreated group with 58 of 377 patients (15.4%), (fig 2.), (OR 0.16; [95% CI, 0.06 to 0.5]; p<0.001), (table 7, fig 4). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated patients. All hospitalized patients were male, one in his twenties, two in their forties, and one in his seventies. Three
of the 4 hospitalized patients (75%) belonged to risk stratification
group B and one to group A (25%). All patients (100%) reported SOB at
time of consultation. Median days from onset of symptoms to consultation
were 4 days. Of the treatment group 1 patient had to stay only one day in hospital, 2 other patients were discharged as cured, and 1 patient died (s. below). No patient was on a ventilator.
Figure 2. Hospitalization. Treatment with the triple therapy
zinc, low dose HCQ, and azithromycin was associated with significantly
less hospitalizations in comparison to untreated patients of the public
reference data. X2 (1, N=518)=14.17, *P<0.001
Table 7. Clinical Outcome in the Treated Patient Group versus the Untreated Patient Group
Outcome
Treated Group ̶ no. (%) of N=141
Untreated Group ̶ no. (%) of N=377
Odds Ratio
95% CI
P-value
Hospitalization
4 (2.8)
58 (15.4)
0.16
0.06-0.5
<0.001
All-cause death
1 (0.71)
13 (3.5)
0.2
0.03-1.5
0.12
CI=Confidence Interval
One of the 141 patients (0.71%) who belonged to treatment
group A died after being hospitalized. This patient had a history of
cancer and did only take one daily dose of the triple therapy before
hospital admission. With 13 of 377 patients (3.5%, fig 3) more patients died in the untreated group (OR 0.2; [95% CI, 0.03 to 1.5]) (table 7, fig 4).
Although the odds of all-cause death of treated patients were 80% less
than in the untreated group, this difference did not reach statistical
significance (p=0.12).
Figure 3. All-cause deaths. Treatment with the triple therapy
zinc, low dose HCQ, and azithromycin was associated with numerically
less all-cause deaths in comparison to untreated patients of the public
reference data. n.s.=not significant. X2 (1, N=518)=1.98, P=0.16
Figure 4. Odds ratios. The odds of hospitalization of the treated patient group were 84% less than in the untreated patient group,
and was statistically significant (p<0.001). The odds of all-cause
death of the treated patient group were 80% less than in the untreated
patient group, but did not reach statistical significance (p=0.12).
CI=Confidence Interval.
All patients of the treatment group with
the clinical outcome hospitalization or all-cause death got a
prescription for the complete triple therapy zinc, low dose
hydroxychloroquine, and azithromycin.
The outcome of the 3 different risk-stratified groups A), B), and C) was not significantly different.
The 208 patients presenting at the general practice who did not meet the risk stratification requirements and who were not treated with the triple therapy recovered at home and no hospital admissions or deaths were reported.
3.4. SAFETY
In general, the triple therapy with zinc, low dose HCQ, and azithromycin was well tolerated. After initiation of treatment 30 of 141 patients (21%) reported weakness, 20 (14%) nausea, 15 (11%) diarrhea, and 2 (1%) rash (table 8). No patient reported palpitations or any cardiac side effect.
Table 8. Summary of Adverse Events
Event
Patients ̶ no. (%) of N=141
Any adverse event
67 (48)
Weakness
30 (21)
Nausea
20 (14)
Diarrhea
15 (11)
Rash
2 (1)
......
4. DISCUSSION
This first retrospective case series study with COVID-19 outpatients in primary care setting
showed that risk-stratified treatment early after onset of clinical
symptoms, with the triple therapy zinc, low dose HCQ, and azithromycin
was associated with significantly less hospitalizations (odds ratio 0.16; p<0.001) in comparison to untreated patients
(public reference data) of the same community. Based on the performed
risk stratification prevalence of the comorbidities hypertension,
hyperlipidemia, and diabetes were the highest in group A (>60 years
and clinical symptoms), asthma and other lung diseases were the highest
in group B (<60 years and SOB), and obesity and autoimmune disease
were the highest in group C (<60 years, clinical symptoms, and
defined comorbidities). Most frequent symptoms of these COVID-19
patients were cough followed by fever while available median body
temperature measurements were in a normal range. Almost 50% of
risk-stratified and treated patients were suffering from SOB while
breaths per minute and blood oxygen saturation were still in the normal
range. Median time from onset of symptoms to first medical
consultation was 4 days (IQR 3-6). Approximately 16% of patients
received co-medications known to be associated with zinc deficiency,
such as antihypertensive drugs. No patient experienced any known severe
adverse events that were considered drug related during treatment or
follow up.
