COVID-19 Update April 13, 2020 | Volume 1 | Issue 3 The following reports were written by second year students from the Hackensack Meridian School of Medicine at Seton Hall University for the COVID-19 Best Practices elective. These reports have been reviewed by Jeffrey R. Boscamp, MD, Vice Dean and Professor of Pediatrics. Individual reports can be found via https://library.shu.edu/COVID19_elective/BestPractice Table of Contents: • Ivermectin as a Possible COVID-19 Treatment … Pg. 1-2 • Seasonality of COVID-19: Will the Warm Weather Stop the Pandemic? … Pg. 2-4 • Use of N95, Surgical, and Homemade Masks … Pg. 5-8 • Clinical Presentation of COVID-19 in Children … Pg. 8-10 • Effects of COVID-19 on Pregnancy: Is Vertical Transmission Possible? … Pg. 10-12 • Hydroxychloroquine Update: Reanalysis of Gautret et. al. Study … Pg. 12-13 • Use of Helmet Ventilators for Covid-19 Patients … Pg. 13-14 • D-Dimer Level as a Prognostic Indicator and Therapeutic Value of Prophylactic Heparin … Pg. 14-15 • Possible Therapies for Convalescent Pulmonary Management of COVID-19 … Pg. 16-17 • Can Nitric Oxide be used to treat Covid-19? … Pg. 17-18 • Does O2 Saturation Speak to the Severity of Covid-19? …Pg. 19-20 • What is the Role of ECMO for Severe Covid-19? … Pg. 20-21 • Convalescent Plasma as a Treatment Option for Patients with COVID-19 … Pg. 22 • Who Can Receive or Donate Convalescent Plasma? … Pg. 23 • Anticoagulation in Coivd-19 … Pg. 24-25 • Update on QT monitoring in Covid-19 when treated with Hydroxychloroquine and/or Azithromycin … Pg. 25-26

IVERMECTIN AS A POSSIBLE COVID-19 TREATMENT By Austin Krebs

Summary: Given these effects, ivermectin makes sense as an investigation for an effective COVID-19 drug. One in vitro Ivermectin has demonstrated in vitro efficacy against RNA study examined the effects of serial dilutions of ivermectin on viruses such as influenza and dengue. A recent study has Vero/hSLAM cells infected with SARS-CoV-2. After 24 demonstrated in vitro effectiveness of ivermectin against hours, there was a 93% reduction in supernatant viral RNA SARS-CoV-2, with an effective loss of nearly all viral (indicative of released virions). A 99.8% reduction of cell- material noted after 48 hours in treated cells. Clinical trials are associated viral RNA (indicative of unreleased virions) was needed to further explore this potential therapy. seen in the same time frame. At 48 hours, there was an

observed 5000 fold decrease in viral RNA in the ivermectin- Evidence to Date: treated cells compared to controls, which represented an Several antiviral agents have been explored as possible effective loss of nearly all viral material. This was therapeutic options to address the COVID-19 pandemic. One demonstrated by no further decrease in viral material at 72 option among them is ivermectin, an antiparasitic medication hours. No toxicity was observed at any of the tested time that has been shown to display antiviral properties against a points. The IC50 of ivermectin was determined to be 2uM.4 number of different pathogens in vitro. Ivermectin was Ivermectin could be an effective drug to combat COVID-19 identified to inhibit the nuclear import of the HIV-1 integrase based on these results, and clinical trials are necessary to protein by interfering with its interaction with the nuclear α/β1 explore its efficacy. importin.1 Additionally, ivermectin has been demonstrated to limit infection by other RNA viruses such as Dengue virus, References West Nile Virus, and influenza through a similar mechanism 1. Wagstaff, Kylie M., et al. “An AlphaScreen®-Based affecting this same importin.2 Studies have implicated a role Assay for High-Throughput Screening for Specific 3 for the α/β1 importin in SARS-CoV infection. Inhibitors of Nuclear Import.” Journal of Biomolecular

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Screening, vol. 16, no. 2, Feb. 2011, pp. 192–200. PubMed, doi:10.1177/1087057110390360. Seasonality of COVID-19: Will 2. Caly, Leon, et al. “Nuclear Trafficking of Proteins from the Warm Weather Stop the RNA Viruses: Potential Target for Antivirals?” Antiviral Research, vol. 95, no. 3, Sept. 2012, pp. 202–06. Pandemic? ScienceDirect, doi:10.1016/j.antiviral.2012.06.008. By Candace Pallitto 3. Wulan, Wahyu N., et al. “Nucleocytoplasmic Transport of Nucleocapsid Proteins of Enveloped RNA Viruses.” Frontiers in Microbiology, vol. 6, Frontiers, 2015. Overview and Background Frontiers, doi:10.3389/fmicb.2015.00553. As summer approaches the United States, many people are 4. Caly, Leon, et al. “The FDA-Approved Drug Ivermectin wondering the effect that this change in weather will have on Inhibits the Replication of SARS-CoV-2 in Vitro.” the spread of COVID-19. Seasonal cycling of respiratory Antiviral Research, Apr. 2020, p. 104787. ScienceDirect, viruses like coronaviruses and influenza has been observed, doi:10.1016/j.antiviral.2020.104787. particularly with peaks during winter months in temperate climates. While the reason for this seasonal cycling is integrated and multifactorial, it is easier to understand when broken down into two main factors: environmental effects and human components.[1] These factors are not mutually exclusive and most heavily intersect at the level of human immunity where environmental effects like temperature and humidity can play a direct role on the ability to fight infections. The environmental factor can be further divided into temperature, humidity, and sunlight exposure, but most current literature about climate effect on COVID-19 focuses on temperature and humidity. Human factors include behavioral changes, such as travel, school, and amount of time spent indoors, and immunity.

Previous data shows that other viruses in the coronavirus family and influenza prefer cooler temperatures and lower humidity in temperate climates, which possibly contributes to their resurgences every fall and winter.[1] In addition, COVID-19 is most structurally similar to SARS-CoV (SARS), which occurred during winter months and is found to be able ot survive up to 5 days at 22-25°Celsius and relative humidity of 40-50%, which are indoor conditions. SARS also has shown to have infectivity that lasts for 2 weeks at slightly lower temperatures and lower humidities.[2] In regards to influenza, seasonality of the virus with increased transmission at cool temperatures and low humidity only explains its role in temperate climates. However, there is evidence that seasonal outbreaks of influenza also occur in tropical areas and transmission seems to be highest during rainy seasons with greatest levels of humidity. In addition, many tropical areas see significant influenza activity year round, which indicates that temperature and humidity may not be the strongest predicting factor of the seasonality of the virus.[3] There are other factors, most likely human factors, including increased time spent indoors and changes in immunity that can play a significant role in the transmission of the virus.

