Treatment

BACKGROUND

• The B.1.617.2 (Delta) variant of SARS-CoV-2 virus was first detected in India in December of 2020. Since then, the variant has spread across the globe, with a notable increase in the United Kingdom.

• The Delta variant is characterized by spike protein mutations, allowing it to have greater replication, increased viral loads, and higher transmissibility.

• The following study investigates the effectiveness of BNT162b2 (Pfizer–BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca) against the Delta variant

METHODS:

• Using a test-negative case-control design, researchers investigated the effectiveness of vaccinations against symptomatic disease caused by either the delta variant, or the predominant strain, the alpha variant.

• Variants were identified based on sequencing and spike (S) gene status.

• Data on symptomatic cases in England were used to estimate the proportion of cases with either variant in conjunction with the patients’ vaccination status.

RESULTS:

• After one dose of either the BNT162b2 or ChAdOx1 nCoV-19 vaccines, efficacy was lower for the delta variant (30.7%) than for the alpha variant (48.7%)

• After the second dose of BNT162b2, efficacy for the delta variant (88.0%) was comparable to the alpha variant (93.7%). This was also true for the second dose of ChAdOx1 nCoV-19; the effectiveness for the delta variant was 67.0% and for the alpha variant 74.5%.

CONCLUSION

• Only modest differences in vaccine efficacy were determined between alpha and delta variants after completion of second doses.

• These findings support two-dose vaccine uptake efforts among vulnerable populations.

• The present study investigates the reactions to localized cutaneous injections of the Moderna COVID-19 vaccine, called "COVID arm".

• A retrospective case study was conducted at Yale New Haven Hospital's Dermatology Services, with a sample of 15 patients who developed reactions from January 20th- February 12th of 2021.

• The delayed localized cutaneous reactions appeared a median of 7 days post vaccination. They were described as pruritic, painful, and as edematous pink plaques.

• Skin biopsy specimen revealed this was consistent cell-mediated immunity seen in a dermal hypersensitivity reaction.

• 11 out the 15 patients developed a similar localized cutaneous reaction after receiving the second dose, and 10 out of these 11 patients developed the second reaction sooner than the first.

• Polyethylene glycol, a component of both Moderna and Pfizer vaccines, may play a role in delayed hypersensitivity reactions. However, more research is warranted, such as patch testing of patients with COVID arm using vaccine components.

• The authors conclude that COVID arm reactions are distinct to immediate hypersensitivity reactions (eg, anaphylaxis and urticaria) and are not a contraindication for subsequent vaccinations.

Methods

• Women giving birth and discharged from April- November 2020 were identified by ICD-10 codes from the Premier Healthcare Database.

Results

• Out of 406, 446 women hospitalized for childbirth, 6380 (1.6%) were positive for COVID-19.

• Of the women giving birth with COVID-19, 212 (3.3%) needed intensive care, 86 (1.3%) needed mechanical ventilation, and 9 (0.1%) died in the hospital.

• When compared to women without COVID-19, women with COVID-19 were more likely to be younger, black/Hispanic, and have comorbidities.

• Rates of in-hospital mortality, myocardial infarction, venous thromboembolism (VTE), preeclampsia, and preterm birth were greater for women who gave birth with COVID-19.

• The use of chest imaging, intensive care treatment, and mechanical treatment was also greater in women giving birth with COVID-19.

Limitations

• This study had the following limitations: potential for misclassification by ICD-10 codes, lack of confirmatory testing and imaging findings, disease severity, inability to distinguish between asymptomatic and symptomatic COVID-19 cases, low event rates, and residual confounding.

Discussion/Conclusion

• High rates of preeclampsia, preterm birth, thrombotic events, and death in women giving birth with COVID-19 underscores the need to develop strategies minimize risk.

• These findings also emphasize the importance of including pregnant women in COVID-19 clinical trials for vaccines and treatment, for which they have been largely excluded.

Background

• Remdesivir, a prodrug of an adenosine analogue, has demonstrated activity against SARS-CoV-2 in vitro, and clinical trials have used a 10-day course of remdesivir based on previous efficacy data in a MERS clinical trial and safety data in an Ebola clinical trial

• Establishing the shortest duration of effective treatment with remdesivir is important: could help reduce hospital stays, limit adverse events, and extend limited supply of the drug

• This report describes the results of an open-label, randomized, multicenter trial evaluating the efficacy and safety of treatment with remdesivir for 5 or 10 days in patients with severe COVID-19 disease

Methods:

Patients

• Enrolled patients were at least 12 years of age, had SARS-CoV-2 infection confirmed by polymerase chain reaction assay within 4 days before randomization, had radiographic evidence of pulmonary infiltrates, and had either an oxygen saturation of 94% or lower breathing ambient air or who were receiving supplemental oxygen

• Exclusion criteria: mechanical ventilation or extracorporeal membrane oxygenation (ECMO), signs of multiorgan failure, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 5 times upper limit of normal, estimated creatinine clearance of less than 50 ml/min (by Cockcroft-Graft formula), or treatment with other agents with putative activity against COVID-19

Trial Design and Oversight

• Phase 3 trial enrolled patients at 55 hospitals in several countries between Mar. 6 and Mar 26, 2020

• Patients randomly assigned 1:1 to receive remdesivir for 5 days or 10 days (randomization not stratified); all patients received 200 mg remdesivir on day one followed by 100 mg remdesivir on remaining 4 or 9 days

• Supportive care continued, and patients who were discharged were not mandated to complete the entire course

• Trial approved by IRB or ethics committee at each institution

Clinical and Laboratory monitoring

• Patients assessed by physical examination and documentation of respiratory status, adverse events, and concomitant medications

• On trial days 1, 3, 5, 8, 10, and 14, blood samples were obtained for complete blood count and measurements of creatinine, glucose, total bilirubin, and liver aminotransferases

• Clinical status assessed daily on 7-point scale described below

End Points

• Primary efficacy end point was clinical status assessed on day 14 according to a 7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, receiving invasive mechanical ventilation or ECMO; 3, hospitalized, receiving noninvasive ventilation or high-flow oxygen devices; 4, hospitalized, requiring low-flow supplemental oxygen; 5, hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to Covid-19); 6, hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for remdesivir administration); and 7, not hospitalized

• Secondary end point of trial was proportion of patients with adverse events occurring on or after first remdesivir dose up to 30 days after last dose

• Prespecified exploratory end points included time to clinical improvement (defined as an improvement of at least 2 points from baseline), time to recovery (defined by the National Institute of Allergy and Infectious Diseases as an improvement from a baseline score of 2 to 5 to a score of 6 or 7), time to modified recovery (defined as an improvement from a baseline score of 2 to 4 to a score of 5 to 7 or from a score of 5 to a score of 6 or 7), and death from any cause

Statistical Analysis

• Sample size of 400 patients (200 in each group) would provide greater than 85% power to detect an odds ratio for improvement of 1.75, using a two-sided significance level of 0.05

• A proportional odds model was used, with treatment as the independent variable and baseline clinical status as a continuous covariate

• The conclusion would be that 10 days of treatment was superior to 5 days of treatment if the lower bound of the two-sided 95% confidence interval of the odds ratio (10 days to 5 days) on day 14 was greater than 1

• For time-to-event end points, the hazard ratio and its 95% confidence interval were estimated from a cause specific proportional-hazards model that included treatment and baseline clinical status as covariates and treated death as the competing risk

• For events associated with prespecified times, the difference in the proportion of patients with an event under evaluation between treatment groups and its 95% confidence interval were estimated from the Mantel–Haenszel proportions, with adjustment according to baseline clinical status

• For end points other than the primary end point, 95% confidence intervals have not been adjusted for multiplicity and should not be used to infer effect

Results

• 402 patients enrolled, and 397 began treatment (200 assigned to 5 day course, 197 assigned to 10 day course); treatment groups balanced in demographic characteristics but not in baseline disease characteristics (greater proportions of patients in 10-day group were in the two highest severity disease groups)

• 13 patients required invasive mechanical ventilation or deviated from protocol between enrollment and beginning of treatment; 4 of these assigned to 5-day group and 9 of these assigned to 10-day group

• High flow oxygen required by more patients in 10-day group than 5-day group at beginning of treatment (30% vs 24%, respectively); patients in 10-day group had significantly worse clinical status than 5-day group (P=0.02)

• 172 of 200 patients enrolled in 5-day group completed the course of trial treatment (median 5 days); reasons for some patients not completing treatment were hospital discharge ad adverse events

• 86 of 200 patients enrolled in 10-day group completed the course of trial treatment (median 9 days); reasons for some patients not completing 10-day course were discharge from hospital, adverse events, and death

• By day 14, 16 patients in 5-day group and 21 patients in 10-day group had died, and 120 and 103 patients had been discharged, respectively

Efficacy

• 65% of patients in 5-day group showed clinical improvement of at least 2 points on 7-point scale, compared with 54% of 10-day group

• After adjusting for imbalances in baseline clinical status, distribution of clinical status on day 14 was similar between 5-day and 10-day groups (P=0.14)

• Median duration of hospitalization for patients discharged by the end of the 14-day period was 7 days for 5-day group and 8 days for 10-day group; more patients discharged from 5-day group than 10-day group (60% vs 52%), and mortality was lower (8% vs 11%, respectively)

• Discharge rates were higher for any enrolled patients who had symptoms for less than 10 days prior to first remdesivir dose (62%) compared to those with symptoms for 10 or more days prior to first dose (49%)

• Proportions of patients who recovered (from score of 2-5 to score of 6-7) was 64% for 5-day group and 54% for 10-day group

• Median time to recover was 10 days for 5-day group compared to 11 days for 10-day group

• Post-hoc analysis of outcomes among patients on invasive mechanical ventilation or ECMO on at day 5 of trial showed 40% mortality in 5-day group compared to 17% mortality in 10-day group

• Characteristics associated with shorter time to clinical improvement were an age <65 years, black and white race, a baseline oxygen requirement of low-flow oxygen or ambient air, no use of a biologic medication, and enrollment outside Italy

Safety

• Percentages of patients who experienced adverse events were similar between 5-day group (70%) and 10-day group (74%), with serious adverse events in 21% of 5-day group patients and 35% of 10-day group patients; grade 3 or higher adverse event occurred in 30% of 5-day group and 43% of 10-day group

• Most common adverse events: nausea (10% in 5-day group vs 9% in 10-day group), acute respiratory failure (6% vs 11%), increased ALT (6% vs 8%), and constipation (7% both groups); percentages of patients who discontinued treatment due to adverse events was 4% in 5-day group and 10% in 10-day group

• Acute respiratory failure (9% in 10-day group vs 5% in 5-day group) and respiratory failure (5% vs 2%, respectively) more common in 10-day group

• Laboratory abnormalities grade 3 or higher reported in 27% of 5-day group and 34% of 10-day group