A growing number of reports provide evidence for for the effectiveness or otherwise of a range of COVID-19 drug treatments. Therefore,
a living systematic review and network meta-analysis was published to
assess how trustworthy the evidence is using the Grading of
Recommendations Assessment, Development, and Evaluation (GRADE) approach
[24]. Based
on their most recent update from July 21, 2020 the authors conclude
that glucocorticoids probably reduce mortality and mechanical
ventilation in patients with COVID-19 compared with standard care.However,
the effectiveness of most interventions is uncertain because most of
the randomised controlled trials have been small so far and have
important study limitations [24].
Another meta-analysis focused on the effectiveness of chloroquine derivatives in COVID-19 therapy [25].
The authors concluded that chloroquine derivatives are effective in
improving clinical and virologic outcomes and may reduce mortality by a
factor of 3 in patients affected with COVID-19. They further conclude that big data are lacking basic treatment definitions and are subject of conflict of interest [25]. At the time of this manuscript submission, only one peer-reviewed study had analyzed the key health outcomes of COVID-19 patients diagnosed in primary care setting [3]. Because of this gap in data, the value of this study is multifold. It
provides much needed recommendations for risk stratification and a
treatment regimen to prevent hospitalization and death of COVID-19
patients. Diagnosis of COVID-19 for all patients in this
analysis was confirmed by PCR or IgG tests compared with a recent study
in which less than 3% had a diagnosis confirmed by laboratory tests [26]. To
start the triple therapy as early as possible after symptom onset is
critical for treatment success, because SARS-CoV-2 viral load seems to
peak at day 5 to 6 after symptom onset [27], [28], [29] and severe cases progress to acute respiratory distress syndrome (ARDS) after only 8 to 9 days [30, 31]. Early antiviral treatment is an established protocol to manage severe disease progression, as was shown, for example, by a cumulative case control study during the 2009 H1N1 influenza pandemic in Canada [32].
For patients at high risk for severe viral disease progression, it is
recommended to start antiviral therapy as early as possible [33, 34]. Early treatment might be also critically important to effectively reduce SARS-CoV-2 viral load [5], and this underscores the role of early intervention by primary care physicians as reported herein.
A further strength of this approach was the simple risk stratification of symptomatic outpatients to determine the need for therapy, a strategy not yet applied in COVID-19 primary care[35], but routinely implemented in primary care for other diseases [36]. Underlying assumptions of the risk stratification used in this setting are different than other recommendations [37]. Here, age stratified high risk was defined as >60 years (typically defined as >65 years) to encompass the common increase of comorbidity incidences in this age group [38].
Patients ≤60 years with SOB, even without reduced pulse oximetry
values, were treated because it was assumed virus will likely spread
from upper to lower respiratory tract [39]. Also treated were patients ≤60 years with clinical symptoms and prognostically relevant comorbidities[37]. By applying this risk stratification approach, respective care was tailored to patients with a higher likelihood for hospitalizations or fatalities, which ensured that the medical principles of “patient first” and “doing no harm” were maintained [40]. As a result, 62% of COVID-19 patients were treated with standard of care only and recovered at home, and only 38% needed treatment with the triple therapy.
The antiviral potential of HCQ was broadly described in vitro and in vivo[41], [42], [43]. HCQ has a long terminal elimination half-life of 32 days in plasma and 50 days in blood [44]. Therefore, the treatment approach was conservative,
with starting dose being the same as maintenance dose and with a short
treatment duration of only 5 days, being even more conservative than
other recommendations [42]. HCQ-dependent intracellular increases in pH might directly interfere with pH-dependent SARS-CoV-2 replication [19].