Environmental Factors: Temperature, Latitude, and Humidity

Most of the current literature to date is pointing to a likely climate related aspect to the spread of COVID-19, but many of these studies do not incorporate human components, such as 2 containment strategies or behavioral aspects. Preliminary data hygiene and close proximity.[3] While COVID-19 does not from a pre-print study that reviewed transmission until seem to have the same impact on school-age children in terms February 29th, suggested that temperature may play a role, but of severity and overall prevalance as other coronaviruess or resulted a pseudo R2 value of 0.44 with temperature and 0.39 the flu, it is known that asymptomatic carriers are likely agents without temperature, which shows minimal effect of for propagating the disease, which offers an important outlet temperature from this data.[4] Some pre-print studies have for human-behavior related containment strategies.[10] indicated that there is association between latitude and the spread of the virus, particularly that areas above 30°N were To further understand the global spread of COVID-19, human initial epicenters of the disease. It also suggests that as the behavior, specifically travel patterns are important to consider. pandemic progresses, there may be a trend of increased cases One of the pre-prints mentioned above assumed that China south of -30° latitude to areas such as Brazil and South Africa, had equal probability of transmission globally given that it is which have begun to show a higher case rate as of March well-connected to the rest of the world. A different pre-print 27th.[5,6] A study released March 9, 2020 found that the initial from Brazil challenges this statement and the role of climate in epicenters of the disease were found along 30- 50°N’ zone; the global progression of this pandemic. The study analyzed from Wuhan, China to South Korea, Japan, Iran, Northern climate, socioeconomic, and air transportation factors and Italy, and Seattle as the initial epicenter in the United States found that global transportation networks as measured by with average temperatures of 5-11°C and relative humidity Eigenvector Centrality1 was the only significant factor in their between 44-84%.[7] Furthermore, since that research was model ( p < 0.004).[11] They specifically analyzed the spatial conducted there were significant outbreaks in parts of England pattern of air transit in 44 countries that had over 100 cases of and Germany with average temperatures of 5-11° in February COVID-19 and the data for time included at least 10 days after 2020. There were also predictions for New York City to have the 100th case. This study shows similar results to the climate significant COVID-19 outbreaks based on this data. This studies in terms of areas that became epicenters and areas temperature, humidity, and latitude data was re-iterated in a where the disease spread, but shows the implications of human pre-print report that compared daily spread of the virus in factors on the disease progression. It specifically points out geographic and climatic spaces, with stronger association to Brazil, which is considered a well-connected country with climatic space.[8] This report also found an average varying tropical climate patterns and is currently experiencing environmental temperature associated with positive cases to be one of the highest rates of increase of COVID-19 in its 5.81°C. Furthermore, this study states that “China is well- exponential phase. Furthermore, relying too heavily on climate connected to the world” and assumes equal probability of data may delay responses in more tropical regions with lower transmission without providing specific evidence for this socioecononmic status that could see a worse progression of statement.[8] the pandemic.

The studies above mainly focus only on environmental Immunity parameters and do not take into account a significant aspect of disease transmission- the role that human immunity and Another seasonal factor that is related to humans, but is also behavior plays. Furthermore, a majority of the information heavily integrated with temperature is human immunity. about COVID-19 and how it behaves in temperature and Research has shown that colder temperatures and lower humid settings are extrapolated from SARS, which also did humidity decrease the ability to fight respiratory infections. not seem to persist in higher temperatuers with higher Some of the reasons include vasoconstriction in the respiratory humidities. A pre-print study that analyzed absolute humidity tract, leading to decreased blood flow and consequently less relationship to the spread of COVID-19 by analyzing cold and leukocytic and phagocytic activity in these areas. There is also dry provinces of China indicates no clear association between decreased mucociliary clearance in the nasal and lower disease transmission and absolute humidity.[9] It also respiratory tracts, making it easier for infections to invade the mentions the importance of recognizing that weather alone mucosa.[3,12,13] will not mitigate the spread of this disease. Immunity also plays a role in pandemic vs. epidemic infections. Epidemic influenza variations seem to follow a Human Factors seasonal pattern in temperate climates, but pandemic influenza Behavior infections, such as 2009 A/H1N1 did not follow the usual seasonal pattern and it was found among the more humid Seasonality of viruses, such as coronaviruses that cause the months of spring, summer, and fall.[14] A likely reason for common cold and influenza, are thought to be also related to this overall spread of the pandemic was lower immunity to changes in human behavior, specifically school closures and this strain of influenza. The fact that COVID-19 is a new overall less time spent indoors where respiratory droplets are strain plays a large role in its worldwide spread and it is easily transmitted. School-aged children are often popular possible that there could be future cyclical epidemics if it is targets for these diseases due to their relatively poor hand

1 Eigenvector Centrality analyzses the level of influence that a node has on a network. A high Eigenvector Centrality refers to a node pointing to many other nodes, meaning it has high influence on that network. 3 found that there is lasting immunity in some people, but more 8. Araujo MB, Naimi B. Spread of SARS-CoV-2 information is still needed. Coronavirus likely to be constrained by climate. March 2020. doi:10.1101/2020.03.12.20034728. Conclusion 9. Luo W, Majumder MS, Liu D, et al. The role of absolute humidity on transmission rates of the COVID-19 Current data of the spread of COVID-19 and information outbreak. 2020. doi:10.1101/2020.02.12.20022467. about the seasonal natures of upper respiratory viruses indicate 10. Yu X, Yang R. COVID-19 transmission through COVID-19 could become a seasonal epidemic like influenza. asymptomatic carriers is a challenge to containment. There is also some support, although not peer-reviewed or Influenza and Other Respiratory Viruses. April 2020. validated, that as temperatures and humidity increase, the doi:10.1111/irv.12743. transmission of the disease may be reduced. However, these 11. Túlio Pacheco Coelho M, Fabricio Mota Rodrigues J, environmental factors will not be enough to mitigate the full matos Medina A, et al. Exponential phase of COVID19 potential effects of the pandemic and if relied on too heavily, expansion is not driven by climate at global scale. April could produce delayed responses in areas thought to be less 2020. susceptible or cause a relapse in areas where the weather is https://www.medrxiv.org/content/10.1101/2020.04.02.200 changing. Interventions on human behavior should continue, 50773v1. particularly social distancing.[15] Furthermore, it is possible 12. Mäkinen TM, Juvonen R, Jokelainen J, et al. Cold that the United States, particularly the New York and New temperature and low humidity are associated with Jersey area may see a decline in the pandemic that is more increased occurrence of respiratory tract infections. likely related to human behavior interventions such as travel Respiratory Medicine. 2009;103(3):456-462. restrictions and continued social distancing measures, rather doi:10.1016/j.rmed.2008.09.011. than warmer weather and higher humidity alone. 13. Kudo E, Song E, Yockey LJ, et al. Low ambient humidity impairs barrier function and innate resistance against influenza infection. Proceedings of the National Academy References of Sciences. 2019;116(22):10905-10910. doi:10.1073/pnas.1902840116. 1. Moriyama M, Hugentobler WJ, Iwasaki A. Seasonality of 14. Shaman J, Goldstein E, Lipsitch M. Absolute Humidity Respiratory Viral Infections. Annual Review of Virology. and Pandemic Versus Epidemic Influenza. American 2020;7(2). Journal of Epidemiology. 2011;173(2):127-135. https://www.annualreviews.org/doi/10.1146/annurev- doi:10.1093/aje/kwq347. virology-012420-022445. 15. Prem K, Liu Y, Russell T, et al. The effect of control 2. Chan KH, Peiris JSM, Lam SY, Poon LLM, Yuen KY, strategies that reduce social mixing on outcomes of the Seto WH. The Effects of Temperature and Relative COVID-19 epidemic in Wuhan, China. The Lancet Public Humidity on the Viability of the SARS Coronavirus. Health. December 2020. Advances in Virology. 2011;2011:1-7. doi:10.1101/2020.03.09.20033050. doi:10.1155/2011/734690. 3. Tamerius J, Nelson MI, Zhou SZ, Viboud C, Miller MA, Alonso WJ. Global Influenza Seasonality: Reconciling Patterns across Temperate and Tropical Regions. Environmental Health Perspectives. 2011;119(4):439- 445. doi:10.1289/ehp.1002383. 4. Bannister-Tyrrell M, Meyer A, Faverjon C, Cameron A. Preliminary evidence that higher temperatures are associated with lower incidence of COVID-19, for cases reported globally up to 29th February 2020. 2020. doi:10.1101/2020.03.18.20036731. 5. Triplett M. Evidence that higher temperatures are associated with lower incidence of COVID-19 in pandemic state, cumulative cases reported up to March 27, 2020. April 2020. doi:10.1101/2020.04.02.20051524. 6. Araujo MB, Naimi B. Spread of SARS-CoV-2

Coronavirus likely to be constrained by climate. March 2020. doi:10.1101/2020.03.12.20034728. 7. Sajadi MM, Habibzadeh P, Vintzileos A, Shokouhi S, Miralles-Wilhelm F, Amoroso A. Temperature and Latitude Analysis to Predict Potential Spread and Seasonality for COVID-19. SSRN Electronic Journal. March 2020. doi:10.2139/ssrn.3550308.