• Grade 4 creatinine clearance reductions reported in 12% of 10-day group vs 3% of 5-day group

Discussion

• This trial did not find a significant difference in efficacy between 5-day and 10-day courses of intravenous remdesivir treatment of patients with severe COVID-19 who did not require mechanical ventilation at baseline

• After adjusting for baseline imbalances in disease severity, both 5-day and 10-day groups showed similar outcomes as measured by clinical status at day 14, time to clinical improvement, recovery, and death from any cause

• Results cannot be extrapolated to critically ill patients as few were included in this trial

• Apparent trend toward better outcomes for 5-day treatment group vs 10-day treatment group may be due to 10-day group including a significantly higher percentage of patients requiring mechanical ventilation and high-flow oxygen as well as a higher proportion of men in the 10-day group (68% vs 60%), who are known to have worse outcomes

• This trial is not a test of efficacy of remdesivir as no placebo group was included

• Phase 1 studies of remdesivir have shown transient elevations in liver enzymes; in this trial, 2.5% of patients in the 5-day group and 3.6% of patients in the 10-day group discontinued treatment due to aminotransferase elevations

• Patients in 10-day group had more grade 3 or higher creatinine elevations and had more declines in creatinine clearance compared to the 5-day group

• It is unclear whether these above adverse events occurred more frequently in the 10-day group due to the longer treatment time with remdesivir or due to other factors, which may include the fact that patients in 10-day group had significantly worse baseline disease severities and COVID-19 may cause liver and renal injury

• Limitations:

  • Lack of placebo control group

  • Open-label design, which was employed due to low supply of available matched placebo vials and desire to discharge patients from the hospital as soon as medically indicated regardless of treatment completion status; as a result, only 44% of 10-day group completed full course of treatment

  • No SARS-CoV-2 viral-load results available in this trial

• Patients who progress to mechanical ventilation may benefit from 10-day course of remdesivir; more research in this area is needed

Introduction

• The COVID-19 pandemic has placed a spotlight on vaccine development

• Vaccines are currently under development and some are undergoing clinical trials

• A vaccine approved for public use in the absence of extensive safeguards may not only affect COVID-19 prevention efforts, but may also cause harm in public trust for vaccination efforts worldwide

Vaccine Hesitancy and Refusal

• Vaccine hesitancy and refusal have been increasing long before the COVID-19 pandemic

• Outbreaks of measles and other vaccine-preventable illnesses, such as pertussis and influenza, have increased in recent decades

• Distrust in vaccines is partly driven by widespread misinformation from online sources and skeptical communities

• Physicians and scientists promote vaccines whose benefits far outweigh their risks and which have been extensively studied to establish their safety

• However, beliefs that vaccines cause harm persist, despite scientific evidence to the contrary

• The authors argue that, to maintain the public trust, physicians and scientists must not promote a vaccine that has bypassed established safety standards in its development and testing

Historical Precedents

Salk Polio vaccine

• Inactivated polio vaccine developed by Jonas Salk declared “safe, potent, and effective” following largest public health experiment in the nation’s history

• Vaccine had showed success in trials, but outcry for public release of vaccine led to five pharmaceutical companies producing the vaccine with little oversight and releasing it prematurely in some cases

• Cutter Laboratories polio vaccine was contaminated with live poliovirus and 70,000 children who received this vaccine developed muscle weakness, 164 were permanently paralyzed, and 10 died

• This event forced the federal government to intervene and establish a regulatory landscape to ensure the safety and effectiveness of vaccines

1976 Influenza Vaccine

• Fearing emergence of a new swine flu strain reminiscent of the 1918 pandemic, the U.S. created a government-backed mass vaccination program

• This attempt to quickly vaccinate the public failed in multiple ways. One manufacturer produced the incorrect strain; the vaccine tested in children caused some to develop adverse reactions of fever and sore arms while others did not amount an immune response at all; and reports emerged claiming that this vaccine may have caused Guillain-Barré syndrome in a very small number of cases, findings that remain controversial but contributed to early the early momentum of the antivaccine movement

• The pressure to rapidly develop a vaccine undermined scientific integrity and damaged public trust

Potential Adverse Consequences

• Immense pressures to develop a vaccine must not supplant rigorous scientific practice

• The authors argue that developers must adhere to stepwise procedure through clinical trials and adhere to the scientific method to safeguard against a potentially ineffective or harmful vaccine

• The authors argue that harm done by a rushed COVID-19 vaccine may cause a drop in vaccination for other diseases, cause a resurgence of vaccine-preventable diseases, and harm the public trust in vaccines

Authors’ Concluding Arguments

• Safeguards, including technological advances and regulatory oversight in vaccine development, should be communicated to the public during the vaccine development process

• Novel trial designs such as those that include challenge studies should be considered

• Desperation for a vaccine must not result in the suspension of scientific principles and ethical research values

• Physicians should not administer inadequately vetted vaccines; researchers should not endorse them without sufficient data

Introduction

This Perspective seeks to outline promising platforms and current and anticipated challenges in the development of SARS-CoV-2 vaccines as determined by the Coalition for Epidemic Preparedness Innovation.

Background

Recent vaccine development efforts in response to pandemics, including H1N1 influenza, Ebola, and SARS, have stressed the need for novel pandemic vaccine development-and-manufacturing platforms that may be adapted to newly emerging pathogens. Such efforts have received investment from vaccine and biotech companies as well as support from the U.S. government and other nations. The Coalition for Epidemic Preparedness Innovation (CEPI), an international nongovernmental organization, is supporting the development of vaccines for five epidemic pathogens on the World Health Organization (WHO) priority list, aiming to develop reserves of investigational vaccines that have completed phase 2a trials which could undergo clinical trials during future outbreaks. CEPI also supports development of platform technologies for newly emerging pandemics.

Potential Vaccine Development Platforms

CEPI’s ideal vaccine development platform “would support development from viral sequencing to clinical trials in less than 16 weeks, demonstrate elicitation of consistent immune responses across pathogens, and be suitable for large-scale manufacturing using a pathogen-agnostic platform”.

Platforms under development:

• DNA- and RNA-based vaccines

  • May be made quickly through synthetic processes

  • Rapid testing and release may be facilitated by developer familiarity with these types due to platforms for personal oncology vaccines

  • Regulators have experience in reviewing applications and with manufacturing of such vaccines

• Recombinant-subunit vaccines

• Next-generation sequencing and reverse genetics technologies may cut development time of conventional vaccine types

• Table: Vaccine Platforms, Their Attributes, and the Status of Vaccine Candidates

Challenges of SARS-CoV-2 Vaccine Development

• Debate regarding optimizing antigen design to target the SARS-CoV-2 spike protein

• Preclinical experience with SARS and MERS vaccine candidates raise concerns about exacerbating lung disease

  • This adverse effect may be associated with type 2 helper T-cell response

  • Testing in suitable animal model will be necessary, but it is still too early to define good animal models

  • Rigorous safety monitoring in clinical trials will be critical

• Potential duration of vaccine-induced immunity and number of vaccine doses required is not yet known

• Developing a vaccine quickly challenges the normal linear process for vaccine development

  • Traditional vaccine development uses a linear process, with multiple pauses for development and manufacturing review, that may take years

  • Vaccine development during a pandemic requires a different paradigm, with a fast start and many steps occurring in parallel, elevating financial risks

    • For example, animal studies and phase 1 clinical trials may be carried out concurrently

    • Goal is to shorten development so vaccine may be available quickly

    • Comparison of traditional paradigm vs outbreak paradigm

• The use of new platforms to develop vaccines quickly may require facilities to adapt new technologies and manufacturing processes before it is known if that vaccine is viable

• It is uncertain whether new platforms will be able to produce effective vaccines in sufficient quantities, so it is critical to also develop vaccines using tried-and-true methods as well

• Conducting clinical trials presents additional challenges:

  • Uncertain where and when outbreaks will occur

  • Randomized controlled trials with placebo groups may not be accepted by populations in a high-mortality pandemic scenario

• There is currently no global entity responsible for financing or ordering vaccine manufacture in a pandemic

• Pandemics generate simultaneous demand around the world for vaccines

  • Clinical and serologic studies will be required to identify populations at highest risk in need of vaccination

  • Such studies could form the basis for establishing a globally fair vaccine allocation system

Broader Discussion

If the pandemic abruptly ends, vaccines should still be developed and stockpiled and ready for clinical trials and emergency authorization if an outbreak should recur. A global financing system that promotes development of effective vaccines quickly and while ensuring fair allocation and protecting private-sector partners from significant financial losses will be a critical component in preparing for future pandemics.

Limitations

CEPI has limited funds to allocate to additional SARS-CoV-2 vaccines and will need to secure funding for further investigational efforts.

Table 1 (Vaccine Platforms, Their Attributes, and the Status of Vaccine Candidates) only shows some current vaccine candidates, where “[a] more complete and continually updated list is available from the WHO.”, cited below:

World Health Organization. Draft landscape of Covid-19 candidate vaccines. April 20, 2020

Background

Much of the scientific discussion generated from the COVID pandemic has focused on acute care of COVID patients, ethical allocation of resources, and mental health status of health care workers. As this initial wave of the pandemic starts to wind down, the attention has shifted to caring for those who are recovering from COVID. There is a demand for rehabilitation services to care for those who have severe sequelae following a COVID infection. Previous literature has shown that the elderly population has been hardest hit by the pandemic, with a high incidence of severe disease and mortality. An additional study reported that approx. 30% of affected patients will require rehabilitation after a COVID infection. Elderly patients with COPD who have undergone respiratory rehabilitation had improvements in their respiratory function and quality of life. Therefore, the authors of this study felt it was important to evaluate whether timely respiratory rehabilitation can help maximize respiratory function and improve the quality of life in elderly patients recovering from COVID-19.

Study Design

To evaluate the impact of a 6-week respiratory rehabilitation program on the lung function and quality of life of elderly patients recovering form COVID-19, researchers evaluated a total of 72 patients from Hainan General Hospital Central Hospital and Huanggang Central Hospital (China). To qualify, these participants had to have a positive diagnosis of COVID-19, aged ≥ 65, MMSE score above 21, FEV1 ≥70%, and have no other respiratory diseases or moderate/severe heart disease. 36 of these participants underwent a 6-week respiratory rehabilitation program, the rest served as controls and did not receive rehabilitation interventions. The authors assessed changes in PFTs including plethysmography and DLCO, functional tests (6-min walk distance test), Quality of life (QoL) assessments (SF-36 scores), activities of daily living (Functional Independence Measure, FIM scores), and mental status tests (SAS anxiety and SDS depression scores).

