COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study

International Journal of Antimicrobial Agents

Volume 56, Issue 6, December 2020, 106214

COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study.

RolandDerwanda

VladimirZelenkoc

https://doi.org/10.1016/j.ijantimicag.2020.106214

Highlights

•First COVID-19 outpatient study based on risk stratification and early antiviral treatment at the beginning of the disease.

• Low-dose hydroxychloroquine combined with zinc and azithromycin was an effective therapeutic approach against COVID-19.

ABSTRACT

The aim of this study was to describe the outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low-dose hydroxychloroquine and azithromycin (triple therapy) dependent on risk stratification. This was a retrospective case series study in the general practice setting. A total of 141 COVID-19 patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the year 2020 were included. The main outcome measures were risk-stratified treatment decision and rates of hospitalisation and all-cause death. A median of 4 days [interquartile range (IQR) 3–6 days; available for n = 66/141 patients] after the onset of symptoms, 141 patients (median age 58 years, IQR 40–67 years; 73.0% male) received a prescription for triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients in the same community were used as untreated controls. Of 141 treated patients, 4 (2.8%) were hospitalised, which was significantly fewer (P < 0.001) compared with 58 (15.4%) of 377 untreated patients [odds ratio (OR) = 0.16, 95% confidence interval (CI) 0.06–0.5]. One patient (0.7%) in the treatment group died versus 13 patients (3.4%) in the untreated group (OR = 0.2, 95% CI 0.03–1.5; P = 0.12). No cardiac side effects were observed. Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset using triple therapy, including the combination of zinc with low-dose hydroxychloroquine, was associated with significantly fewer hospitalisations.

Keywords

SARS-CoV-2

COVID-19

Outpatients

Zinc

Hydroxychloroquine

Azithromycin

1. Introduction

In December 2019, the novel 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].

As of June 2020, the diagnosis and treatment of COVID-19 have been almost exclusively studied from an inpatient perspective, including intensive care with mechanical ventilation. Only one study has described the characteristics and key health outcomes of COVID-19 diagnosed patients in an outpatient setting [3]. This is surprising as primary care physicians often see COVID-19 patients first. Thus, they could play a critical role in early diagnosis, treatment and management of disease progression and virus spread. This assumption is supported by the established principle in medicine that speed of eradication is linked to the outcome of life-threatening infections [4].

The early clinical phase of COVID-19 has not been the focus of much research so far, even though timing of antiviral treatment seems to be critical [5]. The optimal window for therapeutic intervention would seem to be before the infection spreads from the upper to lower respiratory tract and before severe inflammatory reaction ensues [6]. Therefore, diagnosis and treatment of COVID-19 outpatients as early as possible, even based on clinical diagnosis only, may have been an underestimated first step to slow down or even stop the pandemic more effectively. Based on clinical application principles of antiviral therapies, as demonstrated in the case of influenza A [7], antiviral treatments should be used early in the course of infection.

Due to the lack of a vaccine or 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 such as rheumatoid arthritis and systemic lupus erythematosus (SLE) [9,10]. HCQ is currently listed as an essential medication for SLE by the World Health Organization (WHO) [11]. With more than 5.6 million prescriptions in the USA, HCQ was the 128th most commonly prescribed medication in 2017 [12]. In the meantime, the 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 in hospitalised and often sicker patients [13], [14], [15], [16], and one publication was recently withdrawn [17,18]. As of June 2020, no studies of COVID-19 outpatients treated with HCQ at an early stage of the disease have been reported.

The 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 (RdRp) activity [21]. It has been hypothesised 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 a preprint [23]. Nevertheless, many studies with HCQ as 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 the onset of symptoms when hospitalised 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 deficiency, dependent on co-morbidities and drug treatments [22], none of these studies were designed to include zinc supplementation as combination treatment.