Also, chloroquine and probably HCQ have characteristics of a zinc
ionophore resulting in increasing intracellular zinc concentrations [20]. The
dose of elementary zinc in this study was similar to doses previously
studied to successfully prevent infections in the elderly[45]. Antiviral effects of zinc against a variety of viruses have been demonstrated during the last decades [46]. Zinc, in addition to its role as a general stimulant of antiviral immunity, is known to specifically inhibit coronavirus RNA-dependent RNA polymerase [21]. Based on HCQ’s ionophore properties, it has been hypothesized that zinc may enhance the efficacy of HCQ in treating COVID-19 patients [22]. In addition, zinc might inhibit the serine protease furin [47]. Furin is expressed on endothelial cells, monocytes/macrophages, and smooth muscle cells in human atherosclerotic plaques [48] and therefore might play a critical role for the severe cardiovascular complications of COVID-19. As furin might be responsible to favor SARS-CoV-2 spreading compared with other beta coronaviruses [49, 50] and as furin-inhibition protects from certain viral-dependent infections [51], it may be important to evaluate the potential role of zinc in inhibiting this pathway.
Azithromycin was added to the treatment regimen as preliminary data provides evidence for more efficient or synergic virus elimination in conjunction with bacterial superinfection [13, 52]. Although there is a synergistic antiviral effect between zinc, HCQ, and azithromycin, zinc supplementation may be instrumental for the outcome of patient populations with severe clinical courses. Zinc deficiency was confirmed in a large number of healthy elderly [53] and in diabetic patients[54].
In addition, it has been documented that the antihypertensive drugs
hydrochlorothiazide, angiotensin-converting-enzyme inhibitors, and
angiotensin 2 receptor antagonists can result in an increased urinary
excretion of zinc with subsequent systemic zinc deficiency [55]. Age, comorbidities, and relevant co-medications align well with the majority of described COVID-19 patients at high risk, including the risk-stratified population of this analysis. Zinc deficiency might explain why certain patient groups seem not to benefit from HCQ in monotherapy. During
the 5-day treatment with the triple therapy and during follow up, no
severe adverse events were observed and no cases of cardiac arrhythmia
were reported in this general practice, which is in accordance with
available safety data of more than 300,000 patients [56].
Inherent to all retrospective analyses, our study has certain limitations such as non-randomization and blinding of treatment.
Also, only the outcome data of the untreated control group based on the
public reference were available; because no other data on patient
characteristics or clinical symptoms were available no risk adjustment
was possible. Therefore, confounding factors and selection bias, among
other issues, might exist. The demographic composition of the treatment
group might have also had an influence on our findings. Because many physician appointments had to be managed by telehealth, vital parameters were not available for the majority of patients. Viral load and ECG data were not analyzed. Treatment with the triple therapy resulted in a numerically lower rate of all-cause deaths. In
the absence of clinical details about the untreated patient group, the
lower rate of all-cause death in the treated group was not statistically
significant. However, the patients in the treated group were
all positively risk-stratified while the risk of the untreated group was
obviously lower as this group included high- and low-risk patients. When we compared the outcome of all risk-stratified patients in the study group (treated and non-treated) with the control patients (not stratified, treated with standard therapy), hospitalization and all-cause death were significantly less in the study group (p<0.0001
and p = 0.0154, respectively). These data were not shown in the results
section because relevant clinical information was not completely
available for all patients in the control group to allow risk adjustment
between groups.
In this study, the ratio of males and average age was
comparable with a relevant number of other studies, but distribution of
comorbidities was not [57].
The latter was expected because outpatients usually have a different
distribution of age and especially of comorbidities than critically ill
inpatients. As expected the prevalence of hypertension, hyperlipidemia, and cardiovascular disease correlated positively with age
while asthma correlated negatively. Approximately 50% of
risk-stratified and treated patients presented with SOB while the
parameters breaths per minute and blood oxygen saturation were still
within the normal range. These patients would usually not be considered for hospital admission, although SOB might be considered an alarming early sign of disease progression. Based on the implemented risk stratification, these patients were identified and treated immediately.
Indeed, 3 of 4 hospitalized patients were in risk stratification group B including patients especially with SOB and also the hospitalized patient of group A reported SOB at time of consultation. This supports the assumption that COVID-19 patients with SOB are at much higher risk for disease progression and need to be monitored closely.
In contrast to many other studies, the most frequent symptom was cough and not fever [58, 59].
Changes in smell or taste in one third of patients and a negative
correlation with age were similar to findings from other groups[60]. While mean time from onset of symptoms to treatment was only 4.8 days (median 4 days), previously reported time spans range from 6.3 days [61], to 8 days[16], up to 16.6 days[14], or it was often even not reported[62].
In most of these studies, COVID-19 disease had most likely already
progressed at the time of presentation to stages II or even stage III of
the disease[6].