Discussion

The study found that the participants who underwent the respiratory rehabilitation intervention showed significant differences in FEV1(L), FVC(L), FEV1/FVC%, DLCO% and 6-min walk test compared to control participants. The experimental group also showed a statistically significant increase in quality of life scores using the SF-36 assessments. There were no statistically significant changes in functional independence measures. The mental status tests showed that only symptoms of anxiety were significantly reduced, and no significant change in symptoms of depression. The study team attributes the success in improving lung function to the rehabilitation programs ability to improve the function of the respiratory muscles. The exercise regime that is part of respiratory rehabilitation is attributed to improved scores on the 6min walk test. The exercise has previously shown to improve patients’ ventilation and gas exchange, cardiovascular function and limb muscle strength. The authors noted that the rehabilitation program did not improve living ability (ADLs), and rationalize that this may be due to the short duration of the intervention. The statistically significant improvement in anxiety symptoms in this study matched the trend of a similar study with COPD patients. Furthermore, in this study the positive changes in depression symptoms were not statistically significant which mirrors the results of a similar respiratory rehabilitation intervention with COPD patients. Although this study was done in China, I believe the results are generalizable to the States. Though the rehabilitation intervention was shorter than what may be required for these patients long term, the study demonstrated the importance of timely respiratory rehabilitation in elderly patients recovering from COVID-19. It is important for PM&R specialists to anticipate the demand for rehabilitation services, not only for lung function but for heart and neurological function etc. in this new patient population.

Purpose/Background

This study asks if general anesthesia and epidurals can safely be administered in COVID patients needing cesarean. Few data exist on the outcomes of many common anesthesia procedures with COVID patients and risks of transmission to the medical teams performing these procedures is similarly unknown. The risk of potentially introducing the virus into the CSF were unknown in these patients with active infection.

Methods

Retrospective case reports of 17 women needing Cesarean delivery and being COVID positive in Wuhan China. 14 received continuous epidurals. 3 needed general anesthesia for emergency surgery. Information regarding the isolation and cleaning protocols at this hospital were given. All patients, neonates, medical team members were tested for SARS-CoV2. Basic statistical measures regarding demographics, clinical characteristics and outcomes are reported.

Results

No medical staff nor neonates tested positive for SARS-CoV2. The rates of critical illness in this population were lower than in the general COVID population. There were no adverse events as a result of anesthesia reported for mothers nor neonates. 86% of mothers receiving epidural experienced intraoperative hypotension.

Discussion

Data from this study, albeit limited, are encouraging; general and neuraxial techniques were able to be preformed safely without transmission of the virus.

Neonatal transmission was non-existent and to date SARS-CoV2 has not been detected in breast milk, amniotic fluid, cord blood. Presence of the virus in placental tissue is still unknown so elective Cesarean is still recommended. Transmission to the neonate in vaginal delivery is unknown.

Neuraxial anesthesia is recommended, due to SARS-CoV2 effect on lung tissue. Though the general anesthesia group suffered no adverse events.

Purpose/Background

Intubation presents a significant risk to healthcare workers. Rapid sequence intubation with hi-flow nasal cannula reduces the exposure time for healthcare workers compared to standard BVM oxygenation. Which may in turn reduce rates of transmission.

Methods

This was a prospective RCT. 58 patients were sorted into either hi-flow or BVM groups. 6 anesthesiologists preformed fiber optic intubations in batches of 10 with patients evenly from each group. Primary outcome was time to intubation. Secondary outcomes included oxygenation status. Co-morbidities and demographic information were also gathered.

Results

Time to intubation was significantly lower in the hi-flow group. Hi-flow also had a higher lowest SpO2 and lower need for rescue face mask ventilation during intubation attempts.

Discussion

Hi-flow has been shown to improve oxygenation. The authors suspect that improved time required for intubation was as result of decreased need for interuption to perform rescue BVM. Fiber-optic tracheal intubation has the added benefit of increasing the distance between patient and anesthesiologist. While time to intubation was significantly reduced in the study it remains unclear how significant a reduction of 8 seconds per intubation on average would be on transmissibiilty.

Discussion

This article provide several recommendations for best practices surrounding patients with COVID-19 in the emergency department nearing the end of life. Although care should not differ overall from palliative care best practices, a number of modifications must be made with regard to COVID-19, as to balance symptom management with minimizing transmission to health care providers. Notably, these include avoiding the use of fans, high-flow oxygen, and all nebulized treatments as to avoid aerosolized SARS-CoV-2. Similarly, patients should not be extubated in the ED, given that extubation is an aerosol-generating procedure. Ventilatory support should be decreased to ensure patient comfort. Visitation should adhere to local protocols, and family members must follow droplet and contact precautions, video conferencing if possible.

More broadly, the authors state that decision-making should be addressed early in the patient’s illness and should not be affected by overall resource abilities without the oversight of administrators and ethicists. Finally, the staff who are providing end-of-life care should also be supported as to minimize burnout and compassion fatigue.

Introduction

Hydroxychloroquine has been suggested as a potential treatment for COVID-19, with its anti-inflammatory and antiviral properties. This study examined the association between hydroxychloroquine use and respiratory failure (intubation or death) at a medical center in New York City. The authors hypothesized that hydroxychloroquine usage would be associated with a lower risk of composite end point of intubation or death, adjusting for major predictors of respiratory failure.

Methods

This study was conducted at the New York-Presbyterian Hospital-Columbia University Irving Medical Center (CUIMC). Patients who received hydroxychloroquine 24 hours after arrival at the emergency department (study baseline) and had been confirmed COVID cases through RT-PCR were included in the study. The primary end point event was determined to be from study baseline to intubation or death.

Results

1376 patients were included in the analysis. 346 patients (25.1%) had a primary end point (180 were intubated, 166 died before intubation). Of the 1376 patients, 811 (58.9%) received hydroxychloroquine. In the unadjusted analysis, patients who received hydroxychloroquine were more likely to have a primary end point than those who did not. But once the data was adjusted for (multivariate analysis with inverse probability weighting according to propensity score), there was no significant association between hydroxychloroquine usage and the primary end point.

Discussion

Given the observational nature of the study, the harms and/or benefits of hydroxychloroquine cannot be definitively concluded with this data. However, it can be said that the risk of intubation or death was not significantly different among patients who received hydroxychloroquine and those who did not.

What is the purpose of these responses?

• • To warn the public and Caly et al that the findings in the ivermectin study should be taken with a grain of salt

Main points:

• • In the ivermectin study (review below), Caly and colleagues confirmed in an in vitro assay that ivermectin, an FDA-approved anti-parasitic agent, showed potent inhibitory properties against SARS-CoV-2 infection, decreasing viral RNA levels by 99.8% within 2 days

  • Main points made by Dr. Craig Rayner:

    • The pharmacokinetics of ivermectin was not mentioned

      • Ivermectin has a short half life of 3-5 hours, which requires multiple doses of ivermectin in real life

      • The max plasma concentration of ivermectin decreases by approximately 80% with oral administration

      • Ivermectin does not primarily localize in the lungs

    • After using a physiologic-based pharmacokinetic model, the data from Caly and with generous assumptions, the IC50 in the plasma and lung tissue was over 9 times and 21 times greater, respectively, than Caly’s original findings

  • Main points made by Dr. Francois Noel:

    • The IC50 mentioned in the paper (2-3 uM) is significantly higher than the IC50 (in nM range) effective against parasites

    • High ivermectin concentrations most likely will lead to off-target effects and toxicity in humans

  • Main points made by Drs. David Jans and Kylie Wagstaff:

    • Ivermectin is a host-directed agent, meaning that it targets host proteins, not a viral component

    • Regardless of concentration (even at lower doses), ivermectin can still cause off-target effects since it does not directly inhibit viral proteins

What is the purpose of this study?

• • To test whether ivermectin, an FDA-approved anti-parasitic agent, has inhibitory activity against SARS-CoV-2 infection

Main points:

• • Using an in vitro cell culture model with Vero/hSLAM cells and the isolated SARS-CoV-2 Australia/BIC01/2020, this group showed promising results that confirm that ivermectin has antiviral activity against this strain of SARS-CoV-2

  • There was a 93% decrease and a 99.8% decrease in viral RNA after 24 hr and 48 hr of 5 uM ivermectin treatment

  • They claim that no toxicity was present but they did not provide a cytotoxicity coefficient 50%

  • Ivermectin targets a different part of the SARS-CoV-2 life cycle (replication) than other active compounds like hydroxychloroquine (entry)

    • More in vitro and in vivo studies need to be performed with these compounds

    • It would be interesting to see if ivermectin and hydroxychloroquine could work synergistically together first in an in vitro model

What is the purpose of this study?

• • To compare the effectiveness of chloroquine and hydroxychloroquine as a potential therapeutic and prophylactic agent against SARS-CoV-2 infection

Main points:

• • Using an in vitro cell culture model with Vero cells derived from African green monkey kidney and the isolated SARS-CoV-2 C-Tan-nCoV Wuhan strain 01, this group was able to confirm that both chloroquine and hydroxychloroquine were both active against this strain of SARS-CoV-2

  • Hydroxychloroquine was more potent and had a greater max inhibition than chloroquine, indicating that hydroxychloroquine may lead to fewer off-target effects

    • Hydroxychloroquine had an EC50 of 0.72 uM while chloroquine had an EC50 of 5.47 uM

    • A cytotoxicity assay was not performed in this study so it is unclear whether viral inhibition at higher drug concentrations was due to the compound or due to cell death

    • Both chloroquine and hydroxychloroquine showed potential as a prophylactic treatment, but hydroxychloroquine showed to be almost three times as effective

  • Using a physiologically-based pharmacokinetic (PBPK) model, the group was able to predict the dosages of hydroxychloroquine and chloroquine to potentially treat SARS-CoV-2 infection

    • Further in vivo testing is required but based on their PBPK model, they suggest a loading dose of 400 mg twice per day and a maintenance dose of 200 mg twice per day for 4 days

    • In this model, they used virtual subjects with ages between 20 and 50, and divided the sexes as 50:50

Introduction

• There are currently no effective treatments for the SARS-CoV-2 virus.

• Severe COVID-19 infection and respiratory failure has been associated with host immune response and excessive production of proinflammatory cytokines.

• Immune-modulatory treatments such as IL-6 and IL-1 antagonists have been suggested as possible therapeutics for COVID-19.

Background

• Use of tocilizumab, an interleukin-6 inhibitor, was reported to be effective in improving clinical outcomes in a small number of patients with severe COVID-19 in China.

• Baricitinib is an anti-inflammatory drug that inhibits cytokine release and is used in treatment of rheumatoid arthritis.

• Baricitinib is a Janus kinase inhibitor and has an affinity for AP2-associated protein AAK1 which has been suggested to potentially reduce SARS-CoV-2 endocytosis.

Study Design

• 12 patients (10 males, 2 females) with a median age of 63.5 years who had moderate COVID-19 pneumonia were treated with baricitinib (4 mg/day/orally) for 2 weeks.

• The open-label trial was conducted in Prato and Alessandria, Italy and approved by the Azienda-USL Toscana Centro Committee for off-label use of drugs.

