Illustration: Nadine D
To compare outcomes among hospitalized COVID-19 patients ordered to receive hydroxychloroquine and azithromycin plus zinc sulphate versus hydroxychloroquine and azithromycin alone.
Methodology. This was a retrospective observational study. Data was collected from medical records for all patients with admission dates ranging from 2 March 2020 through to 11 April 2020. Initial clinical characteristics on presentation, medications given during the hospitalization, and hospital outcomes were recorded. The study included patients admitted to any of four acute care NYU Langone Health Hospitals in New York City. Patients included were admitted to the hospital with at least one positive COVID-19 test and had completed their hospitalization. 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.
Results. Patients taking zinc sulphate 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 relevant comorbidities. The addition of zinc sulphate did not impact the length of hospitalization, duration of ventilation or intensive care unit (ICU) duration. In univariate analyses, zinc sulphate 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 sulphate 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 sulphate may play a role in therapeutic management for COVID-19
While practicing at the epicentre 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 azithromycin . Our providers within the infectious diseases division, clinical pharmacy and hospitalists discussed the use of zinc sulphate 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 sulphate to treat and prevent COVID-19 infection and its use is being considered in several trials (NCT04326725, NCT04377646, NCT04370782, NCT04373733, NCT04351490). To our knowledge, we provide the first in vivo evidence on the efficacy of zinc sulphate in addition to hydroxychloroquine in COVID-19 patients. The main finding of this study is that the addition of zinc sulphate to hydroxychloroquine and azithromycin was found to be associated with a decrease in mortality or transition to hospice among patients who did not require ICU level of care, but this association was not seen for patients who were treated in the ICU. This result may reflect one of the proposed mechanisms by which zinc sulphate 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]. To further examine the ability of zinc to prevent viral replication and disease progression, future studies should measure viral RNA levels in clinical specimens before and after zinc administration. Our findings suggest a potential protective effect of zinc, potentially enhanced by a therapeutic synergistic mechanism of zinc sulphate with hydroxychloroquine, if used early on in presentation with COVID-19.
After adjusting for the timing of zinc sulphate 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 sulphate to a zinc ionophore such as hydroxychloroquine may reduce the need for ICU care in patients 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, we do not know whether the observed added benefit of zinc sulphate to hydroxychloroquine and azithromycin on mortality would have been seen in patients who took zinc sulphate alone or in combination with just one of those medications since few patients at our hospitals received zinc sulphate as stand-alone therapy. The optimal dose and formulation of zinc supplementation necessary to inhibit RNA-dependent RNA polymerase activity of coronaviruses also remains unknown. Early reports suggested higher doses may be necessary, ranging from 50 to 150 mg elemental zinc/day, and such doses have been proved to be safe for short periods of time when used for other viruses or in improving immune reconstitution [20–23]. In addition, although other formulations of zinc supplementation exist, in the form of acetate or gluconate, our hospital formulary had sulphate, which generally has a higher elemental amount of zinc per tablet. Therefore, further investigation is required to determine whether sulphate is the preferred formulation when used to treat coronaviruses, or if another formulation may be better tolerated. Given the recent concern regarding the potential for side effects associated with hydroxychloroquine, future studies should examine whether zinc sulphate would provide benefit as a stand-alone therapy or in combination with another zinc ionophore. In addition, as zinc is hypothesized to inhibit viral RNA polymerase, future studies are needed to determine if zinc synergistically acts with other antiviral medications. We also do not have data on the time at which the patients included in the study initiated therapy with hydroxychloroquine, azithromycin and zinc. Those drugs would have been started at the same time as a combination therapy, but the point in clinical disease at which patients received those medications could have differed between our two groups. Finally, the cohorts were identified based on medications ordered rather than confirmed administration, which may bias findings towards favouring equipoise between the two groups.
Conclusion
Zinc sulphate 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 sulphate in COVID-19 patients and support the initiation of future randomized clinical trials investigating zinc sulphate against COVID-19.
Reference & Source information: https://www.microbiologyresearch.org/
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