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especially when using a mask that has exceeded its shelf Use of N95, Surgical, and life. Here is the link to the video they provide. Homemade Masks Alernatives to N95s: The CDC mentions that when N95 By Candace Pallitto masks are not available, alternatives to N95s approved by NIOSHA can be used and include[5]: Overview - Filtering facepiece (FFP) respirators that are at least as protective as N95 (N99, N100, P95, P99, P100, R95, R99, While COVID-19 is thought to be primarily transmitted and R100). However, if these filtering facepiece through respiratory droplets, there is concern about respirators have exhalation valves, they should not be aerosolization of the virus and this has sparked growing concern about the supply of N95 masks in healthcare settings. used in surgical settings. COVID-19 was found to be 0.125 microns (125nm) in - Elastomeric half-mask and full facepiece air purifying spherical diameter. N95 masks filter 95% of particles that are respirators use replacable filter cartridges and are 0.1-0.3 microns in size and aerosols are considered less than 5 generally made of a synthetic or rubber material so they microns in diameter.[1] Because of the tight fit and high can be cleaned and re-used. Again, many of these have fitration efficiency of N95 masks, the Center for Disease exhalation valves and should not be used in surgical Control and Prevention (CDC) recommends their use in settings. airborne precautions and are listed as the “preferred” mask for - Powered air purifying respirators- These use battery- personal protective equipment (PPE) against COVID-19.[2] In powered air blower that pulls air through attached filters order to preserve the supply of N95 and medical/surgical or cartridges that are generally made of high-efficiency masks for healthcare workers while also reducing the particulate air (HEPA) filters. These should also not be transmission of COVID-19 in the community, the CDC provides instructions on how to construct homemade cloth used in surgical settings for potential contamination with facemasks to protect individuals.[3] However, many hospitals blower exhaust or exhalation. are allowing healthcare workers to wear homemade masks due - Non- NIOSHA approved respirators which include those to the shortage of surgical and N95 masks, but these from other countries that have to gain approval similar to homemade masks are made of varying fabrics and their NIOSHA criteria. Examples of these include KN95 masks effectiveness has not been rigorously analyzed.[4] This report from China. The full list can be found on the CDC summarizes alternatives to N95 masks, use of surgical vs. N95 website here under “When N95 Supplies are Running masks, information about materials for homemade masks, and Low.” new approaches for addressing the mask shortage. Surgical/Medical Masks vs. N95: The CDC lists surgical N95 masks: The CDC notes that use of a N95 or higher masks as an alternative to N95 as part of full PPE, but does respirator is “preferred,” but that medical/surgical facemasks not consider them to be adequate respiratory protection for are an alternative for general PPE for healthcare workers protection from smaller airborne particles. The confusion taking care of COVID-19 patients.[2] This is in addition to a surrounding the aerosolized nature of COVID-19 has made it face shield or goggles, isolation gown, and one pair of clean, difficult to appropriately determine which clinical settings or non-sterile gloves. Link to pdf procedures should have N95 masks. - Surgical N95 respirators are only recommended when - While the CDC guidelines prefer healthcare workers to there are airborne and fluid hazards, such as splashes or wear N95 masks while taking care of COVID-19 patients, sprays of bodily fluids. Otherwise standard N95 they specify when to choose N95 masks or respirators, such has industrial N95 masks, can be used. If surgical/medical facemasks based on symptoms of the surgical N95 respirators are not available, but there is patient and distance form the patient positive or suspected increased risk for splashes, sprays, or splatters of bodily of COVID-19[5]: fluids, then a facesheild should be worn over the standard o A surgical/medical facemask can be used when the N95. patient is masked and the healthcare provider has to - Expired N95 masks: N95 masks that have exceeded their be within 6ft of the patient. shelf life have been tested and found to operate in o No mask or respirator is needed when the patient is accordance with National Institute for Occupational masked and the healthcare provider will remain Safety and Health (NIOSHA). These are the models that greater than 6ft away are recommended on CDC website: 3M 1860, 3M 1870, o A NIOSHA-approved N95 respirator, elastomeric, or 3M 8210, 3M 9010, 3M 8000, Gerson 1730, PAPR should be used when the patient is unmasked Medline/Alpha Protech NON27501, Moldex 1512, or the mask needs to be removed and during aerosol Moldex 2201 generating procedures (AGPs). - CDC recommends to assess the masks for any damage - The London Health Sciences Centre more specifically and perform User Seal Check each time a N95 is worn, states settings and procedures that require N95 masks in setting of COVID-19. They note outside critical care 5

settings a fluid resistant mask with eye shield can be worn - Cloth masks have been used in healthcare settings during (i.e. N95 masks are not required). These are the settings previous pandemics and in other countries so there is and procedures they list where N95 mask should be worn some data on their effectiveness. No studies have (including other full PPE, such as face shield)[6]: demonstrated equal or superior protection to N95 masks. o Settings: While there is some data on this subject, it is very limited ▪ Critical Care and it is difficult to obtain evidence from well-designed ▪ Operating Room randomized controlled trials because compliance is often ▪ Emergency Department an issue.[7] o Procedures: Aerosol Generating Medical Procedures - One studied cited by most articles on this topic analyzed (AGMP) the filtration effectiveness of different frabrics. They ▪ *Intubation found that cloth facemasks that consisted of 2 layers of ▪ *Bronchoscopy (including insertion of pure cotton, pure polyester, or cotton/polyester blends did percutaneous tracheostomy) not sufficiently filter out particles 100-300nm.[8] These ▪ *CPR mixtures of fabrics were examined in cloth masks, ▪ *Extubation sweatshirts, T-shirts, towels, and scarves. They used ▪ *2Endoscopy polydisperse aerosol penetration because this is the ▪ Bag-mask-valve ventilation (with a filter) method to test penetration of masks like N95 masks as ▪ CPAP or Non-Invasive Ventilation (until well as monodisperse aerosol penetration, which more COVID-19 negative result) specifically assess how the masks filter particles <400nm ▪ High flow or humidified oxygen in size. They found that the polydispersion and ▪ Non-humidified oxygen at > 50% monodispersion penetration results were similar to that of ▪ Tracheostomy insertion/tube some FDA-approved surgical masks studied in change/decannulation previously, but they did not analyze droplet protection or ▪ Use of cough-assist device splash protection in those studies. The Hanes sweatshirt ▪ Open suctioning made of 70% cotton and 30% polyester was found to have ▪ Any procedure that may cause a breach in least polydisperion and monodispersion penetration for ventilator circuit particles <60nm, but found to be similar to other ▪ Ventilator circuit change (clamp the ETT sweatshirts for particles >60nm. This study did not look at momentarily when changing circuit or switching fit either.[7] from manual ventilation to mechanical - One pre-print study found that homemade masks made of ventilation) cloth and 4 layers of paper towels was able to filter ▪ Inhaled anaesthetic 95.15% of avian influenza virus from aerosols, which was - Key Takeaway: In order to ensure adequate protection of used to replicate COVID-19.[9] The methods of this study our healthcare workers and further conserve the supply of were not clearly defined, but it indicates the importance of PPE equipment, it is important that surgical N95 masks adding layers to increase protection. are allocated to appropriate and high-risk settings as well - CDC recommends that when using a bandana to make a as that surgical masks are used when appropriate. mask that a coffee filter should be added. Coffee filters generally filter particle sizes about 10-20 microns so more Homemade Masks than one should be used and they should be used in The CDC does not consider homemade masks as PPE and addition to other materials. Cloth masks with better fit are should be used by community members in order to preserve preferable. the supply of N95 and surgical/medical masks for healthcare - Analysis of fit: N95 masks have a fit factor of 100. Most professionals. The CDC mentions using cotton, T-shirts, studies of cloth masks do not assess fit, but one prototype bandanas, and coffee filters. However, there are many articles that consisted of 8 layers with alternating thread on the internet that discuss the use of other materials, such has directions and 3 ties around the head had a fit factor of 67. HEPA vacuum filters. Here is the summary of evidence The original prototype consisted of 4 layers, but surrounding these practices and safety considerations: inadequate results from previous prototypes lead to an