This first retrospective case series study of COVID-19 outpatients was done to show whether (i) a simple-to-perform outpatient risk stratification might allow for a rapid treatment decision shortly after onset of symptoms and (ii) whether the 5-day triple therapy with zinc, low-dose HCQ and azithromycin might result in fewer hospitalisations and 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 SARS-CoV-2 infection treated in a community in New York State, USA, between 18 March 2020 and 14 May 2020. The outcome of patients treated with a specific triple therapy was compared with public reference data of patients in the same community who were not treated with this therapy.

2.2. Confirmation of COVID-19 diagnosis

The COVID-19 diagnosis was confirmed if patients tested positive for SARS-CoV-2 by PCR of nasal or pharyngeal swab specimens (majority of tests by Roche, Basel, Switzerland; 99.1% sensitivity and 99.7% specificity; other tests used with lower frequency included: DiaSorin: 500 copies/mL; Thermo Fisher: 10 genomic copy equivalents/reaction; Seegene: 1250 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 had a record of a positive test result were included in the analysis. The PCR assays were authorised by the US Food and Drug Administration (FDA) without clinical sensitivity/specificity data owing 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 aged >18 years at diagnosis were included in the analysis as the treatment group. All patients were White. Patients received a prescription for 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); or Group C, age ≤60 years, clinically symptomatic and with at least one of the following co-morbidities: hypertension, hyperlipidaemia, diabetes mellitus, obesity [body mass index (BMI) ≥ 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 also included in this group.

Laboratory-confirmed COVID-19 patients from the same community who were not treated with the described triple therapy and their 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 for treated patients were collected from electronic health records in the year 2020. Demographics, as reported by the patient, and current medical history of hypertension, hyperlipidaemia, diabetes mellitus, obesity (BMI ≥ 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 was documented: cough/dry cough; fever; SOB; changes to or no smell or taste; sore throat; headache; runny nose/clear rhinorrhoea; sinus congestion; diarrhoea/vomiting; cold symptoms; feeling sick; weakness; and low back pain. If reported, the number of days since onset of symptoms was documented.

The following vital signs, if available, were collected and documented: heart rate (beats/min), respiratory rate (breaths/min), systolic and diastolic blood pressure (mmHg), body temperature (°C), oxygen saturation measured by pulse oximetry (O2 %), body weight (kg) and/or BMI.

The main co-medications were characterised based on primary care prescriptions active at the time of diagnosis, documented as categorical variables, 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 received 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 tract infections. Patients were not treated with HCQ if they had known contraindications, including QT prolongation, retinopathy or glucose-6-phosphate dehydrogenase deficiency. As usual and following best practice, patients were informed about possible drug-related side effects. Reported events, if any, were documented as required.

Selection of the used zinc supplement and of drugs, dosages and the combination thereof were based on treatment guidelines, positive reports from other countries such as South Korea, emerging first clinical evidence, and based on the discretion of the treating physicians.

2.5. Outcomes

Two outcomes were studied: COVID-19 related hospital admission and all-cause death during time of follow-up of ≥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 one prescription for HCQ, with or without zinc, for 5 days were included in the retrospective analysis and were categorised 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 triple therapy were included in the analysis. For this untreated control group, only outcome data for hospitalisation and all-cause death were 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 as frequencies (%) for categorical variables. For comparison with the results of other studies, the mean and standard deviation were calculated as needed. Normality of distribution for continuous variables was assessed by the Shapiro–Wilk test. A two-tailed Student's t-test was used for parametric analysis, and a Wilcoxon signed-rank test was used for non-parametric 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 χ2 test. The odds ratio (OR) was calculated for comparison of the outcome of the treatment group with the untreated control group. An α value of 0.05 was considered as a significance level. 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 was exempt under 45 CFR § 46.104(d)(4). Ref. 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-positive 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). Of the 335 patients, 208 did not meet the defined risk stratification criteria and 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 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 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%) received a prescription of HCQ, 136 (96.5%) of zinc sulfate and 133 (94.3%) of azithromycin, while 1 patient (0.7%) received doxycycline instead. Instead of triple therapy, 1 patient (0.7%) in the treatment group received HCQ only, 7 patients (5.0%) received HCQ and zinc, and 4 patients (2.8%) received HCQ and azithromycin.