Findings

• Patients treated with baricitinib showed clinical improvement at both week 1 and week 2 compared to baseline, and none were transferred to the ICU.

• Fever, SpO2, PaO2/FiO2, CRP, and modified early warning score (MEWS) significantly improved in baricitinib-treated patients over two weeks, and no adverse events were reported.

• Major limitations of this study include the open-label design, lack of randomization, small number of treated patients, and lack of a proper control group.

Conclusion

• Baricitinib therapy improved clinical and laboratory parameters of twelve patients treated over two weeks.

• None of the patients required ICU support, and no adverse effects were reported after 2 weeks.

• Further studies are needed to demonstrate efficacy of baricitinib before its use as a therapeutic should be generalized to all COVID-19 patients.

*In press, corrected-proof

Introduction: JAK Pathway Inhibitors

This review looks at the feasibility of trialing different JAK pathway inhibitors in the treatment of COVID-19 patients. The JAK pathway is key to the activation and development of the “cytokine storm” which can lead to a hyperimmune response to infection. Several JAK inhibitors have already been developed, and now they are being tested for efficacy in improving outcomes among COVID-19 patients.

Key Points

• COVID-19 patients admitted to ICU-level care had increased levels of IL-2, IL-6, IL-10, IFN-gamma, TNF-alpha, and many other cytokines and chemokines.

• Tocilizumab and sarilumab, anti-IL-6R antibodies, have been studied in CAR T-cell driven cytokine release syndrome (CRS) which is similar to inflammation in COVID-19. Pilot studies in COVID patients has shown some respiratory and laboratory improvement.

• BTK inhibitor ibrutinib has been shown in a case series and preclinical studies to provide some lung protection from injury.

• Baricitinib is a disease-modifying anti-rheumatic drug (DMARD) and is a first-generation JAK inhibitor. Clinical trials have shown that in addition to standard-of-care therapy, baricitinib improves clinical presentation, pulmonary function tests, and C-reactive protein (CRP) levels in COVID-19 patients. It is also associated with a decrease in intensive care transfers.

• Negative side effects of baricitinib include possible herpes zoster reactivation, reduction of NK cell levels, and increased thromboembolic risk. More prospective clinical trials are needed with these drugs before they can be recommended for repurposing.

Significance

• The data in humans is too limited to support or refute the concerns of using RAAS inhibitors during the COVID-19 pandemic. This article recommends against withdrawal of RAAS inhibitors in high-risk patients with known or suspected COVID-19. They use two arguments: 1. there are uncertain effects of RAAS inhibitors on ACE2 levels and 2. there may be a hypothetical benefit to ACE2 in patients with lung injury.

Background

• SARS-CoV-2 interface with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2 (ACE2) and has been proposed to be a potential factor in their infectivity. There are concerns about the use of RAAS inhibitors during the ongoing COVID-19 pandemic.

Review of literature

• • There is no rigorous data showing a clear relationship between hypertension and COVID-19 deaths. Instead, age is emerging as the strongest predictor of COVID-19-related deaths and may explain the current data.

  • Only 30-40% of patients in China with hypertension are treated with any antihypertensive. RAAS inhibitors are only used in 25-30% of treated patients.

  • Animal models and human studies have inconsistent findings with respect to effects of ACE and ARB inhibitors on ACE2 protein levels, with some showing increased ACE2 levels.

  • Restoration of ACE2 appeared to reverse devastating lung-injury process in preclinical models of other viral infections and safely reduced angiotensin 2 levels in a phase 2 trial evaluating acute respiratory distress syndrome in humans.

  • Administration of recombinant ACE2 normalizes angiotensin 2 levels in human explanted hearts with dilated cardiomyopathy.

Analysis

• • Clinical trials are under way to test the safety and efficacy of RAAS modulators, including recombinant human ACE2 and the ARB losartan in COVID-19.

  • Abrupt withdrawal of RAAS inhibitors in high-risk patients, including those who have heart failure or have had myocardial infarction, may result in clinical instability and adverse health outcomes.

  • Until further data is available, RAAS inhibitors should be continued in stable patients who are at risk for or with COVID-19.

Remdesivir is an investigational antiviral drug that has previously shown activity in cell culture and animal models against SARS-CoV, MERS-CoV and SARS-CoV-2. The drug prevents viral RNA synthesis by inhibiting RNA polymerase. It is currently not approved for any indications.

One randomized, double-blinded, placebo-controlled trials conducted by the National Institute of Allergy and Infectious Disease and another open-label trial sponsored by Gilead showed potential benefits of Remdesivir administration, outweighing the potential risks of the drug, for patients hospitalized with severe COVID-19.

Remdesivir is currently approved under the EUA for patients (adults and children) with suspected, or laboratory confirmed COVID-19 and severe disease (SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation). Remdesivir should be administered in in-patient hospital settings, using intravenous infusion and in accordance with dosing regimens detailed in the Facts Sheet.

Background

• There are currently no vaccines for COVID-19, and investigation into potential therapeutic drugs is ongoing.

• Monoclonal antibodies (mAbs) are a candidate treatment method under investigation.

• The SARS-CoV-2 receptor binding domain (RBD) and associated S1 and S2 proteins are likely the best targets for a mAb treatment, as they facilitate viral entry through interaction with ACE2.

Study Design

• 26 patients who had recently recovered from COVID-19 were tested for IgG antibodies to the SARS-CoV-2 S1 protein and the RBD.

  • An ELISA-based inhibition assay was then used to determine whether anti-RBD IgG antibodies actually blocked the binding of the SARS-CoV-2 RBD to ACE2.

• Once IgG antibodies effective at blocking the RBD-ACE2 interaction were identified, they were cloned for further experimental assays.

  • In order to clone the antibodies of interest, peripheral blood mononuclear cells were taken from each of the patients with the relevant antibodies. Flow cytometry was then used to isolate anti-RBD IgG positive B cells. RT-PCR was used to amplify the IgG variable light and heavy chains (VLs & VHs) from each B cell, and cloned VLs and VHs were inserted into plasmids encoding constant regions of human IgG antibodies.

• The anti-RBD mAbs were tested to determine efficacy in binding to the SARS-CoV-2 RBD and in inhibiting RBD-ACE2 binding.

• A SARS-CoV-2 pseudovirus was then used to test infection ability in the presence of the anti-RBD mAbs.

Results

• All 26 patients were found to have anti-S1 and anti-RBD IgG antibodies; however, only 3 contained anti-RBD antibodies effective at blocking the RBD-ACE2 interaction.

  • From these 3 patients, 3 pairs of VHs and VLs were cloned, creating 3 potential mAb treatments.

• All 3 mAbs were able to bind to the RBD, and 2 were effective at blocking the RBD-ACE2 interaction.

  • These 2 mAbs were also effective at preventing SARS-CoV-2 pseudovirus infection.

Conclusions

This study was able to produce 2 mAbs that effectively blocked the binding of a SARS-CoV-2 pseudovirus RBD to ACE2, preventing viral entry. While further investigation is ongoing, these antibodies could potentially serve as a novel COVID-19 treatment method.

Tocilizumab is a humanized anti-human IL-6 receptor antibody of the IgG₁ subclass that prevents a cytokine storm in patients progressing to cardiovascular collapse, multiple organ dysfunction and death. Chinese and Italian guidelines have supported the use of tocilizumab as a treatment option for patients with severe COVID-19. Specifically, a dosage of 8 mg/kg and a second dose after 12 hours, with a third dosage sometimes necessary.

It is critical to rule out several contraindications prior to administration:

1. Transaminase levels > 5 times the upper limit of normal

2. Neutrophil count < 500 cells/µL

3. Platelet counts < 50,000 cells/µL

4. Presence of sepsis

5. Complicated diverticulitis/intestinal perforation, cutaneous infection or immunosuppressive anti-rejection therapy

Three patients in Italy who were diagnosed with COVID-19 and developed rapid respiratory insufficiency were prescribed tocilizumab.

Patient 1: 71 y.o. male with a previous history of HTN hospitalized for worsening flu-like symptoms, dyspnea, fever and poor respiratory exchange. Antiviral therapy (lopinavir/ritonavir plus hydroxychloroquine) did not improve symptoms. Following administration of tocilizumab, fever resolved after 3 days, with PaO2-to-Fio2 ratio improving. Repeat testing was negative for SARS-CoV-2.

Patient 2: 45 y.o. previously healthy male hospitalized for fever, worsening dyspnea and chest pain. Antiviral therapy was initiated, some initial improvements were seen but he developed dyspnea for mild efforts, an increase in CRP and bilateral interstitial pneumonia. Following administration of tocilizumab, clinical conditions improved, with resolution of fever and rapid reduction in CRP. It is unclear whether the patient fully recovered and tested negative on repeat SARS-CoV-2 testing.

Patient 3: 53 y.o. male with a previous history of HTN admitted for non-resolving flu-like symptoms with interstitial bilateral pneumonia on X-ray imaging. Antiviral therapy was initiated, however respiratory symptoms worsened. Tocilizumab was administered in three doses with progressive resolution of dyspnea. Similar to patient 2, it is unclear whether the patient fully recovered and tested negative on repeat

Conclusions

Tocilizumab may be indicated as a potential therapeutic option in the treatment of Covid-19. Rapid relief of fever and respiratory symptoms were observed in these three patients. Further studies are needed to determine if certain levels of IL-6 are critical for the selection of candidates for tocilizumab therapy.

Key Points

• Tocilizumab is a humanized recombinant monoclonal antibody that is an interleukin (IL)-6 receptor antagonist currently FDA approved for the treatment of cytokine release syndrome.

• CT has a major role in COVID-19 patients with a false negative PCR result, and in the monitoring of disease progression and evaluation of treatment efficacy.

• Two day Tocilizumab treatment showed promising changes on CT imaging in a patient with COVID-19 pneumonia

Case Report

Day 1

A 64-year old man presenting with initial symptoms of syncope.

• Chest X-ray showing mild linear densities in the lower and middle left lung fields.

• COVID-19 was detected via throat swab sample, real-time polymerase chain reaction (RT-PCR).

• Worsening CRP, WBC and serum lactate levels prompted admission to a COVID-19 ward.

Day 6

• The patient began experiencing worsening dyspnea, decreased oxygen saturation and elevated IL-6 levels 80 ng/L (normal < 6 ng/dL).

• Unenhanced chest CT showed presence of diffuse bilateral air space opacities, including ground glass opacities, consolidation with prevalent posterior, peripheral distribution, mild bilateral pleural effusion and mediastinal lymphadenopathy.

Days 7 and 8

• Ventilation was started and the patient received 2 doses of tocilizumab (8 mg/kg), 12 hours apart.

Days 9

• CRP and WBC counts dropped.

• The patient’s clinical presentation improved and ventilation support

Day 14

Repeat CT showed marked improvement of findings, with reduction of air cell opacities, density reduction of consolidation, pleural effusion and mediastinal lymphadenopathy.

