A brief 1-3 sentence summary is included at the top of each article followed by a more in depth analysis of the article. The articles are divided into three sections: Management, Epidemiology & Transmission, and Foundational Articles.
Study Title: Effect of High Dose Zinc and Ascorbic Acid Supplementation vs. Usual Care on Symptom Length and Reduction Among Ambulatory Patients with SARS Cov-2 Infection
Summary: The purpose of this study was to assess the efficacy of high dose zinc & ascorbic acid in reducing the severity & duration of symptoms associated with acute SARS-Cov-2 infection in ambulatory patients. 214 patients participated in a randomized double blind trial that assessed reduction in severity of symptoms (fever, shortness of breath, cough, fatigue) via a 4 point scale after receiving 10 days of high dose zing (50 mg), ascorbic acid (8000 mg), both, or standard of care treatment. The researchers found that patients who received high dose anti-oxidant supplementation experienced no significant reduction in symptom severity compared with the group who received the standard of care treatment.
Background: Zinc gluconate & ascorbic acid are commonly available over the counter supplements that are recommended for symptoms management of viral illnesses. Zinc has been theorized to help fortify neutrophil response to inflammation and ascorbic acid has well-documented anti-oxidant properties that help fight inflammation as well. There is limited evidence to suggest that these supplements can aid in recovery from viral illness.
- 520 patients from 2 primary trial sites in Ohio and Florida were screened to yield a final group of 214 patients who were above the age of 18, nonpregnant, had no chronic kidney/liver disease, or history of calcium oxalate stones.
- Patients were randomized via a 1:1:1:1 allocation strategy to one of 4 different treatment groups:
- 50 received standard of care (no supplemetation) for 10 days
- 48 received only ascorbic acid 8000 mg for 10 days
- 58 received only high-dose zinc 50 mg for 10 days
- 58 received ascorbic acid 8000 mg and zinc 50 mg for 10 days
- Patients were asked to rate their symptoms via a 4 point symptom severity scale prior to initiating treatment and every day during the course of treatment.
- Primary Outcome: The number of days required to reach a 50% reduction in symptom severity.
- Secondary Outcomes: Number of days required to reach complete reduction in symptoms, cumulative severity score at day 5 of treatment, hospitalizations, deaths, adjunctive prescribed medications and adverse effects of study supplements.
|Mean # of days to 50% reduction in symptoms|
|Standard of Care||6.7 days, SD 4.4|
|High Dose Zinc (50 mg)||5.9 days SD 4.9|
|Ascorbic Acid (8000 mg)||5.5 days, SD 3.7|
|Zinc 50 mg+ Ascorbic Acid 8000 mg||5.5 days, SD 3.4|
Statistical significance of # of patients achieving 50% reduction in symptoms, p = 0.4
Statistical significance of time (days) to achieving 50% reduction in symptoms, p = 0.38
Conclusions: Based on the findings, OTC supplementation of zinc and ascorbic acid played no significant role in accelerating recovery rate for ambulatory patients with SARS-Cov-2. While the biological benefit of these supplements in reducing inflammation has been well established, there is no clinical indication that these provide any symptomatic relief for patients.
Study title: Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19
Summary: The purpose of this study was to assess the safety and efficacy of the baricitinib plus remdesivir novel combination therapy in hospitalized adults with COVID-19. 1,033 patients participated in a double-blind, randomized, placebo-controlled trial that assessed time to recovery (days) and clinical status at day 15 when receiving either a combination treatment of baricitinib plus remdesivir or a control of remdesivir plus placebo. The researchers found that the combination treatment is associated with quicker recovery time, accelerated recovery, and fewer adverse events when compared with remdesivir monotherapy.
Background: Current research shows remdesivir to be a promising treatment for COVID-19 infection, notably for treating pulmonary symptoms. However, studies show that despite promising safety and efficacy of remdesivir treatment, a persisting hallmark of the COVID-19 infection is dysregulated systemic inflammation which adversely contributes to disease outcomes. Thus, baricitinib has been suggested as a potential therapy for controlled dysregulated inflammation by inhibiting intracellular JAK signaling that causes fulminant cytokine release in severe COVID-19 infection. The purpose of this double-blind, randomized, placebo-controlled trial was to assess the safety and efficacy of the novel combination therapy of baricitinib plus remdesivir in hospitalized infected adults.