Table 1. COVID-19 diagnostics by PCR and IgG tests of patients in the treatment group

COVID-19 diagnostic [n (%)]Risk-stratified groupAll patients (N = 141)Group A (N = 69)Group B (N = 48)Group C (N = 24)SARS-CoV-2 PCR test51 (74)39 (81)14 (58)104 (74)SARS-CoV-2 IgG test18 (26)9 (19)10 (42)37 (26)

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 1. Study population. N = 141 COVID-19 patients, all with a laboratory-confirmed SARS-CoV-2 infection, were included in the analysis as the treated group. N = 377 positively tested COVID-19 patients of the public reference were included in the analysis as the untreated group. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

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. Of the 141 patients, 69 (48.9%) belonged to group A, 48 (34.0%) to group B and 24 (17.0%) to group C. The age ranged from 18–80 years and the median age was 58 years (IQR 40–67 years). The median age of patients in groups A, B and C was 67, 39 and 45 years, respectively. A total of 103 patients (73.0%) were male with a male-to-female ratio of 2.71. The most common co-morbidities included hypertension (28%), obesity (28%), hyperlipidaemia (23%) and diabetes mellitus (18%), whilst the least common co-morbidities were liver disease (2%), heart failure (1%) and stroke (1%). One patient (0.7%) was pregnant at initiation of treatment. There was a positive and significant correlation between age and hypertension (r = 0.3309, P = 0.001), hyperlipidaemia (r = 0.26306, P < 0.001) and cardiovascular disease (r = 0.16757, P < 0.05), whilst asthma was negatively correlated with age (r = –0.30867, P < 0.001).

Table 2. Baseline demographic and clinical characteristics of patients in the treatment group

Characteristic Risk-stratified group

 All patients (N = 141) Group A (N = 69) Group B (N = 48) Group C (N = 24) 

Age (years) [median (IQR)] 67 (64–69) 39 (24–47) 45 (36–50) 58 (40–67) 

Male sex [n (%)]46 (67)40 (83)17 (71)103 (73) 

Co-morbidities/coexisting conditions [n (%)] 

Any condition 44 (64) 31 (65) 24 (100) 99 (70) 

Hypertension 27 (39) 4 (8)8 (33) 39 (28) 

Hyperlipidaemia 21 (30)7 (15) 5 (21) 33 (23) 

Diabetes mellitus16 (23) 4 (8)5 (21) 25 (18)

Obesity a 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; COPD, chronic obstructive pulmonary disease.

a Body mass index (BMI) ≥30 kg/m2.

The median time between onset of clinical symptoms and medical consultation was 4 days (IQR 3–6 days; available for 66/141 patients; mean 4.8 ± 2.7 days) (Table 3). There was no significant correlation between age and days from onset of clinical symptoms to consultation (P > 0.05). Days from onset of symptoms to consultation were not significantly different between the groups (P > 0.05).

Table 3. Patients with reported days since onset of symptoms in the treatment group

Characteristic Risk-stratified group All patients (N = 141) Group A (N = 69) Group B (N = 48) Group C (N = 24) 

Patients with reported days [n (%)] 32 (46) 25 (48) 9 (38) 66 (47)

Days since onset of symptoms [median (IQR)] 4 (3–6) 3 (3–6.5) 4 (3–5.5) 4 (3–6)

IQR, interquartile range.

The most common clinical symptoms included cough (87.2%), fever (77.3%), SOB (46.1%) and changes to or no smell or taste (30%), whilst the least common clinical symptoms were sinus congestion (16%), diarrhoea/vomiting (5%) and low back pain (3%). Table 4 shows the symptoms of all patients and stratified by groups A, B and C. There was a significant negative correlation between age and changes to 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 symptom [n (%)]