Cloth Facemasks: The CDC recommends use of cloth additional 4 layers to be added. This was made from a facemakes for the general public in order to preserve the Hanes Heavyweight 100% preshrunk cotton Tshirt.[10] supply of N95 masks and medical/surgical masks for - Key takeaway and tips healthcare workers. Review of the literature yields the o Multiple layers should be used (A flashlight can be used following in regards to evidence for cloth masks: to assess thickness of the mask by seeing if you can shine a light through the mask. There is no evidence for this

2 High-risk AGMP 6

method as a method of adequate filtration, but it can be - BioAid is a company that has produced a patent-pending helpful.) re-usable N95 mask. Some of the features of these masks o Different materials should be used if possible, but cotton are that they use a replaceable cartridge with a HEPA or should be the primary material MERV13 filter and can be sterilized in clinical or home- o Try to get the mask to fit as closely as possible. based methods. The mask is within NIOSH requirements. o These masks do not replace the importance of social - This could prevent reliance on having masks shipped distancing, but instead offer additional protection when from overseas. individuals have to enter public areas for necessities, such as food shopping. References HEPA Filters: There is a lot of talk about how to convert 1. Lewis D. Is the coronavirus airborne? Experts can't agree. high-efficiency particular air (HEPA) filters found in Nature News. https://www.nature.com/articles/d41586- household vacuum filters into facemasks since thse are the 020-00974-w. Published April 2, 2020. Accessed April 3, filters found in PAPRs. HEPA filters are designed to filter 2020. aerosols with particles 0.3microns in diameter with a 2. CDC. Coronavirus Disease 2019 (COVID-19). Centers minimum efficiency of 99.97%[11] There are many websites for Disease Control and Prevention. showing people how to make these filters into facemasks and https://www.cdc.gov/coronavirus/2019-ncov/hcp/using- claiming they offer ultimate protection. While they most likely ppe.html. Revised April 3, 2020. Accessed April 8, 2020. are highly effective at filtering particles, there are no studies 3. CDC. Coronavirus Disease 2019 (COVID-19). Centers that assess homemade facemasks using HEPA filters for Disease Control and Prevention. compared to medical masks or N95 masks. The safety https://www.cdc.gov/coronavirus/2019-ncov/prevent- considerations of this material as a face-mask are also not getting-sick/diy-cloth-face-coverings.html. Revised April known. Here are some aspects to take into consideration 4, 2020. Accessed April 7, 2020. before using this material: 4. Abd-Elsayed A, Karri J. Utility of Substandard Face o If you want to use a HEPA filter to make homemade Mask Options for Health Care Workers During the mask, it is important to note that most HEPA filters COVID-19 Pandemic. Anesthesia & Analgesia. March contain fiberglass, which can shed and become an irritant 2020:1. doi:10.1213/ane.0000000000004841. to the respiratory tract.[12] This risk is increased when 5. CDC. Coronavirus Disease 2019 (COVID-19). Centers for Disease Control and Prevention. cutting the material. Therefore, HEPA filters should not https://www.cdc.gov/coronavirus/2019- have direct contact to the face if you are to make a mask ncov/hcp/respirators-strategy/index.html. Revised April 4, with this material. 2020. Accessed April 8, 2020. o This theoretically could provide added protection if 6. LHSC. Guidelines for Aerosol Generation Medical inserted into home-made cotton masks, but the filter paper Procedures (AGMP) for Failed ARI Screen or Unable to should be easily removable and replaceable for when the Assess or Confirmed COVID-19. London Health mask needs to be washed. However, there is no evidence Sciences Centre. on effectiveness or safety of this practice. https://www.lhsc.on.ca/media/8476/download. April 7, o Key takeaway: 2020. Accessed April 8, 2020. ▪ This seems like a great idea, but be careful doing 7. Chughtai AA, Seale H, Macintyre CR. Use of cloth masks using the material, particularly directly on the face in the practice of infection control – evidence and policy ▪ There is no evidence that this is safe or effective gaps. International Journal of Infection Control. Other ways to address the mask supply issue: 2013;9(3). doi:10.3396/ijic.v9i3.020.13. 8. Samy Rengasamy, Benjamin Eimer, Ronald E. Shaffer, Other new ideas: Simple Respiratory Protection—Evaluation of the - University of Florida: Department of Anesthesiology is Filtration Performance of Cloth Masks and Common Fabric Materials Against 20–1000 nm Size Particles, The making masks using highest-grade surgical equipment Annals of Occupational Hygiene, Volume 54, Issue 7, wrap (Haylard H600 fabric). There are no released studies October 2010, Pages 789–798, for the effectiveness of these masks, but this material has https://doi.org/10.1093/annhyg/meq044 bacterial filtration efficiency (BFE) of 98.9-99.9% of 9. Ma Q-X, Shan H, Zhang H-L, Li G-M, Yang R-M, Chen airborne microbes.[13] They do not mention viral J-M. Potential utilities of mask wearing and instant hand filtration efficiency. hygiene for fighting SARS-CoV-2. Journal of Medical - This could be a promising alternative once more Virology. 2020. doi:10.1002/jmv.25805. information is released. 10. Dato VM, Hostler D, Hahn ME. Simple Respiratory - Link to how they make these masks and “Mask Do’s and Mask. Emerging Infectious Diseases. 2006;12(6):1033- Don’ts” 1034. doi:10.3201/eid1206.051468. 11. DOE Technical Standard: Specification for HEPA Filters Other companies: Used by DOE Contractors.