- 1,033 patients from 67 trial sites representing 8 countries
- 515 receivedremdesivir (≤10 days) plus baricitinib (≤14 days)
- 518 received remdesivir (≤10 days) plus oral placebo (control)
- Outcomes measured were: 1) time to recovery (days) and 2) clinical status at day 15
|remdesivir plus baricitinib group||remdesivir plus placebo group|
|Median time to recovery||7 days||8 days|
|Median time to recovery for ventilated patients||10 days||16 days|
- Patients in the combination treatment group had a 30% higher odds of improvement in clinical status at day 15 compared with the control group (Odds Ratio = 1.3)
- On average, fewer serious adverse events were reported in the combination treatment group compared to the placebo group
Conclusion: Based on the findings, the researchers report that the combination treatment of remdesivir plus baricitinib is associated with a quicker recovery time and a quicker improvement in clinical status most notably for high risk patients on ventilators (i.e.high-flow oxygen or noninvasive ventilation) when compared with the placebo treatment of remdesivir alone. Moreover, the combination treatment was also associated with fewer adverse events. These findings suggest a beneficial role of baricitinib-remdesivir co-therapy for improving outcomes in high risk adults with COVID-19 infection who are receiving assisted ventilation.
Study title: Evaluation of the Risk Prediction Tools for Patients with Coronavirus Disease 2019 in Wuhan, China
Summary: This study identified the National Early Warning score and oxygen saturation score as efficacious risk stratification tools for predicting in-hospital mortality due to COVID-19.
Background:The purpose of this retrospective observational study was to identify which pre-existing risk stratification tool is most efficacious for predicting in-hospital death in COVID-19 patients. The following widely accepted risk stratification tools which were assessed included: the National Early Warning Score, the National Early Warning Score 2, the Rapid Emergency Medicine Score, confusion, respiratory rate, blood pressure, the Age 65 score, and the Sepsis-Related Organ Failure Assessment. By identifying the risk stratification tool most efficacious at predicting degree of illness, the researchers aimed to target these patient for immediate critical care intervention with the goal of reducing in-hospital death due to COVID-19.
Methods: 673 adult COVID-19 patients (51% male, between 50-69 years) between January 30thand March 14th2020 seeking treatment at West Campus of Wuhan Union hospital in Wuhan, China were included in the study. Date about demographics, pre-existing comorbidities, vitals, mental status, oxygen saturation, and supplemental oxygen upon admission were extracted from medical records and used to score all the aforementioned risk stratification tools for each patient to predict their risk of in-hospital mortality. Mortality outcomes were compared to the predicted scores. It was reported that 121 patients (18% of the sample) died due to COVID-19.
Table 1: Characteristics of the study cohort.
What is an ROC curve? ROC curvesare a graphical depiction illustrating the connection/trade-off between clinical sensitivity and specificity for every possible cut-off for a test or a combination of tests.
What is the main finding of the study’s ROC curve? This study’s ROC curve compares the specificity and sensitivity of the various risk stratification tools for predicting in-hospital death due to COVID-19. The main finding is: the National Early Warning/ National Early Warning 2 Score and the oxygen saturation score were the most significant predictors of in-hospital death.
Conclusion: Based on the results, the researchers suggest the efficacy of the National Early Warning/ National Early Warning 2 Score and oxygen saturation score are most accurate in predicting in-hospital death due to COVID-19. This finding is important because it can help healthcare providers identify patients with poor prognosis who are in need of critical care intervention, with the ultimate goal of reducing in-hospital mortality due to COVID-19. More research needs to be conducted to replicate and confirm these results.
Study Title: Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients with COVID-19
Brief Summary: This prospective meta-analysis looked at 7 randomized controlled trials with a total of 1703 patients to determine if systemic corticosteroids reduce 28-day mortality. The authors determined that 28-day mortality was lower in critically ill COVID-19 positive patients who received corticosteroids compared with standard care (odds ratio of 0.66).
Background: Corticosteroids, such as low-dose dexamethasone, have shown promise in reducing mortality in certain cases in COVID-19 patients who are hospitalized. The authors of this study conducted a meta-analysis on existing studies that examined the role of low-dose dexamethasone in managing patients with COVID-19.
Methods: The authors conducted a prospective meta-analysis that included data from 7 randomized clinical trials conducted in 12 countries between February 26, 2020 to June 9, 2020. In total, these studies included 1703 critically ill patients with COVID-19; the median age of these patients was 60 years and 29% were women. In total, 678 patients received one of the systemic corticosteroids of dexamethasone, hydrocortisone, or methylprednisolone and the other 1025 served as placebo. The main outcomes measured were all-cause mortality (i.e. death for any reason) 28 days after randomization and serious adverse effects.