• Summary

Hydroxychloroquine, an antimalarial drug also used in chronic rheumatic disease, and chloroquine has been promoted as effective therapeutic agents against COVID-19 by some studies. However, the accuracy and reliability of this claim are yet to be adequately supported. Borba et al’s study conclusion should be revised to denote that coadministration of high-dose chloroquine, and by extension hydroxychloroquine, with azithromycin and maybe oseltamivir “is potentially associated with increased mortality among patient with severe, suspected COVID-19” and not “that high-dose chloroquine was toxic and that the likely mechanism was arrhythmogenesis”. Several trials are currently underway that may further elucidate the safety and efficacy of hydroxychloroquine.

• About Borba et al’s study:

  • Aim:

    • To assess the safety of different doses of chloroquine, that were thought to display antiviral effect, as a pharmacologic treatment for COVID-19 patients in a parallel, double-blinded, randomized clinical trial in Brazilian population.

  • Method:

    • They compared two groups - high-dose chloroquine 600 mg BID for 10 days (12 g total) vs low-dose chloroquine 450 mg BID on day one and once daily for 4 days (2.7 g total).

    • Primary outcome was death assessed at 28 day; secondary outcome was death assessed at 13 days, ECG anomalies, recovery of viral RNA, and clinical events.

  • Results:

    • Treatment was initiated based on clinical suspicion of infection due to delay in testing. 31 of 40 patients (77.5%) in the low-dose group eventually tested positive for COVID-19; and 31 of 41(75.6%) tested positive in the high-dose group.

    • The originally planned sample size of 440 was halted at only 81 after serious safety concerns surfaced.

    • 6 of 40 (15%) patients in the low-dose group died vs 16 of 41 patients (39%) in the high-dose group.

    • QTc prolongation was present in 4 of 36 patients (11.1%) in the low-dose group vs 7 of 37 patients (18.9%) in the high-dose group.

    • Ventricular tachycardia was observed in 2 patients in the high-dose group, and 3 of 5 patients in the high-dose group had underlying heart disease.

    • There was no obvious association of prolonged QTc and death, and no torsades de pointes was observed.

  • Limitations:

    • Treatment was initiated based on clinical suspicion of infection due to delay in testing. Not all patients tested positive for COVID-19.

    • Chloroquine was co-administered with azithromycin and oseltamivir making the conclusions questionable.

Background

• To date, there remain no treatments for COVID-19; therefore, there is a necessity to continue research and evaluation of potential therapeutics.

• The most recent Chinese guideline emphasized the use of convalescent plasma for emergent therapy for management of severe COVID-19 cases.

• While some data shows improvement in patients with severe COVID-19 who have received convalescent plasma, there remain issues with its use that must be addressed.

Study Design

• Letter to the Editor

Key Points

• Prior studies with SARS have shown that convalescent plasma therapy is more effective earlier in disease course, thus consideration must be given to optimal timing of therapy.

• The effect of convalescent plasma on COVID-19 is determined by

  • SARS-CoV-2 neutralizing antibody titer level has been shown to determine the therapeutic effect of the convalescent plasma for patients with severe COVID-19; therefore, the timing of convalescent plasma acquisition from donors is particularly important and could limit the widespread application of its use (e.g. more patients in need than recovered).

  • Adverse reactions to convalescent therapy include fever, chills, anaphylaxis, and transfusion-related acute lung injury, and must be considered before treating patients.

  • Additionally, risks of transfusion-transmitted infections including HIV, syphilis, hepatitis B virus, and hepatitis C virus must also be considered and weighed against potential benefits as well.

Conclusion

• In evaluating convalescent plasma as a potential treatment for COVID-19, challenges must be addressed including timing, source, risks, adverse reactions, and distribution.

Emerging evidence has come to show that COVID-19 can be complicated by disseminated intravascular coagulation (DIC), a prothrombotic state with a high risk of venous thromboembolisms. Recent recommendations now suggest that all hospitalized patients with COVID-19 receive thromboprophylaxis.

Coagulopathy and COVID-19

There is between a 13% to 31% in the rate of venous thromboembolism (VTE) occurrence in ICU patients without thromboprophylaxis. In a study recently done by Cui et al, they reported the prevalence of VTE in 81 COVID-19 patients admitted to the ICU with pneumonia, who were not receiving thromboprophylaxis at 25% (40% of these patients ended up passing away). Coagulopathy is known to be a complication in the majority of patients who die because of COVID-19, and low molecular weight heparin (LMWH) has been shown to lower mortality. D-dimer, a marker for fibrin formation and degradation and thus coagulopathy, has been shown to be a good prognostic tool for predicting VTE in COVID-19 patients. The International Society on Thrombosis and Hemostasis (ISTH) states that in COVID-19 patients with markedly elevated d-dimer, without major symptoms suggesting severe disease, hospital admission should still be considered for these patients.

Anticoagulant therapy in COVID-19

Thus, anticoagulant therapy might improve the prognosis for severely ill COVID-19 patients who are at an increased VTE and mortality risk. It is also of note, that all severe COVID-19 patients in ICUs share the same predisposing factors for VTE as those who are hospitalized on the wards – namely, isolation and thus immobilization. COVID-19 does have additional risks which might also contribute to this association, however, such as endothelial damage, microvascular thrombosis and occlusion, and perhaps even autoimmune. More research needs to be done to establish these associations.

International Society on Thrombosis and Hemostasis Recommendations on thromboprophylaxis for COVID-19 patients

All patients who require hospital admission should receive a prophylactic dose of LMWH, taking into consideration any contraindications.

American Society of Hematology Recommendations on thromboprophylaxis for COVID-19 patients

All hospitalized patients with COVID-19 should receive prophylaxis with LMWH or fondaparinux (in the case of a history of HITT) unless there is an increased risk of bleeding. Use mechanical thromboprophylaxis if anticoagulants are unavailable or contraindicated.

Antihypertensive Background

Several editorials and letters have proposed controversial hypotheses about the potential detrimental/protective effects of antihypertensive drugs acting on the renin-angiotensin-aldosterone system (RAAS) in patients with COVID-19. Drugs inhibiting the RAAS can be further classified via biological target and include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and direct renin inhibitors (DRIs). Both ACEIs and ARBs have been shown to significantly increase the expression and activity of ACE2, which is highly expressed in the heart and lungs.

Current Findings

The spike protein of SARS-CoV-2 binds to ACE2 receptor of the target cell. Therefore, Fang et al. proposed that patients with cardiac diseases. Hypertension, or diabetes mellitus treated with ACE2-increasing drugs might be at a higher risk for severe SARS-CoV2 infection. The authors propose the alternative use of calcium channel blockers (CCBs) due to lack of increased ACE2 expression or activity. However, recently published data suggests that RAAS inhibitors may be beneficial in patients with COVID-19 and recommended against medication alterations. The current article supports this view and highlights the importance of continuing ACEI/ARB treatments.

Argument for Continued ACEI/ARB Usage

There is limited research supporting withdrawal or replacement of ACEI/ARB therapy, with a majority of current data derived from in vitro studies. In addition, studies examining SARS-CoV suggested a protective effect of ARBs against COVID-19 due to the interaction of the coronavirus spike protein and ACE2. This results in ACE2 downregulation and subsequent excessive production of angiotensin by ACE. It has been suggested that this exaggerated stimulation determines increased pulmonary vascular permeability, which mediates increased lung pathology. Therefore, chronic treatment with antihypertensives leads to increased ACE2 expression and may be protective against lung injury in patients infected with SARS-CoV-2. Furthermore, discontinuing antihypertensives in patients with comorbidities may lead to deterioration of chronic disease and increased mortality due to cardiovascular disease. CCBs are not approved for treatment in patients with hypertension, heart failure, and diabetic nephropathy or after acute myocardial infarction. Finally, drug regulatory agencies worldwide have not recommended switching from ACEIs/ARBs to other antihypertensive drugs for the current COVID-19 outbreak.

Antimalarial drugs have been proposed as treatments to reduce the viral load of SARS-CoV-2. In-vitro studies have shown chloroquine and hydroxychloroquine to inhibit transmission by preventing viral spread. Their method of action is through the alkalinisation of the intracellular phagolysosome, thus preventing virion fusion and uncoating.

What current clinical studies have shown of their efficacy in treating SARS-CoV-2

A clinical study in China suggested that the use of chloroquine might have been associated with reduced fever, increased resolution of lung lesions on CT, and delayed disease progression.

Two French studies suggested that hydroxychloroquine combined with azithromycin could reduce the viral load in COVID-19 patients.

However, the Surviving Sepsis Campaign guidelines on managing critically ill COVID-19 patients concluded that there is insufficient evidence to use these drugs in ICU patients.

How can we explain the discrepancy?

1. Clinical observations on the effects of these antimalarial drugs have not been studied in critically ill COVID-19 patients, who are on many more medications and having organ failure, which are things which could contribute to the chance of increased adverse drug events.

2. The clinical data obtained in the studies mentioned above regarding the efficacy of using hydroxychloroquine have several limitations such as a small cohort of patients (20 in the French study), the absence of randomization, and lack of a control group.

3. Viral load is important in determining the severity of the disease, but the use of antivirals and their effectiveness against severe cases of COVID-19 has not been proven.

4. No placebo-controlled clinical trials have been conducted to support the safety and efficacy of using hydroxychloroquine and chloroquine in managing severe COVID-19 cases.

In conclusion, the effectiveness of antimalarial drugs in severe COVID-19 cases remains unknown and further studies need to be conducted to clarify the exact role in which chloroquine and hydroxychloroquine should be utilized in critically ill COVID-19 patients.

Introduction

• There remains no current FDA approved treatment for SARS-CoV-2, and currently patients with COVID-19 continue to receive supportive care.

• In the search for effective treatments, many patients have received compassionate-use or off-label therapies.

Background

• Remdesivir, a nucleotide analogue prodrug, is an antiviral that functions by inhibiting viral RNA polymerases

• Remdesivir has been shown to have broad-spectrum activity against filoviruses and coronaviruses, and in vitro testing has also shown activity against SARS-CoV-2.

• It has been shown to have a favorable clinical safety profile with a safety database of greater than 500 persons that includes both healthy volunteers and patients who had Ebola infections

• This report describes outcomes of a cohort of patients hospitalized with severe COVID-19 who received compassionate-use treatment with remdesivir.

Study Design

• This was a manufacturer-funded (Gilead Sciences) case series of patients with COVID-19 who received a 10-day course of remdesivir (1-day loading dose of 200 mg followed by 9 days of 100 mg qd).

• This study was an open-label program and did not have a predetermined number of patients, number of sites, or duration.

Findings

• 53 patients (aged 23 to 82 years, 75% male) who received remdesivir were included in the study analysis; 22 were in the United States, 21 in Europe, 9 in Japan, and 1 in Canada.