In many studies, often only limited information is provided about
co-medications and specifically about clinical symptoms at admission [62]. The
latter would be very important to better understand the differences of
clinical presentation between inpatients and outpatients, and thus the urgency for early anti-COVID-19 treatment in outpatient setting [63]. The potential of zinc to enhance the antiviral efficacy of HCQ was already described in detail elsewhere [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 [64].
These and our findings indicate that proper dosing of HCQ with its long
half-life might be key for the favourable outcome of COVID-19 patients.
In critical care, drugs with short half-lives are usually preferred.
Especially in critically ill COVID-19 patients, higher doses of HCQ may
have unforeseeable effects, for example, on insulin sensitivity in obese
patients [65] and glucose levels in diabetics [66, 67]. Besides glucose levels, it is important to closely monitor renal function which is increasingly affected during progression of COVID-19 [68]. Because
HCQ is substantially excreted by the kidneys, the risk of toxic
reactions is greater in patients with impaired renal function [69].
4.1. POTENTIAL IMPLICATIONS FOR CLINICIANS AND POLICY MAKERS
Clinical experience from severely ill inpatients with pneumonia who were treated with high dose HCQ are not readily transferable to the outpatient setting with upper respiratory disease only.
For outpatients with a median of only 4 days after onset of symptoms,
COVID-19 represents a totally different disease and needs to be managed
and treated differently [63]. A simple to perform outpatient risk stratification, as shown here, allows rapid treatment decisions and treatment with the triple therapy zinc, low dose HCQ, and azithromycin and may prevent a large number of hospitalizations and probably deaths during the SARS-CoV-2 pandemic. This might also help to avoid overwhelming of the health care systems.
Declaration of Competing Interest
The author Roland Derwand is/was at the time of writing an employee of Alexion Pharma Germany GmbH. His engagement and contribution to this study and publication was private and independent from his employer. The author Martin Scholz is/was at the time of writing External Senior Advisor for the company LEUKOCARE in Munich, Germany, and is/was Managing Director at Starts- and -Ups Consulting, Frankfurt, Germany. Vladmir Zelenko is/was general practitioner in New York State. All three authors confirm that this article content has no conflict of interest.
Acknowledgements
We thank all the patients and families involved in this
study; the practitioners Dr. Rosy Joseph, Dr. Avery Knapp, Dr. Hillel
Isseroff, Dr. William Grace, Dr. Sam Sandowski, and Dr. James Todaro for
medical support; Chandra Duggirala, and Manoj Duggirala for operational
and technical support; Mendel Mochkin (CrowdProtocol Foundation) for
supporting the IRB submission; the reviewers Vjosa C. Mujko (Invivo
Brands LLC) and Tzvi Jacobs who improved the language of this
publication.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethical Approval
The study was approved by the Western Institutional Review Board and it was exempt under 45 CFR § 46.104(d)(4). Ref. Number: D4-Excemption-Zelenko (06-16-2020)
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support
from any organisation for the submitted work; no financial
relationships with any organisations that might have an interest in the
submitted work in the previous three years; no other relationships or
activities that could appear to have influenced the submitted work.
REFERENCES
[1] D. Wu, T. Wu, Q. Liu, et al.The SARS-CoV-2 outbreak: What we know
[2] D. Atri, H.K. Siddiqi, J. Lang, et al. COVID-19
for the Cardiologist: A Current Review of the Virology, Clinical
Epidemiology, Cardiac and Other Clinical Manifestations and Potential
Therapeutic Strategies
[7] A.M. Fry, D. Goswami, K. Nahar, et al.Efficacy
of oseltamivir treatment started within 5 days of symptom onset to
reduce influenza illness duration and virus shedding in an urban setting
in Bangladesh: a randomised placebo-controlled trial
[9] D.J. Wallace The
use of chloroquine and hydroxychloroquine for non-infectious conditions
other than rheumatoid arthritis or lupus: a critical review
[10] C. Gordon, M.B. Amissah-Arthur, M. Gayed, et al.The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults
[13]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. Int J Antimicrob Agents 2020:105949. doi:
10.1016/j.ijantimicag.2020.105949 [published Online First: 2020/03/25]
[16] M. Mahevas, V.-T. Tran, M. Roumier, et al.No
evidence of clinical efficacy of hydroxychloroquine in patients
hospitalized for COVID-19 infection with oxygen requirement: results of a
study using routinely collected data to emulate a target trial
[17]Mehra
M.R., Ruschitzka F., Patel A.N. Retraction—Hydroxychloroquine or
chloroquine with or without a macrolide for treatment of COVID-19: a
multinational registry analysis. The Lancet doi:
10.1016/S0140-6736(20)31324-6
[18]The
Lancet E. Expression of concern: Hydroxychloroquine or chloroquine with
or without a macrolide for treatment of COVID-19: a multinational
registry analysis. The Lancet doi: 10.1016/S0140-6736(20)31290-3
[21] A.J. te Velthuis, S.H. van den Worm, A.C. Sims, et al.Zn(2+)
inhibits coronavirus and arterivirus RNA polymerase activity in vitro
and zinc ionophores block the replication of these viruses in cell
culture
[22] R. Derwand, M. ScholzDoes
zinc supplementation enhance the clinical efficacy of
chloroquine/hydroxychloroquine to win today’s battle against COVID-19?