The primary results were as follows:
- There were 222 deaths among the 678 patients who received one of the three corticosteroids
- There were 425 deaths among the 1025 patients who received usual care
- The odd ratio of death was 0.66 (P<0.001), which is statistically significant; this suggests that corticosteroids carry a mortality benefit
- This relationship was strongest for Dexamethasone, which had a mortality odds ratio of 0.64 (P< .001)
- In contrast, hydrocortisone and methylprednisolone did not has a statistically significant mortality benefit
The secondary results were as follows:
- Risk of bias was characterized as “low” for 6 out of the 7 studies, suggesting high quality of data
- Six trials reported serious adverse effects
- 64 events occurred in the 354 patients that received corticosteroids
- 80 events occurs in the 342 patients randomized to usual care or placebo
Conclusions: Administration of systemic corticosteroids, particularly low-dose dexamethasone, is associated with a lower mortality rate at 28 days.
Study Title: A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19
- Randomized, double blind, placebo controlled trial across the US and parts of Canada
- Tested hydroxychloroquine as postexposure prophylaxis
- Subjects were adults with a confirmed COVID-19 household or occupational exposure at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high risk exposure) or while wearing a face mask but no eye shield (moderate risk exposure)
- Within 4 days of exposure participants were randomly assigned to either placebo or hydroxychloroquine
- Primary outcome was the incidence of either laboratory confirmed COVID-19 or illness compatible with COVID-19 within 14 days of exposure
- n=821 asymptomatic participants
- 87.6% had a high risk exposure
- The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was −2.4 percentage points (95% confidence interval, −7.0 to 2.2; P=0.35).
- Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
- After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure.
Study title: Acetylated K676 TGFBIp as a severity diagnostic blood biomarker for SARS-CoV-2 pneumonia
Summary: This study found that TGFβIp and TGFBIp K676Ac, immune system signaling molecules, can potentially be used as blood biomarkers for differentiating critically ill COVID-19 cases at risk for pneumonia and in need of urgent ICU care from less symptomatic COVID-19 patients.
Background: The death toll due to COVID-19 is continuously rising daily, thus creating an urgent need for tools that can be used to target severely ill patients requiring immediate intervention. This study identified transforming growth factor-beta (TGFβ), a cytokine/cell-signaling molecule, as a reliable blood biomarker that can potentially be used as prognostic and therapeutic tool for distinguishing severely symptomatic COVID-19 patients.
Methods: Levels of TGFβIp (a TGFβ-induced protein) and TGFBIp K676Ac (a post-translationally modified TGFβ-induced protein) in the blood were measured using an ELISA assay in 113 COVID-19 positive patients residing in either an ICU (10 patients) or non ICU (85 patients) settings. Plasma was collected from 20 healthy non-COVID positive individuals and analyzed as a control.
Results: Scatterplots A and B compare levels of TGFβIp and TGFBIp K676Ac, respectively, among healthy individuals, COVID-19 non-ICU cases, COVID-19 ICU cases, and recovered and discharged COVID-19 cases. Both measured serum biomarkers were significantly elevated in severely ill ICU cases as compared to mildly ill non-ICU cases, recovered/discharged cases, and non-COVID patients. Also, both biomarkers were also significantly increased in non-ICU cases as compared to recovered/discharged and non-COVID patients.
Conclusion: The data suggests serum TGFβIp and TGFBIp K676Ac levels are blood biomarkers that can be used as a predictive prognostic and therapeutic decision making tools for targeting critically ill COVID-19 patients in order to provide optimal life-saving care. Implications of this research include potential to reduce in-hospital mortality due to COVID-19.
Study Title: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
Background: The authors evaluate the effectiveness of hydroxychloroquine on respiratory viral loads.
- Location France
- n=42; hydroxychloroquine n=26 and control n=16
- Treatment: 600 mg of hydroxychloroquine daily (azithromycin was added based on clinical presentation)
- Measurement: viral load of nasopharyngeal swabs
- Comparison: untreated patients from another center or cases refusing the protocol)
- End point: presence or absence of virus at Day 6
- Figure taken from paper. Percentage of patients with PCR positive nasopharyngeal samples from inclusion to day 6.