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https://www.standards.doe.gov/standards- documents/3000/3020-astd-2015 Clinical Presentation of COVID- 12. CDC. Coronavirus Disease 2019 (COVID-19). Centers for Disease Control and Prevention. 19 in Children https://www.cdc.gov/niosh/npg/npgd0288.html. Revised By Catherine Hahn October 4, 2019. Accessed April 7, 2020. 13. HALYARD* H600 Sequential Sterilization Wrap. Halyard Health AU. Summary https://products.halyardhealth.com.au/surgical- The majority of cases of COVID-19 in children are solutions/sterilization-solutions/halyard-h600-sequential- asymptomatic, mild, or moderate in severity. Preliminary data sterilization-wrap.html. Accessed April 7, 20 shows that 13% of children with infection are asymptomatic, though this number is likely to be much higher as asymptomatic children are less likely to be tested.1 Children who are symptomatic typically will experience symptoms of an upper respiratory infection, including cough, pharyngeal erythema, and fever. Most cases do not progress to lower respiratory tract infections. There is a small subset of pediatric cases that have shown gastrointestinal symptoms including nausea, vomiting, and diarrhea. Unlike the adult population, there does not appear to be a reliable set of laboratory findings consistent with coronavirus infection in children. However, an isolated case in an infant showed elevated IL-6 levels associated with severe infection, which is in accordance with data from the adult population. Most children will not show any CT findings, suggesting mild infection. In those with CT findings, the most common abnormality is ground-glass opacities. The presence of consolidation with halo sign on CT appears to more prevalent in children with coronavirus compared to adults.

Incidence and Epidemiology

It appears that children are less susceptible to COVID-19 infection compared to adults. An analysis by the Chinese Center for Disease Control and Prevention examined epidemiological patterns in 72,314 cases of patients with SARS-CoV-2. Of these, 965 patients (1.3%) were between the ages of 0 and 19 years old, showing that children account for a minority of these infections.2 Most of the pediatric cases have arisen from family clusters, with data showing between 56- 76% of children have a family member with confirmed infection.3,4 In a retrospective analysis of 2143 pediatric patients by Dong et al., the vast majority of cases were mild to moderate in severity with a small group of severe and critical cases. Approximately 5.9% of cases were severe or critical compared to 18.5% of adult cases.1 The median age of diagnosis was seven years old and there was no significant difference in incidence between males and females. Infants and younger children appeared to be more vulnerable to severe and critical infection. Infants less than 1 year old made up 53.8% of critical cases and children under the age of 6 years old contributed to almost 60% of severe infections. The mortality rate appears to be very low in children. In this study, there was one confirmed death of a 14-year-old boy out of 1 2143 cases.

Clinical Symptoms Most children with COVID-19 infection are asymptomatic or have mild infection. However, there appear to be distinct 8 patterns in the pediatric population for children with consolidation with halo sign (10/20), fine mesh shadow (4/20), symptomatic infection. A study from Wuhan Children’s and tiny nodules (3/20). There were no cases of pleural Hospital assessed the frequency of different clinical features in effusion or lymphadenopathy. The presence of halo sign on 171 pediatric cases.4 The most common symptoms were cough CT appears to be somewhat typical in the pediatric population (48.5%), pharyngeal erythema (46.2%), and fever of at least while it is relatively uncommon in adults.10,12 Resolution of 37.5°C (41.5%). There were also cases that showed infection defined as negative nucleic acid testing was gastrointestinal symptoms, including diarrhea (8.8%) and associated with complete absorption of lesions in some cases vomiting (6.4%).4 Other less common symptoms included and a decrease in consolidations in other cases with the fatigue (7.6%), rhinorrhea (7.6%), and nasal congestion persistence of ground-glass opacities.10 Thus, due to common (5.3%).The majority of children will temporarily have upper imaging findings among children, CT can be a powerful tool respiratory infections and very few progress to pneumonia.5 to aid in diagnosis when testing is delayed and to follow Another study from Wuhan Children’s Hospital examined the progression and resolution of infection. characteristics of 8 children with severe infection.6 In this cohort of patients, all of the patients presented with tachypnea References (8/8), and other common presenting features included cough (6/8), fever (6/8), expectoration (4/8), nausea/vomiting (4/8), 1. Dong Y, Mo X, Hu Y, et al. Epidemiological diarrhea (3/8), fatigue/myalgia (1/8), headache (1/8), and Characteristics of 2143 Pediatric Patients With 2019 constipation (1/8).6 Coronavirus Disease in China. Pediatrics. March 2020:e20200702. doi:10.1542/peds.2020-0702 2. Wu Z, McGoogan JM. Characteristics of and Important Laboratory Findings Lessons from the Coronavirus Disease 2019 (COVID-19) Compared to adults, there does not seem to be a consistent Outbreak in China: Summary of a Report of 72 314 Cases pattern of laboratory markers that coincide with coronavirus from the Chinese Center for Disease Control and infection in children. Preliminary studies in adults have shown Prevention. JAMA. February 2020. recurring patterns of elevated liver enzymes, anemia, doi:10.1001/jama.2020.2648 increased inflammatory markers, and sometimes 3. Jiatong S, Lanqin L, Wenjun L. COVID-19 epidemic: hyperglycemia.7 This does not appear to be the case in disease characteristics in children. Journal of Medical children. A retrospective analysis by Henry et al. examined Virology. doi:10.1002/jmv.25807 laboratory findings in 66 pediatric cases. There was a wide 4. Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in array of leukocyte indices, as 69.6% had a normal leukocyte Children. New England Journal of Medicine. 2020. count, 15.2% had an increased leukocyte count, and 15.2% doi:10.1056/NEJMc2005073 had a decreased leukocyte count.8 Most children had normal 5. Hong H, Wang Y, Chung H-T, Chen C-J. Clinical neutrophil counts with 4.6% above the normal range and 6% characteristics of novel coronavirus disease 2019 below the normal range. This contrasts with what is typically (COVID-19) in newborns, infants and children. Pediatrics seen in the adult population. In adults, both increased & Neonatology. 2020. doi:10.1016/j.pedneo.2020.03.001 leukocyte and neutrophil counts have been associated with 6. Sun D, Li H, Lu X-X, et al. Clinical features of severe progression of infection. Regarding inflammatory markers, pediatric patients with coronavirus disease 2019 in only 13.6% of cases had elevated C-reactive protein and Wuhan: a single center’s observational study. World J 10.6% had elevated procalcitonin. In the adult population, Pediatr. March 2020. doi:10.1007/s12519-020-00354-4 elevation of both of these markers has been associated with infection.8 An isolated case report in an infant suggests that 7. Ludvigsson JF. Systematic review of COVID-19 in elevated IL-6 is associated with increased severity of children shows milder cases and a better prognosis than infection.8 This is consistent with preliminary data showing adults. Acta Paediatrica. doi:10.1111/apa.15270 that elevated levels of IL-6 are strongly associated with the 8. Henry BM, Lippi G, Plebani M. Laboratory abnormalities need for mechanical ventilation in the adult population.9 in children with novel coronavirus disease 2019. Clinical Further research needs to be done on the association between Chemistry and Laboratory Medicine (CCLM). IL-6 and prognosis and using IL-6 as a possible therapeutic 2020;1(ahead-of-print). doi:10.1515/cclm-2020-0272 target. 9. Herold T, Jurinovic V, Arnreich C, et al. Level of IL-6 predicts respiratory failure in hospitalized symptomatic CT Findings COVID-19 patients. medRxiv. April The most common finding on CT in children is ground-glass 2020:2020.04.01.20047381. opacities.4,10,11 In the retrospective analysis by Lu et al. doi:10.1101/2020.04.01.20047381 examining 171 patients at Wuhan Children’s Hospital 32.7% 10. Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and of patients had ground-glass opacities on CT.4 Other findings CT features in pediatric patients with COVID-19 included local patchy shadowing (18.7%), bilateral patchy infection: Different points from adults. Pediatric shadowing (12.3%), and interstitial abnormalities (1.2%).4 In a Pulmonology. doi:10.1002/ppul.24718 smaller study by Xia et al. examining 20 pediatric patients 11. High-Resolution Computed Tomography Manifestations with COVID-19 viral pneumonia, all patients had subpleural of 5 Pediatric Patients with 2019 Novel Coronavirus: 10 lesions. Findings included ground-glass opacities (12/20), Journal of Computer Assisted Tomography. 9