[23] P. Carlucci, T. Ahuja, C.M. Petrilli, et al.Hydroxychloroquine
and azithromycin plus zinc vs hydroxychloroquine and azithromycin
alone: outcomes in hospitalized COVID-19 patients
[25]Million
M., Gautret P., Colson P., et al. Clinical Efficacy of Chloroquine
derivatives in COVID-19 Infection: Comparative meta-analysis between the
Big data and the real world. New Microbes and New Infections. https://doi.org/ 10.1016/j.nmni.2020.100709
[35]Esper
R.B., da Silva R.S., Oikawa F.T.C., et al. Empirical treatment with
hydroxychloroquine and azithromycin for suspected cases of COVID-19
followed-up by telemedicine. In: Prevent Senior Institute SP, Brazil,
ed. São Paulo, 2020:25
[38] M. van den Akker, F. Buntinx, J.F. Metsemakers, et al.Multimorbidity in general practice: prevalence, incidence, and determinants of co-occurring chronic and recurrent diseases
[42] X. Yao, F. Ye, M. Zhang, 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)
[45] A.S. Prasad, F.W. Beck, B. Bao, et al.Zinc
supplementation decreases incidence of infections in the elderly:
effect of zinc on generation of cytokines and oxidative stress
[48] P. Stawowy, H. Kallisch, N. Borges Pereira Stawowy, et al.Immunohistochemical localization of subtilisin/kexin-like proprotein convertases in human atherosclerosis
[49] B. Coutard, C. Valle, X. de Lamballerie, et al.The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade
[50] J.K. Millet, G.R. WhittakerHost cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein
[51] S.A. Shiryaev, A.G. Remacle, B.I. Ratnikov, et al.Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens
[52] J. Andreani, M. Le Bideau, I. Duflot, et al.In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect
[53] R.B. Ervin, J. Kennedy-StephensonMineral
intakes of elderly adult supplement and non-supplement users in the
third national health and nutrition examination survey
[54] R.A. Anderson, A.M. Roussel, N. Zouari, et al.Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus
[56] J.C.E. Lane, J. Weaver, K. Kostka, et al.Safety
of hydroxychloroquine, alone and in combination with azithromycin, in
light of rapid wide-spread use for COVID-19: a multinational, network
cohort and self-controlled case series study
[57] S. Richardson, J.S. Hirsch, M. Narasimhan, et al.Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area
[61] M. Million, J.C. Lagier, P. Gautret, et al.Early
treatment of COVID-19 patients with hydroxychloroquine and
azithromycin: A retrospective analysis of 1061 cases in Marseille,
France
[63] H.A. Risch Early
Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that
Should be Ramped-Up Immediately as Key to the Pandemic Crisis
[64] Yu
B., Li C., Chen P., et al. Low dose of hydroxychloroquine reduces
fatality of critically ill patients with COVID-19. Sci China Life Sci
2020:1-7. doi: 10.1007/s11427-020-1732-2 [published Online First:
2020/05/18]
[66] A. Pareek, N. Chandurkar, N. Thomas, et al.Efficacy
and safety of hydroxychloroquine in the treatment of type 2 diabetes
mellitus: a double blind, randomized comparison with pioglitazone
[67] A. Gupta Real-World
Clinical Effectiveness and Tolerability of Hydroxychloroquine 400 Mg in
Uncontrolled Type 2 Diabetes Subjects who are not Willing to Initiate
Insulin Therapy (HYQ-Real-World Study)