- Note post day 3 from study start those on hydroxychloroquine and those on hydroxychloroquine and azithromycin had significantly lower positive COVID-19 tests when compared to control.
- Hydroxychloroquine is efficient in clearing viral nasopharyngeal carriage of SARS-CoV-2 in COVID-19 patients in only three to six days, in most patients.
- The results suggest a synergistic effect of the combination of hydroxychloroquine and azithromycin. Azithromycin has been shown to be active in vitro against Zika and Ebola viruses
- In some cases hydroxychloroquine failed. The cause for a failure of hydroxychloroquine treatment should be investigated by testing the isolated SARS-CoV-2 strains of the non-respondents and analyzing their genome, and by analyzing the host factors that may be associated with the metabolism of hydroxychloroquine.
Study Title: Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019
Original Article: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767593
JAMA Commentary: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767588
Brief Summary: In this study from Greece, authors evaluated the clinical and biochemical effects of the gout drug colchicine in patients hospitalized for COVID-19. Data showed a lower rate of clinical deterioration in patients that received colchicine compared to a standard treatment group. However, there were no differences in clinically important biomarkers reviewed.
Background: The purpose of this study was to assess the effects of colchicine, a drug commonly used to treat gout with anti-inflammatory properties, on hospitalized COVID-19 patients. The researchers collects data on clinical outcomes as well as cardiac and inflammatory biomarkers.
Methods: This study was a a prospective, open-label, randomized clinical trial, meaning that some of the patients were given colchicine and then followed. In total, 105 COVID-19 patients were included in the study, with 55 receiving colchicine and the other 50 receiving standard medical treatment. The study took place in 16 hospital in Greece from April 3rd to April 27th.
The researchers followed three variables. The first, maximum high-sensitivity cardiac troponin, is a measure of damage to heart. The second, C-reactive protein, is a measure of inflammation. The third, clinical deterioration, was calculated using a 7-grade clinical status scale, with 1 representing ability to do normal activities and 7 representing death
Results: Approximately, 14% of the patients in the control group (7 out of 50) experienced significant clinical deterioration throughout . In contrast, only 1.8% of the patients in the Colchicine group (1 out of 55) experienced significant clinical deterioration. This difference was statistically significant (P = .02).
In contrast, there was no statistically significant difference between the two groups in terms of high-sensitivity cardiac troponin and CRP.
Interpretation: This study suggests that colchicine may be helpful in reducing the rate of clinical deterioration in patient’s hospitalized for COVID-19. There was no demonstrated difference between colchicine and standard biomarkers of inflammation and heart injury. Due to the small sample size of this study, these results need further research.
Study Title: Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19
Original Article: https://jamanetwork.com/journals/jama/article-abstract/2766943
JAMA Commentary: https://jamanetwork.com/journals/jama/article-abstract/2766943
Brief Summary: Convalescent plasma serves has served a promising therapeutic option for patients with COVID-19, however, till this study there has yet to be randomized controlled trials in support of the use of convalescent plasma. In this article from JAMA, Li et al. present findings from the first randomized clinical trial of convalescent plasma therapy for patients with COVID-19 conducted in China.
Background: Convalescent plasma for the treatment of infectious diseases has been used since the early 20th century and was associated with reduced mortality in other pandemics. Several uncontrolled case series of convalescent plasma use in patients with COVID-19 have suggested a possible benefit. Given encouraging historical precedents and the absence of proven COVID-19 antiviral therapies, convalescent plasma therapy has been proposed as a treatment option. The availability of clinical information generated from randomized clinical trials is therefore of substantial importance.
Methods: In this multicenter, randomized controlled trial based in Wuhan, China 103 participants with laboratory-confirmed COVID-19 that were severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). Both groups were given either convalescent plasma in addition to standard treatment (n = 52) or standard treatment alone (control) (n = 51).
- Primary outcome was time to clinical improvement within 28 days, defined as a patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]).
|Outcome measured||Convalescent plasma + standard treatment||Standard treatment alone||Statistically significant|
|Clinical improvement in 28 days: all participants||51.9% (27/52)||43.1% (22/51)||No|
|Clinical improvement in 28 days: severe disease (respiratory distress and/or hypoxemia)||91.3% (21/23)||68.2% (15/22)||Yes|
|Clinical improvement in 28 days: life-threatening (shock, organ failure, or requiring mechanical ventilation)||20.7% (6/29)||24.1% (7/29)||No|
Conclusions: Convalescent plasma use in this study was associated with some clinical improvement in severely ill patients (respiratory distress and/or hypoxemia), but not in life-threatening critically ill patients (shock, organ failure, or requiring mechanical ventilation). Greater efficacy in less ill individuals (severe disease) is expected because antibody therapies generally work best when administered earlier in disease. Lack of efficacy among patients who were in the life-threatening category, receiving mechanical ventilation and/or with some with multiorgan failure, highlights that the pathologic process in these individuals is likely irreversible.