https://journals.lww.com/jcat/Abstract/publishahead/High _Resolution_Computed_Tomography_Manifestations.990 Effects of COVID-19 on 37.aspx. Accessed April 2, 2020. Pregnancy: Is Vertical 12. Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus Disease 2019 (COVID-19): A Systematic Transmission Possible? Review of Imaging Findings in 919 Patients. American By Catherine Hahn Journal of Roentgenology. March 2020:1-7. doi:10.2214/AJR.20.23034 Summary The effects of COVID-19 on pregnancy appear to be less severe and have better clinical outcomes compared to SARS and MERS. As the pandemic evolves, there is still uncertainty regarding the effects of COVID-19 in utero. From limited data that is currently available, there have been no confirmed cases of vertical transmission. There have been a few neonatal cases of COVID-19, but it is unclear as to whether this was from intrauterine exposure or as a result of environmental exposure after delivery. Therefore, it appears that the risk of intrauterine transmission of COVID-19 is low, but cannot be ruled out.

Effects of SARS and MERS on Pregnancy

As a way to anticipate potential obstetric outcomes at a time when data is limited, it is helpful to turn to knowledge from past outbreaks. In a recent retrospective analysis examining the effects of SARS and MERS on pregnancy, there were no 1 reported cases of maternal-fetal transmission of the viruses. However, it is critical to note that there were reported adverse effects on pregnancy due to infection from these viruses. In a study of 12 mothers with SARS, four out of seven women who presented in the first trimester had spontaneous miscarriages. Further, of the five women who presented after 24 weeks gestation, four had preterm deliveries.1 Another study examining the effects of SARS on placental pathology reported two instances of placental anomalies in mothers who acquired the virus in the third trimester. The placentas showed fetal thrombotic vasculopathy and areas of avascular chorionic villi, resulting in oligohydramnios and intrauterine growth 1 restriction. Turning to MERS, there are 11 documented cases of MERS in pregnancy, and 91% had adverse outcomes. There were two instances of maternal death, one stillbirth, and one neonatal death.1 Therefore, while both SARS and MERS have been associated with adverse outcomes, there have been no documented cases of intrauterine transmission.

COVID-19 & Vertical Transmission An analysis of 37 pregnant mothers from China with COVID- 19 revealed no evidence of vertical transmission of infection.2 All samples of neonatal throat swabs, umbilical cord blood, amniotic fluid, stool, neonatal blood samples, and breast milk were negative for the virus. There were six cases of preterm labor, six cases of premature rupture of membranes, two cases of abnormal amniotic fluid, and two cases of abnormal umbilical cords.2 Unlike the SARS virus, it appears that there are no pathologic changes in placenta as a result of infection.3 In this analysis, there was one documented case of neonatal death nine days after delivery. He initially developed shortness of breath and later died from refractory shock, multiple organ 10 failure, and disseminated intravascular coagulation. None of utero as a result of intrauterine exposure to coronavirus. It is the mothers required mechanical ventilation after delivery and also possible that placental damage could have permitted these there were no reported maternal deaths. antibodies to cross the placenta, which could explain why nasopharyngeal swab tests were negative. This is plausible Another study was recently published by New York- given our knowledge of placental abnormalities as a result of Presbyterian, and the researchers’ findings were consistent SARS-CoV infection. However, preliminary data has not with initial data from China. Out of 18 COVID-positive shown any placental pathologies as a result of SARS-CoV-2.4 mothers who presented for delivery, 4 had symptomatic As such, more data is needed to determine is vertical infection.4 The asymptomatic patients were diagnosed after a transmission is a true possibility. universal screening protocol was implemented for all admissions on the Labor Unit after March 22. Ten deliveries Conclusion were uncomplicated normal spontaneous vaginal deliveries. Eight patients delivered via C-section due to non-reassuring At this time, it appears that the risk of vertical transmission of fetal heart rate (n=3), repeat C-section (n=2), arrest of descent COVID-19 is low, but it cannot be ruled out entirely. At this (n=1), arrest of dilation (n=1), and failed labor induction time, it is not known whether the cases of preterm labor were a (n=1). There was one case of preterm labor. None of the result of coronavirus infection or due to a secondary reason. It newborns showed clinical signs of infection. Fifteen newborns is important to note that there remains a high risk of were negative for COVID-19 infection via nasopharyngeal respiratory droplet transmission of infection to neonates, so swab on day of life (DOL) 0.4 Two infants had inconclusive proper infection control precautions should be taken. In initial screenings, but were negative on DOL 1-2.4 One infant addition, more research needs to be done on the effects of the had indeterminate test results and was treated as a fetus when the virus is contracted during the first or second “presumptive negative”. As of DOL 6, the baby continued to trimester of pregnancy. show no signs of infection. None of the infants had IgM or IgG antibody testing.4 This data in conjunction with data from References China show no confirmed cases of vertical transmission, suggesting that the risk of vertical transmission is low. 1. Da S, Al G. Potential Maternal and Infant Outcomes From (Wuhan) Coronavirus 2019-nCoV Infecting There have been a few reported cases of confirmed COVID-19 Pregnant Women: Lessons From SARS, MERS, and in neonates, but it is difficult to determine at this time whether Other Human Coronavirus Infections. Viruses. this was due to intrauterine exposure or as a result of doi:10.3390/v12020194 environmental exposure after birth. A study published in 2. Panahi L, Amiri M, Pouy S. Risks of Novel Coronavirus JAMA Pediatrics examined the effects of maternal COVID-19 Disease (COVID-19) in Pregnancy; a Narrative Review. 5 infection on 33 newborns at Wuhan Children’s Hospital. Arch Acad Emerg Med. 2020;8(1). Three of the babies tested positive for COVID-19 via https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092922/ 5 nasopharyngeal and anal swabs on DOL 2 and 4. Two of the . Accessed April 7, 2020. babies tested negative on DOL 6 and the remaining baby 3. Chen S, Huang B, Luo DJ, et al. [Pregnant women with tested negative on DOL 7.5 One baby was born at 31 weeks new coronavirus infection: a clinical characteristics and because of fetal distress and required resuscitation at delivery. Clinically, all three patients showed signs of pneumonia on placental pathological analysis of three cases]. Zhonghua chest x-ray and experienced a variety of symptoms including Bing Li Xue Za Zhi. 2020;49(0):E005. lethargy, fever, and vomiting. All samples from these cases doi:10.3760/cma.j.cn112151-20200225-00138 had negative amniotic fluid, cord blood, and breast milk.5 The 4. 43 Pregnant Women with COVID-19: Clinical Course researchers of this paper argue that because they implemented and Outcomes. The ObG Project. strict infection control measures during delivery, it is likely https://www.obgproject.com/2020/03/26/43-pregnant- the positive neonatal results are maternal in origin and the women-with-covid-19-clinical-course-and-outcomes/. possibility of vertical transmission cannot be ruled out.5 There Published March 26, 2020. Accessed April 8, 2020. is an additional case report of an infant testing positive for 5. Zeng L, Xia S, Yuan W, et al. Neonatal Early-Onset 6 COVID-19 at 36 hours of life. Similarly, all samples from Infection With SARS-CoV-2 in 33 Neonates Born to cord blood, placenta, and breast milk were negative for the Mothers With COVID-19 in Wuhan, China. JAMA virus.6 Pediatr. March 2020.