  • 68% had preexisting conditions

  • 64% were receiving invasive ventilation at baseline

• The major finding was that 68% of patients showed improvement in oxygen-support status median follow-up of 18 days.

• Overall, mortality was 13% over a median follow-up of 18 days.

• In regards to drug safety, 60% of patients reported adverse events during follow-up (most common include increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension), and 23% had serious adverse events.

• Some limitations of the study include the small sample size, lack of randomized control group, and lack viral load data.

Conclusion

• In this small cohort of hospitalized patients with severe COVID-19, who were treated remdesivir on a compassionate-use basis, 68% showed clinical improvement.

• Due to the small sample size and study limitations, more studies such as randomized, placebo-controlled trials of remdesivir therapy are needed to support its efficacy and potential future use as treatment.

Summary

Ivermectin seems to have antiviral action against the SARS-CoV-2 clinical isolate in vitro, with a single dose able to control viral replication within 24-48 hours. This is hypothesized to occur through inhibiting importin IMPα/β1-mediated nuclear import of viral proteins such as integrase protein.

Background

Ivermectin is an FDA-approved broad spectrum anti-parasitic agent that in recent years we, along with other groups, have shown to have anti-viral activity against a broad range of viruses in vitro Ivermectin has been shown to generally inhibit nuclear import of host and viral proteins. It has been shown to limit infection by RNA viruses such as dengue virus, West Nile virus, Venezualen equine encephalitis virus, and influenza believed to be due to the reliance of RNA viruses on importin IMPα/β1 responsible for integrase protein (IN) nuclear import. Studies on SARS-CoV proteins have revealed a potential role for IMPα/β1 during infection in signal-dependent nucleocytoplasmic shuttling of the SARS-CoV Nucleocapsid protein that may impact host cell division. This suggests ivermectin’s nuclear transport inhibitory activity may be effective against SARS-CoV-2.

Methods

Infected Vero/hSLAM cells with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.1 for 2 hours, followed by the addition of 5μM ivermectin. Supernatant and cell pellets were harvested 58 at days 0-3 and analysed by RT-PCR for the replication of SARS-CoV-2 RNA.

Results

At 24 hours, there was a 93% reduction in viral RNA present in the supernatant of samples treated with ivermectin compared to vehicle DMSO supernatant, indicative of a reduction in release virions. A 99.8% reduction in cell-associated viral RNA was observed with ivermectin treatment, indicative of a reduction in unreleased and unpackaged virions. By 48 hours, samples indicated that ivermectin treatment resulted in the effective loss of essentially all viral material. No further reduction in viral RNA was observed at 72 hours. No toxicity of ivermectin was observed at any of the time points tested. Serial dilutions of ivermectin treatment were performed and the IC50 was determined to be ~2μM.

Significance

Ivermectin is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.

Introduction

• The SARS-CoV-2 basic reproductive number (R₀) has been determined to be 2-3

  • This number is the average number of cases transmitted from an infected subject to the susceptible population

• A pandemic with a R₀ of less than 1 will die out on its own

  • For reference, the 1918 Spanish Flu pandemic had an R₀ of 1.8

• The overall mortality rate of SARS-CoV-2 has been determined to be 4.5%

Herd Immunity and a Plausible Strategy Against COVID-19

• Herd immunity is a concept in which immune people provide protection from infection to susceptible people in a population, thus limiting the spread of disease

• The R₀ determines the number of immune people needed to confer herd immunity to the whole population

• In the case of COVID-19, with an R₀ = 2-3, 50 to 66.66% of the population is needed to be immune against it to acquire protection for susceptible individuals in a population through herd immunity

  • This percentage could be higher as some COVID-19 cases are likely going un-reported

Convalescent Plasma Collection

• Convalescent plasma from recovered COVID-19 patients contains antibodies against COVID-19

• Convalescent plasma transfer was shown to be effective in helping Ebola and Influenza patients recover from critical conditions

• Clinically asymptomatic survivors in the US should be considered for potential convalescent plasma donation

  • The survivor should not have displayed symptoms for at least 28 days after discharge or for at least 14 days after discharge and a negative COVID-19 result

  • The antibody titres should be checked, with high titres of neutralizing antibodies being kept in blood banks

Discussion

• Localized herd immunity can help in slowing down the spread of the virus, while more efficacious treatments and vaccines are being discovered

• Convalescent plasma transfer could play a critical role in helping patients fight severe cases of COVID-19, but this process needs to be streamlined to be easily accessible to the patients who need it

This letter serves to call attention to the potential therapeutic effects of statins in treating COVID-19 and prompt that this perspective needs to be more fully investigated, with a particular emphasis on more research needing to be done regarding the basic science behind statins’ potential antiviral activity and the effects of statins on Coronaviridiae.

Discussion

Statins are inexpensive and easily tolerated drugs which have been used to reduce morbidity and mortality due to viral diseases such as influenza. The method of action of statins are through the inhibition of HMG-CoA reductase, which is an enzyme which serves to limit the pathway of mevalonate and cholesterol. Statins are thus substance with anti-inflammatory and immune-modulatory effects.

Potential mechanisms of action in which statins are effective against viral infections:

• Statin-induced reduction of cholesterol in the plasma membrane decreases the ability for viruses to be internalized in the host

• In the initial stage of infection, viruses bind to specific receptors within lipid rafts, which are areas of the plasma membrane high in cholesterol – statins thus considerably reduce the ability of the viral agent to adhere to the host by reducing the percentage of cholesterol in those lipid rafts.

• Lipid rafts also serve as a space where viruses replicate through their phases, and statins serve to destabilize this process

• Many viral pathogens encode for substrates of the mammalian prenylation pathway (mevalonate pathway) with this pathway being beneficial for the propagation of the virus – thus statins are hypothesized to have antiviral activity, by inhibiting HMG-CoAR and reducing expression of prenylated proteins

Introduction

161 cases with a clear source of SARS-CoV-2 infection were collected in this study, from January 20, 2020 to March 1, 2020 in patients with an epidemiological history of COVID-19 and positive SARS-CoV-2 nucleic acid test. Using this data, the duration of carrying was determined for SAR-CoV-2. The authors defined this as “the time from a close contact with the source of infection to the last positive test for nucleic acid.”

Results

The median age of all patients was 44 years old. The median duration for SARS-CoV-2 carrying was 26 days, with no significant differences in duration between male and female patients. There was a significant difference in duration of carrying between patients aged 0-59 and patients 60 years of age and older. For those under 60, their duration of carrying is 20 days, and for 60 years of age and older, their duration of carrying is 28 days. There was also statistical significance between non-severe and severe cases, with non-severe cases having a duration of carrying of 20 days, and the severe cases having a duration of carrying of 27 days.

Discussion

SARS-CoV-2 is contagious at all stages of the disease and with having a median duration of 26 days, the COVID-19 disease may have longer and stronger infectivity than the 2003 SARS epidemic (with its virus titer having peaked at 12-14 days after the onset of illness – meaning it was most infective at that time). Results also show that the duration for carrying SARS-CoV-2 is related to age, and that the persistence of the virus that is more likely in elderly patients is likely to be the factor that precipitates organ damage, leading to the high mortality rate in elderly patients.

Hydroxychloroquine (HCQ) appears to be a promising option for treating COVID-19

• HCQ is a well-known drug, effective in the treatment of malaria and autoimmune diseases

• In vitro antiviral effect has been demonstrated on SARS-Cov-2.

  • • A recent study showed that a chloroquine concentration of 0.36 mg/L decreased viral load by 50% in a cell model

Insufficient dosing guideline studies may lead to serious adverse effects and minimal HCQ efficacy

• The most serious is cardiac toxicity, characterized by prolongation of the QT interval, which can lead to arrhythmia in patients at risk

• HCQ exhibits a strong tissue tropism for the kidney and liver

• Long half-life (several weeks) increases overdose and adverse effect risk in ICU patients with impaired renal and/or hepatic function

This study aimed to characterize HCQ blood levels and pharmacokinetics

• 13 patients were given 200 mg oral HCQ 3x daily, as this study suggests

• 161 HCQ blood levels were recorded and used for the analysis

o 6 samples were below the limit of quantification of the assay

o 8/13 patients (61%) achieved the supposed minimum therapeutic level of 1 mg/L

o 2/13 patients (15.4%) exceeded a concentration of 2 mg/L

o The mean time to reach the minimum therapeutic level was 2.7 days [1–4.5 days]

o HCQ was withdrawn in two patients: due to QT interval prolongation with HCQ blood levels of 0.03 mg/L and 1.74 mg/L, respectively

No current HCQ dosing guidelines exist

• This study demonstrated that the 200 mg 3x daily dosing regimen is inappropriate to reach a supposed target blood level of 1 – 2 mg/L in an ICU population

• Using physiologically based pharmacokinetic models, another study suggested a dosage of 400 mg twice daily for 1 day, followed by 200 mg twice daily for another 4 days

• However, this study suggests that 800 mg 1x daily on the first day can more rapidly reach therapeutic levels in ICU patients

Extracorporeal membrane oxygenation (ECMO) is an advanced life support technique that utilizes a membrane oxygenator to oxygenate the blood using an artificial lung. Historically it has been used for the treatment of acute respiratory distress syndrome (ARDS). Currently there is no approved treatment of COVID-19. Therefore, ECMO may be considered as a rescue therapy for COVID-19 patients with refractory hypoxemia despite ventilation.

ECMO therapy during the H1N1 Influenza pandemic and MERS outbreak appeared to be beneficial, reducing mortality and morbidity rates compared to those not referred for ECMO therapy.

The interim guidance by the WHO suggests that ECMO should be considered as rescue therapy for COVID-19 patients despite lung-protective ventilation efforts. However, this recommendation is limited by only 2 studies that reported clinical outcomes showing mixed results as to the benefits of ECMO at this time.

Current recommendations for ECMO administration should be considered despite optimization of mechanical ventilation for <7days (FiO2 ≥ 0.80, tidal volume of 6 ml/kg predicted body weight, PEEP≥10cmH2O):

(1) PaO2: FiO2 < 50mmHg for > 3 hours;

(2) PaO2: FiO2 < 80 mmHg for > 6 hours;

(3) pH < 7.25 with PaCO2 ≥ 60mmHg for > 6 hours with a respiratory rate increased to 35 breaths per minute, adjusted for plateau pressure ≤ 32 cmH2O

For patients who have lung protective ventilation, lung recruitment maneuver, prone position ventilation, and high-frequency oscillation ventilation, ECMO should be considered as rescue therapy when meeting one of the following criteria:

(1) PaO2/FiO2<100mmHg;

(2) P(A-a)O2>600mmHg;

(3) pH<7.2 and plateau pressure >30cmH2O with respiratory rate more than 35 breaths per minute;

(4) Age<65 years old;

(5) Mechanical ventilation<7d;

(6) Absence of contraindications

ECMO shows promise, but therapy is labor-intensive and costly. As of April 7, 2020, the FDA expanded the use of ECMO therapy in patients with COVID-19 to address the national emergency response to COVID-19. Additional studies are needed to validate ECMO’s efficacy in this cohort of patients.