Study Title: Remdesivir for the Treatment of Covid-19 — Preliminary Report
Brief Summary: This study consisted of 1063 participants and was a double-blind (researchers and participants do not know if they received the drug or a placebo), randomized, placebo-controlled trial of the antiviral remdesivir in adults hospitalized with COVID-19. The primary outcome was time to recovery, which was measured by the number of days to discharge from the hospital. The researchers found patients that used Remdesivir had a lower time to recovery (11 vs. 15 days), which was statistically significant.
Background: The purpose of this study was to determine the therapeutic effects of remdesivir in treating COVID-19 patients. Remdesivir is an antiviral that works as an inhibitor of viral RNA polymerase and has shown activity against SARS-CoV and MERS-CoV; thus, it is speculated to be a promising therapeutic candidate for COVID-19. Double blind, randomized controlled trials allow us to more definitively understand the treatment potential of Remdesivir for COVID-19.
Methods: In this multinational study, 1063 patients were randomized to remdesivir or placebo treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir or placebo. Remdesivir was administered via IV as a 200 mg loading dose on the first day, followed by 100 mg maintenance dose administered daily on days 2 – 10 or until hospital discharge or death. A matching placebo was administered according to the same schedule and in the same volume as the active drug.
Results: The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group.
|Outcome measured||Remdesivir||Placebo||Statistically significant|
|Recovery time (median number of days)||11 days||15 days||Yes|
|Mortality at 14 days (%)||7.1%||11.9%||No|
|Adverse Event (%)||21.1%||27.0%||No|
Conclusions: Preliminary results of this trial suggested that a 10 day course of remdesivir was superior to placebo in reducing length of stay of hospitalized adult patients with COVID-19. Additionally, there was no increased frequency of adverse effects in patients that took remdesivir. Mortality rate at 14 days was lower in patients that took remdesevir, but this difference was not statistically significant. Future studies on Remdesevir should focus on combination therapies to assess and improve COVID-19 patient outcomes such as mortality.
Clinical Outcomes in COVID-19 Patients Treated with Tocilizumab: An Individual Patient Data Systematic Review
Brief Summary: Rare and severe complications of COVID-19 include Cytokine-Release Syndrome (CRS) and Macrophage Activation Syndrome (MAS). Both of these are caused by an excessive inflammatory host immune response that can induce Acute Respiratory Distress Syndrome (ARDS) and death in certain patients. Data from this study suggests Tocilizumab may be a promising treatment for COVID-induced CRS.
Background: COVID-associated CRS/MAS are characterized by viral-induced plasma elevation of Interleukin-6, a pro-inflammatory molecule called a cytokine, which can overwhelm a patient’s immune system and induce shock, ARDS, and death. Current treatments approved for non-COVID associated CRS/MRS include a drug called Tocilizumab which inhibits the Interleukin-6 pathway thereby neutralizing the excessive host immune response. Thus, the purpose of this systematic record review was to assess if Tocilizumab is effective for controlling elevations in plasma Interleukin-6 in COVID-patients at risk for developing CRS and ARDS.
Methods: 29 records of severely ill COVID-19 patients at risk for CRS and ARDS between the dates of April 22nd to April 27th 2020 were analyzed for baseline characteristics, lab findings, and clinical outcomes.
•IL-6 level was consistently significantly higher post initiation of Tocilizumab, supporting diagnosis of COVID-induced cytokine storm.
•C Reactive Protein, a biological marker of inflammation, was consistently significantly decreased post Tocilizumab treatment compared to baseline.
Conclusion: Based on the results, the researchers suggest that treatment with Tocilizumab in high risk COVID-19 patients with significantly high Interleukin-6 plasma levels significantly reduces the hyper-inflammatory state caused by the overactive Interleukin-6 pathway, thus decreasing risk of CRS and ARDS. It is unknown if Tocilizumab therapy significantly impacts mortality rates, and more research is needed for further evaluation of the drug.