doi:10.1001/jamapediatrics.2020.0878 There have been three documented cases of elevated IgM antibodies in neonates born to mothers with confirmed 6. Wang S, Guo L, Chen L, et al. A Case Report of Neonatal coronavirus infection.7,8 Upon delivery, all three of the infants 2019 Coronavirus Disease in China. Clin Infect Dis. 7,8 tested negative for coronavirus via nasopharyngeal swab. doi:10.1093/cid/ciaa225 Only IgG antibodies are able to be transmitted across the 7. Dong L, Tian J, He S, et al. Possible Vertical placenta, and IgM antibodies cannot cross the placenta due to Transmission of SARS-CoV-2 From an Infected Mother their larger molecular structure. IgM testing for SARS-CoV-2 to Her Newborn. JAMA. March 2020. has a sensitivity of 70.2% and a specificity of 96.2%.7 It is doi:10.1001/jama.2020.4621 possible that the IgM antibodies were produced by the fetus in 11

8. Zeng H, Xu C, Fan J, et al. Antibodies in Infants Born to Mothers With COVID-19 Pneumonia. JAMA. March Hydroxychloroquine Update: 2020. doi:10.1001/jama.2020.4861 Reanalysis of Gautret et. al. Study By Daniel Menza

Evidence to Date: This study is a reanalysis of the data from the Gautret et. al. open label non-randomized trial of Hydroxychloroquine and Azithromycin for the treatment of COVID-19 using a Bayesian analysis. The trial compared 26 patients receiving hydroxychloroquine with or without azithromycin to 16 control patients receiving standard treatment, all COVID-19 positive on PCR. The primary endpoint was presence or absence of virus on nasal swab at day 6. The authors made several assumptions and choices in analyzing the data that this new study seeks to examine. The original authors excluded 6 patients from the treatment group analysis, 1 who died, 3 who were transferred to the ICU, 1 who left the hospital, and 1 who stopped the drug because of nausea. There were also 5 patients in the control group who were not tested at day 6, and the authors analyzed these patients as positive. The authors of the new study were concerned that both of these assumptions bias the data towards supporting the hypothesis. In short, when reanalyzed with these assumptions changed, the results were much less strong in supporting the hypothesis that hydroxychloroquine increased viral clearance at day 6 post inclusion in the trial. This means that one of the main pieces of literature supporting the use of hydroxychloroquine and azithromycin in the treatment of COVID-19 suffers from serious flaws in the way it analyzes the data. Details The paper reanalyzed the data in many different ways, using a Bayesian analysis. The nomenclature they used to define the different data sets are defined as follows:

HCQgroup: Those treated with hydroxychloroquine (HCQ) and and those treated with HCQ and azithromycin (AZ) HCQMono: Those treated only with HCQ HCQ+AZ: Those treated with HCQ and AZ Dataoriginal: The data asit was presented in the paper Datadet: The data including the 4 patients who deteriorated (1 who died, 3 who went to the ICU) in the treatment group and counting them as tested positive in the day 6 endpoint Dataxcon: The data including the 4 patients who deteriorated and excluding the 5 patients who were not tested in the comparison group at the day 6 endpoint

Datanegcon: The data including the 4 patients who deteriorated and counting the 5 patients who were not tested in the comparison group at day 6 as testing negative 12

They performed a Bayesian analysis which outputs a Bayes Factor as a result. The Bayes Factor is a measure of how Use of Helmet Ventilators for strongly the data supports the alternate hypothesis (that HCQ Covid-19 Patients and AZ improved viral clearance at day 6) over the null By Eric Stanton hypothesis (that there was no difference in viral clearance between the treatment and the comparison group). A Bayes Factor of 1-3 is classified as anecdotal evidence, 3-10 is Summary classified as moderate evidence, 10-30 is strong evidence and Helmet non-invasive ventilation (NIV) is growing in 30-100 is very strong evidence. A Bayes Factor of less than 1 popularity during the Covid-19 pandemic as a way to decrease indicates evidence that the treatment inhibited viral clearance the need for invasive ventilation. When compared to mask compared to the comparison group. This is the standard way NIV, helmets appear to decrease mortality and intubation rate of interpreting Bayes Factors. The results are included in this in patients with acute respiratory failure. With regards to table. infection transmission, there is no consensus on whether helmet NIV decreases transmission when compared to mask, but it does appear to decrease the dispersion of exhaled air.

Details Non-invasive ventilation (NIV) through either face mask or helmet is a way to maintain positive end expiratory pressure with the goal of reducing risks associated with invasive ventilation such as complications from sedation, use of As you can see, the evidence supporting the use of HCQ and paralytics, pneumonia, and ICU acquired weakness.1 The AZ was much stronger under the assumptions the authors current consensus is mixed when comparing outcomes of operated under than when the deteriorated patients were ARDS patients on NIV vs. high flow nasal canula (HFNC) but included and the untested patients were excluded, which is a it leans towards HFNC as having better outcomes when more intuitive way of looking at the data. This analysis shows compared to NIV. However, these studies focused on the that this data is not as strong in supporting the use of HCQ and comparison of mask NIV, rather than helmet, to HFNC.2 To AZ as the authors may have presented it. date, the evidence comparing HFNC to helmet NIV is limited, hopefully prompting future investigation in the outcomes References between the two methods.

1. Hulme OJ, Wagenmakers E-J, Damkier P, et al. Reply to There is however, numerous studies comparing the outcomes Gautret et al. 2020: A Bayesian reanalysis of the effects of mask NIV to helmet NIV in patients with acute respiratory of hydroxychloroquine and azithromycin on viral carriage failure. In a meta-analysis published in 2016, it was shown in patients with COVID-19. medRxiv. April that helmet NIV was associated with lower hospital mortality 2020:2020.03.31.20048777. (OR 0.43, 95 % CI 0.26 to 0.69), and decreased intubation rate doi:10.1101/2020.03.31.20048777 (OR 0.32, 95 % CI 0.21 to 0.47).3 These advantages have 2. Gautret P, Lagier J-C, Parola P, et al. thought to been attributed to the superior seal offered by the Hydroxychloroquine and azithromycin as a treatment of helmet when compared to the facemask allowing for higher COVID-19: results of an open-label non-randomized PEEP.1 Other benefits cited were increased communication clinical trial. International Journal of Antimicrobial ability and increased cough/sputum clearing as a result of not having a mask tightly fitted to the patients face. Agents. March 2020:105949.