This discussion was prompted when France’s Health Minister, Oliver Veran, stated that people with COVID-19 symptoms should use paracetamol over ibuprofen to treat them, as ibuprofen may exacerbate their condition.

• The European Medicines Agency (EMA) has now stated that there is currently no link between ibuprofen and the worsening of COVID-19.

• Paul Little, a professor of Primary Care Research from the University of Southampton, reiterated what the EMA stated above, along with reminding us that there is, however, evidence of a reasonable link between NSAIDs and respiratory and cardiovascular side effects.

• Researchers from the Centre for Evidence-Based Medicine at Oxford have opened up another avenue in this discussion, in regards to the benefits of having a fever when one has an infection. It shows that the body is appropriately responding to and fighting the infection.

  • They concluded that “The current evidence does not support routine antipyretic administration to treat fever in acute respiratory infections and covid-19.”

Introduction

• Global drug access is one of the key issues in the current COVID-19 pandemic

• Direct anti-viral drugs such as ribavirin have an existing inventory and reliable supply chains and may be priory considerations for therapy

Background

• Ribavirin acts as a guanosine analog and interferes with RNA and protein synthesis to inhibit viral replication; it also works to introduce random mutations that can reduce the fidelity and viability of viruses.

• The aim of this article was to evaluate the studies assessing ribavirin for the treatment of prior novel coronavirus outbreak strains

Study Design

• Review article that primarily examined ribavirin mechanisms of action and use in the SARS-CoV and MERS-CoV outbreaks

Findings

• Ribavirin has multiple mechanisms of action and anti-viral properties may limit viral replication, reducing viral load, pathological tissue damage, and transmission

• SARS-CoV

  • Ribavirin was initially due to the similarity of SARS-CoV to acute respiratory syndrome, for which ribavirin and corticosteroids are typically administered

  • High-dose ribavirin had adverse effects including hemolysis and liver toxicity

• MERS-CoV

  • Ribavirin paired with interferon-α2b and was tested in several MERS-CoV studies but no definitive therapeutic benefit was shown

• COVID-19

  • Direct evidence of antiviral activity of ribavirin has been shown in vitro

Conclusion

• The authors of this article suggest that ribavirin should be considered in combination with other treatments in drug studies due to its in vitro anti-viral activity and wide availability and potential despite limited effective evidence in previous novel coronaviruses

Chloroquine (CQ) and Hydroxychloroquine (HCQ) are generic antiviral agents that have had efficacy against the SARS virus. Given this, there is a growing buzz around the potential utility of these drugs to treat patients with COVID-10.

CQ and HCQ are known to ophthalmologists in the setting of long term-usage for autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. This retinopathy has infrequently been seen before 10 or more years of usage according to the American Academy of Ophthalmology (AAO). In China, physicians are typically administering a 10-day course of 500 mg CQ twice daily or 400 mg HCQ four times daily. It is these extreme dosages that have raised questions as to whether these higher dosage, short-term treatments raise ocular risks.

To mention a few studies, high-dose HCQ has been administered at 1200 mg/day for 6 weeks as a loading dose for SLE, with no visual loss reported. In the treatment of myeloma and solid tumors, a 1200mg/day dose for 4-8 weeks also did not result in any ophthalmologic damage. The evidence so far suggests that high dose HCQ and CQ does accelerate retinal damage, but with a time course of months rather than days.

In a small study with 22 COVID-19 patients in France, the use of 600 mg/day of HCQ for 10 days reduced the viral load and the number of PCR-positive cases fell nearly 50% relative to controls. This dose is only 2x the AAO recommended level on average and should have no risk of retinopathy in this time course.

At this point, ophthalmic screening is not necessary for COVOID-19 patients who take CQ or HCQ for less than 2 weeks as anti-viral therapy. In a period where time and resources are both limited, the addition of labor-intensive and expensive eye exams is not currently recommended. Should protocols arise suggesting the efficacy of CQ and HCQ usage in COVID-19 patients, the risk of retinopathy should be re-evaluated.

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit pathologic findings associated with cytokine release syndrome (CRS). It is hypothesized that this cytokine storm is associated with severe illness and mortality among SARS-CoV-2 patients, so current efforts are in place to modulate this immune response with biopharmaceutical therapy.

CRS and IL-6

• CRS is characterized by the rapid increase in proinflammatory cytokines such as IL-6 in the plasma that lead to increased vascular permeability, alveolar epithelial damage, and subsequent release of fluid and blood into lung tissue.

• This is thought to precipitate dyspnea and respiratory failure in patients with severe SARS-CoV-2 illness.

• Interleukin-6 (IL-6) is produced by a number of innate and adaptive immune cells, but plays a key role in stimulating B cell antibody production and promoting differentiation of T cells by binding to the receptor IL-6R.

• Elevated IL-6 in plasma associated with SARS-CoV-2 infection.

Current use of tocilizumab

• The recombinant humanized monoclonal antibody tocilizumab is an IL-6R antagonist

• Approved indications for rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis.

  • Dosing: 8mg/kg IV drip every 4 weeks to treat RA, with doses tapered to 4mg/kg if aberrant liver enzyme values, neutropenia, or thrombocytopenia are present.

  • Adverse Effects: phase III clinical trials indicated an increase in secondary infection in patients treated with tocilizumab (3.6 cases/100 patient-years) vs. methotrexate (1.5 cases/100 patient years) and slightly increased risk of major adverse cardiovascular event than etanercept with a hazard ratio of 1.05 (95% CI 0.77-1.43)

Tocilizumab clinical trial

• Current clinical trial in China testing tocilizumab for treating severe SARS-CoV-2 illness (note: this is NOT a controlled study)

• Patients meeting one or more criteria for severe or critical infection were treated (n = 21):

  • Severe: dyspnea, RR greater than 30 per min, O2 sat less than 93%, PaO2/FiO2 less than or equal to 300 mmHg

  • Critical: respiratory failure requiring mechanical ventilation, ICU admission, other organ failure

• Findings:

  • 15/21 patients reduced need for O2

  • 19/21 patients exhibited pulmonary lesion absorption (CT imaging)

Conclusions

• Cytokine release syndrome is associated with severe illness and mortality among patients with SARS-CoV-2 infection.

• Tocilizumab is an IL-6 receptor antagonist that has current indications for RA.

• A small, non-controlled clinical trial in China indicated potential efficacy for tocilizumab in treating severe and critical SARS-CoV-2 illness.

• Tocilizumab and other immunomodulating agents may be useful for treating COVID-19 patients presenting with CRS, but further clinical trials are needed.

• ACE2 has been identified as a key receptor for SARS-CoV-2 infections.

• Inhibiting this interaction via a decoy ACE2 receptor might be used in treating patients with COVID19.

• Monteil et al. showed that human recombinant soluble ACE2 (hrsACE2) had a dose dependent effect of viral growth of SARS-CoV-2 and was able to reduce it by a factor of 1,000 to 5,000 in cell cultures.

• Authors showed that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2.

• These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.

• The effects of hrsACE2 in later stages of the disease process are not known at this time.

Background

Antihypertensive medications including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) and their effect in COVID-19 have entered the spotlight in recent weeks. Initial studies suggest that hypertension, diabetes and cardiovascular disease were the most frequent comorbidities in patients with COVID-19 and case fatality rates tended to be high in these individuals.

COVID-19 utilizes ACE-2 receptors for entry into epithelial cells of the lung. Specifically, the ACE2 form that is a structural transmembrane protein with an extracellular domain serves a receptor for the spike protein of COVID-19. Previous studies have established that the levels of ACE2 are significantly increased in patients treated with ACEIs/ARBs. It is this increased expression that could potentially facilitate COVID-19 entry into cells.

Current recommendations on the use of ACEIs/ARBs in patients with COVID-19

• Continuation of RAAS antagonists for patients who are currently prescribed such agents for which indications are known to be beneficial. In the event these patients with CV disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient’s hemodynamic status and clinical presentation.

The bottom line: Currently there is no clinical evidence to suggest that these agents have any harm and patients should continue current therapies.

Intensive Care Medicine. Published online March 28,2020.

• The current pandemic has resulted in the need to optimize management of acute respiratory failure in the intensive care setting for patients with severe illness due to COVID-19.

• The WHO and CDC have issued guidance for screening and diagnosis, but there is a need for better understanding of how to manage critically ill patients.

Background

• The Surviving Sepsis Campaign COVID-19 panel formed of 36 experts from 12 countries determined management recommendations for critically ill patients with severe COVID-19 in the ICU setting.

• The panel was divided into four groups tasked with determining recommendations within each of the following topics:

  • Infection control and testing

  • Hemodynamic support

  • Ventilatory support

  • Therapy

Study design

• Recommendations were generated by a multi-step approach beginning with formulation of questions structured in the Population, Intervention, Control, and Outcome(s) (PICO) format

• The literature search included both COVID-19 and systemic review of SARS, MERS, ARDS and shock

• Quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach

• The evidence to decision framework (EtD) was utilized to formulate recommendations

Findings

• The Surviving Sepsis Campaign COVID-19 panel issued 54 statements (*6 PICO questions had no associated recommendations)

• The guidelines include 35 weak recommendations, 9 strong recommendations, and 4 best practice statements (below)

  • For healthcare workers performing aerosol-generating procedures on patients with COVID-19 in the ICU, we recommend using fitted respirator masks (N95 respirators, FFP2, or equivalent), as opposed to surgical/medical masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protection, such as a face shield or safety goggles)

  • We recommend performing aerosol-generating procedures on ICU patients with COVID-19 in a negative pressure room.

  • For COVID-19 patients requiring endotracheal intubation, we recommend that endotracheal intubation be performed by the healthcare worker who is most experienced with airway management in order to minimize the number of attempts and risk of transmission.

  • In adults with COVID-19 receiving noninvasive positive-pressure ventilation (NIPPV) or high flow nasal cannula (HFNC), we recommend close monitoring for worsening of respiratory status, and early intubation in a controlled setting if worsening occurs.

• For additional recommendations and rationales behind each of the recommendations please use the article link to the guidelines

Conclusion

• The current guideline aims to provide recommendations to support hospital clinicians managing critically ill adults with COVID-19 in the ICU

• Guidelines will be re-released with updated information as it becomes available

Review by Chloe Ferris on 4/1/20.

A Case series of 5 critically ill patients (age range, 36-73) in Shenzhen, China with COVID-19 and ARDS who met the following criteria to receive convalescent plasma:

1. Severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment.

2. PAO₂/FIO₂ of <300

3. Were currently or had been supported with mechanical ventilation

4. No patients were smokers, 4 of 5 had no preexisting medical conditions. All 5 had received antiviral agents and steroids.

Convalescent Plasma Treatment Results

• Quantitative PCR showed reduction in viral titers as early as posttransfusion day 1

• Sequential Organ Failure Assessment (SOFA) scores decreased in all patients

• PAO₂/FIO₂ increased in 4 of 5 patients

• All patients were afebrile on the third day after transfusion

• CT scans demonstrated improvement in pulmonary lesions by day 3 in all patients

• Inflammatory markers CRP, procalcitonin, IL-6 decreased in 4 of 5 patients

• All patients had improvement in clinical status, however clinical trials are still needed to determine effectiveness of convalescent plasma.

Reviewed by Daniel Tuerff on 3/29/20.

During the current COVID-19 epidemic, the anticipated need for invasive mechanical ventilators for management of acute respiratory failure exceeds the estimated availability. There is a significant need to address the increasing demand for adequate respiratory support in the setting of limited supply. In addition to methods of modifying invasive ventilators to support more than one patient, there is the possibility of repurposing non invasive bi level ventilators to address the increase in demand.

• Mount Sinai has created a current working protocol that outlines a potential solution for ventilator shartage

• The protocol provides information on how to repurpose bilevel ventilators as well as how to ventilate and monitor patients with acute respiratory failure while minimizing exposure risks

Protocol Recommendations

• Device modification (Repurposing of ResMED VPAP ST ventilator (VPAP ST))

  • Equipment:

    • ResMed VPAP ST

    • 2 x oxygen feed port (with 20 ft oxygen tubing, capped)

    • Ventilation tubing

    • Inline heated humidifier or HME (inline moisture exchanger)

    • Exhalation port device with high resistance (with attached filter)

    • Gas sampling adaptor for CO2 and flow monitoring

    • Endotracheal tube

Key Steps (*Additional steps and specifics are addressed in the protocol)

• • • Set up VPAP ST and connect it to antimicrobial filter

    • Connect BOTH inline O2 feed ports at VPAP ST outlet (one is kept capped and in reserve for adding high O2)

    • Connect VPAP ST tubing circuit

    • Attach viral filter after exhalation port

    • Attach gas sampling adaptor for CO2 and flow monitoring

    • Set to BiLevel ST mode and attach to ET tube

  • Monitor patient’s ventilation needs and if not met by the above, switch to alternative ventilator system

Exposure mitigation

• • Disconnecting the VPAP ST circuit is an aerosol-generating procedure, and appropriate PPE must be worn

  • Intubation with delivery of ventilation through ET reduces the amount of exhaled gas vented into the room other than by the ventilator circuit to near-zero

  • The design of the ventilator circuit components and configuration is aimed at capturing and filtering all gas exhaled by the patient with non-invasive single limb circuits

Patient selection- the protocol outlines three categories of patients best suited for their design

• • Patients with milder respiratory failure still in need of ventilator support

  • Patients in the context of NO other ventilator support available

  • Patients being weaned from mechanical ventilation

Conclusion

Mount Sinai has created a working protocol for repurposing bi-level ventilators in order to meet the increasing demand for the limited supply of ventilators due to acute hypoxemic respiratory failure secondary to COVID-19. This is a working protocol and will be updated with any re-releases.

Reviewed by Chloe Ferris on 3/31/20.

• Increased Risk of COVID-19 in Pregnancy: pregnant women may be more susceptible to COVID-19 infection due to immunocompromised status and physiological adaptive changes of pregnancy. While maternal management and fetal safety are a major concern, there is minimal information regarding how to care for a pregnant woman infected with COVID-19 and the potential risk for vertical transmission.

Summary of Current Findings

• Yu et al. reports the clinical features and neonatal outcomes of seven pregnant women with COVID-19 pneumonia in Wuhan, China.¹ All patients had caesarean sections with good outcomes for both mother and neonate. Of the three neonates tested for SARS-CoV-2, one was found to be infected with COVID-19. None of the seven neonates developed pneumonia or other clinical symptoms and signs. These findings coincide with the lack of evidence supporting vertical transmission of COVID-19 from mother to baby.

Future Studies

• Given the size of this study, there is insufficient data to establish a standardized treatment for pregnant women with COVID-19. In addition, further research is needed to determine when to deliver and which delivery method, cesarean section or vaginally, is safer.

Reviewed by Dani Rider on 3/31/20

A retrospective study conducted in Wuhan China found that patients with a history of diabetes mellitus or cerebrovascular disease who contracted SARS-CoV-2 experienced higher rates of mortality.(1) This study also found that patients who died as a result of SARS-CoV-2 infection had a higher SOFA score on day 1 of admission. A survey of 1099 patient charts from China found that patients with severe disease had a higher prevalence of underlying comorbidities than those with non-severe disease (38.7% vs 21.0%). Comorbidities detected at higher rates in those with severe disease include COPD, coronary artery disease, diabetes mellitus, hypertension, cerebrovascular disease, cancer of any kind and chronic kidney disease. Patients who developed severe disease were older than those with non-severe disease by a median of 7 years.(2) These conditions are associated with angiotensin receptor blocker (ARB) or angiotensin converting enzyme (ACE) inhibitor therapy.

It has been hypothesized that history of taking an ACE or ARB may increase risk of becoming infected with SARS-CoV-2.(3) This hypothesis is founded on the knowledge that the S-protein of SARS-CoV-2 binds the angiotensin converting enzyme II (ACE II) on the surface of pulmonary epithelium and other epithelial cells.(4,5) ACE II is similar to angiotensin converting enzyme (ACE), which converts angiotensin I to angiotensin II, a potent vasoconstrictor. ACE II degrades angiotensin II (ATII) to angiotensin 1-9 and 1-7 (AT 1-9 and AT 1-7). ACE II exhibits cardioprotective effects by lowering circulating ATII levels and via direct vasodilation by AT 1-7.(6) Long term blockade of the angiotensin converting enzyme or the angiotensin II receptor leads to increased expression of ACE II on epithelial cells in multiple organs including the lungs.(7) For this reason, researchers believe that long term treatment with ACE inhibitors or ARBs may increase susceptibility to viral binding and subsequent entry into host cells. This hypothesis is summarized in a brief letter by Fang et. al to the Lancet and is supported by numerous retrospective studies that demonstrate patients with health conditions for which ACE inhibitors and ARBs are often indicated appear more likely to suffer from severe SARS-CoV-2 related disease.(1–3,8) In a commentary to Science Translational Medicine, Dr. Lowe opposes this hypothesis and suggests that upregulation of ACE II may in fact protect against SARS-CoV-2.(9) The crux of this argument is that severe sequelae of SARS-CoV-2 infection, including acute respiratory distress syndrome (ARDS) and heart failure, are caused by pathological increases in ATII secondary to downregulation of ACE II in response to coronavirus infection.(10) Research on ARDS during the 2003 SARS-CoV outbreak demonstrated that ACE II protects against ARDS and that blockade of the RAAS system rescued animal models of SARS infection from ARDS.(11,12) This suggests that ACE inhibitors and ARBs like Lisinopril and Losartan may protect against severe SARS-CoV-2 related disease, but does not explain the higher rates of severe disease observed in patients with underlying chronic medical conditions. Further research is required to establish which of these opposing hypotheses will advance treatment of COVID-19. Future approaches may include ACE II blockers and/or ACE II upregulation via blockade of the renin-angiotensin-aldosterone system (RAAS). Research on angiotensin II receptor agonists such as Compound 21 during SARS infection may elucidate the pathological role of RAAS dysregulation during SARS-CoV-2 infection.

It is likely that the severity of COVID-19 is multifactorial. Chronic medical conditions such as diabetes mellitus are known to cause immune dysregulation and systemic organ damage.(13) Patients with underlying cardiovascular disease and elevated cardiac troponin who contract COVID-19 were found to have a significantly increased risk of mortality independent of other risk factors. However, there was no significant difference in outcome between patients on ACE/ARB therapy and those who were not.(14) These findings suggest that past medical history may be more informative than current treatment with an ACE inhibitor or ARB.

This article evaluates the growing concern that the association with hypertension is confounded by treatment with specific antihypertensive medications: ACE-I and ARBs

• ACE2 has been shown to be a co-receptor for viral entry for SARS-CoV-2

• ACE-Is and ARBs may increase expression of ACE2 and increase patient susceptibility to viral host cell entry and propagation

  • Animal models as well as some evidence in humans show increased expression of ACE2 in the heart, brain, and urine after treatment with ARBs; however, there is limited evidence showing changes in serum or pulmonary ACE2 levels

• Preclinical data suggest that increasing ACE2 expression can attenuate SARS-CoV-2–induced lung injury, but there is no direct clinical evidence that has proven ACE2 to be an effective treatment for viral-induced lung injury

• There have been advocates for both the use and cessation of ACEIs, ARBs, or both during the treatment for COVID-19 in patients with hypertension

• On March 17, 2020, the American Heart Association, and Heart Failure Society of America, and American College of Cardiology all put out statements advocating for physicians and patients to continue treatment with their usual anti-hypertensive therapy because there is no clinical or scientific evidence to suggest that treatment with ACEIs or ARBs should be discontinued because of the COVID-19 infection

Review by Leigh Anne Kline on 3/25/20.

• There are no available data from randomized controlled trials in humans to support any investigational therapeutics for patients with confirmed or suspected COVID-19 at this time. 1

• There are two phase 1 vaccine candidates, and multiple preclinical vaccine candidates. 2

• A report in Bioscience Trends claims clinical benefit of chloroquine but shows no data to support this. Clinical trials are underway. 3

• Remdesivir is also being investigated. Gilead is not currently accepting new applications for individual compassionate use. 4

• The FDA is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of single patient emergency Investigational New Drug Applications. 5

• Several other therapeutics are in various stages of development.

• No contraindications for NSAIDs, ACE/ARBs at this time. 6, 7

After the first SARS outbreak, the WHO identified defects in wastewater plumbing systems as a mode of virus transmission via transport of “virus laden droplets” through U-bends in bathrooms. This mode of transmission facilitated spread of the virus throughout a 50 story building.

• An experiment using Pseudomonas putida as a model organism indicated that pathogens flushed into the system could transmit to different rooms of a building and be carried in the building’s system airflow.

  • High concentrations of infected individuals under quarantine within a hospital may increase the risk of spread to other parts of the hospital via the wastewater plumbing system.

Recommended measures to prevent spread

• • Address unexplained odors in bathrooms and wash areas

  • Ensure that all water appliances have a functioning U-bend

  • Open a tap on all water appliances for at least 5 seconds per day in order to maintain U-bend water trap seal

  • Seal disconnected pipework immediately

    • Use rubber glove or plastic bag to cover the exposed end

  • Seal any cracks in pipework

  • Monitor whole system

Review by Allison Boone 3/30/20.