doi:10.1016/j.ijantimicag.2020.105949 The other concern with regards to choosing helmet or facemask NIV, especially amidst the Covid-19 pandemic, is the risk of aerosolization and infection transmission. There is concern about the potential aerosolization and transmission of

the Covid-19 virus with use and adjustment of BiPAP masks. A systematic review about the transmission of the SARS- CoV-1 virus during aerosol generating procedures suggested that there is an increased risk of transmission from patients on BiPAP however, it cited wide confidence intervals that were not statistically significant.4 Regardless of this evidence, efforts should be taken to minimize transmission from patients to healthcare workers. It is unclear if helmet ventilators reduce the potential risk of Covid-19 virus transmission when compared to BiPAP masks, but it does appear to reduce the dispersion of exhaled air. In a study that used a human patient 13 simulator, the dispersion distance of exhaled air for two different types of helmets and a facemask were measured. The D-Dimer Level as a Prognostic results are summarized below:5 Indicator and Therapeutic Value • StarMed CaStar R Helmet: negligible air leak noted. • Sea-Long Oxygen Head Tent: radial dispersion through of Prophylactic Heparin the neck interface of 170 mm with inspiratory positive By Eric Stanton airway pressure (IPAP) of 12 cm H2O, and 270 mm with IPAP of 20 cm H2O. • Respironics Total Facemask: dispersion distance through Summary exhalation port of 693 mm with IPAP of 10 cm H2O and distances exceeding 916 mm with IPAP of 18 cm H2O. Elevated d-dimer levels in Covid-19 patients appears to be a These findings are limited by the use of a simulation and do poor prognostic factor. Prophylactic heparin use, especially in not describe actual transmission rates between the different patients with elevated d-dimer levels and SIC score, has a methods of NIV, but it does demonstrate a difference in potential therapeutic value. dispersion of exhaled air which could lead to differences in transmission. Coagulation in Covid-19 Patients Covid-19 patients are thought to be in a hypercoagulable state Bottom Line due to both the endothelial cell dysfunction induced directly Helmet NIV likely decreases mortality and intubation rates in by the virus as well as the hypoxemic state of some patients.1 patients with acute respiratory failure when compared to mask This has led to the potential value of the d-dimer level as a NIV due to increased integrity of seal maintaining adequate prognostic factor as well as the use of heparin in patients PEEP. There is no current consensus regarding the differences demonstrating a coagulopathy. in outcomes of patients on HFNC versus helmet NIV. There is limited data on differences in transmissibility of the Covid-19 Prognostic Value virus between helmet and mask NIV but dispersion of exhaled air appears to be much lower in the helmet NIV. In three studies that looked at d-dimers as a prognostic value, it was found that a level greater than 1.0-2.0 mg/L was considered a poor prognostic factor. The findings of these References studies are summarized below: 1. Patel BK, Wolfe KS, Pohlman AS, Hall JB, Kress JP. • In a retrospective cohort study that looked at 191 Covid- Effect of Noninvasive Ventilation Delivered by Helmet vs 19 patients, a d-dimer level greater than 1.0 mg/L Face Mask on the Rate of Endotracheal Intubation in conferred an odds ratio of 20.04 (95% CI 6.52- 61.56) for Patients With Acute Respiratory Distress Syndrome: A in-hospital death. 2 Randomized Clinical Trial. JAMA. 2016;315(22):2435- • In a retrospective cohort study with 183 Covid-19 2441. doi:10.1001/jama.2016.6338 patients, there was a mean d-dimer level of 0.61 mg/L in 2. Frat J-P, Coudroy R, Marjanovic N, Thille AW. High- the survival group upon admission compared to a d-dimer flow nasal oxygen therapy and noninvasive ventilation in the management of acute hypoxemic respiratory failure. level of 2.12 mg/L in the non-survivor group (p < 0.001). Ann Transl Med. 2017;5(14). 3 doi:10.21037/atm.2017.06.52 • In a retrospective cohort study with 41 Covid-19 patients, 3. Liu Q, Gao Y, Chen R, Cheng Z. Noninvasive ventilation there was a mean d-dimer level of 2.4 mg/L in patients with helmet versus control strategy in patients with acute requiring critical care compared to a d-dimer level of 0.5 respiratory failure: a systematic review and meta-analysis mg/L in those who did not (p < 0.0042). 4 of controlled studies. Crit Care. 2016;20(1). doi:10.1186/s13054-016-1449-4 4. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Use of Anticoagulation Aerosol Generating Procedures and Risk of Transmission One retrospective study of 449 patients that looked at the use of Acute Respiratory Infections to Healthcare Workers: A of heparin in severe Covid-19 patients showed a reduction in Systematic Review. PLoS ONE. 2012;7(4). 28-day mortality when the patient had a sepsis induced doi:10.1371/journal.pone.0035797 coagulopathy score greater than 4 (OR 0.372, 95% CI 0.154- 5. Hui DS, Chow BK, Lo T, et al. Exhaled air dispersion 0.901), or d-dimer greater than 3.0 mg/L (OR 0.412, 95% CI during noninvasive ventilation via helmets and a total 0.207- 0.817). There was no significant difference in 28-day facemask. Chest. 2015;147(5):1336-1343. mortality for patients below these parameters.5 Of the 99 doi:10.1378/chest.14-1934 patients that were in the heparin group, 94 received LMWH (40-60 mg enoxaparin/day) and 5 received unfractionated heparin (10000-15000 U/day).

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Another retrospective study that looked at the use LMWH in China. The Lancet. 2020;395(10223):497-506. non-severe Covid-19 patients an effect on normalizing select doi:10.1016/S0140-6736(20)30183-5 lab values. This study, which included 41 patients, found that 5. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. the LMWH group (N = 21) had significantly lower IL-6 levels Anticoagulant treatment is associated with decreased compared to the control group after treatment (15.76 ± 25.71 mortality in severe coronavirus disease 2019 patients with vs. 78.24 ± 142.41 p = 0.000) as well as significantly lower coagulopathy. J Thromb Haemost. n/a(n/a). doi:10.1111/jth.14817 IL-6 levels within the LMWH group after treatment as 6. Shi C, Wang C, Wang H, et al. The Potential of Low compared to before (47.47 ± 58.86 vs. 15.76 ± 25.71 p = Molecular Weight Heparin to Mitigate Cytokine Storm in 0.006). Additionally, this study found significant differences Severe Covid-19 Patients: A Retrospective Clinical in the percent increase in lymphocytes between the heparin Study. Pharmacology and Therapeutics; 2020. and control groups (but not overall lymphocyte percentage) as doi:10.1101/2020.03.28.20046144 well d-dimer reduction within the heparin group before and 7. Thachil J, Tang N, Gando S, et al. ISTH interim guidance after treatment. 6 However, this study did not contribute to on recognition and management of coagulopathy in improvement in mortality due to anticoagulation treatment as COVID-19. J Thromb Haemost. n/a(n/a). all the patients in the study survived. doi:10.1111/jth.14810 8. Mummery RS, Rider CC. Characterization of the Heparin Guidance Heparin-Binding Properties of IL-6. J Immunol. 2000;165(10):5671-5679. Currently, the interim guidance from the International Society doi:10.4049/jimmunol.165.10.5671 of Thrombosis and Hemostasis recommends considering a 9. Mycroft-West C, Su D, Elli S, et al. The 2019 prophylactic dose of LMWH in all patients who require Coronavirus (SARS-CoV-2) Surface Protein (Spike) S1 hospital admission for Covid-19 in the absence of: Receptor Binding Domain Undergoes Conformational Change upon Heparin Binding. Biochemistry; 2020. • Active bleeding doi:10.1101/2020.02.29.971093 • Platelet count less than 25 X 109/L

Monitoring is advised in severe renal impairment and abnormal PT or APTT are not considered contraindications. 7

Heparin’s Biologic Effect It is speculated that the potential therapeutic effect of heparin in Covid-19 patients extends beyond its traditional role as an anticoagulant. It was proven in-vitro that heparin is capable of binding IL-6, possibly reducing its biological activity.8 Additionally, heparin has been shown to induce a conformational change of the SARS-Cov-2 surface spike protein in vitro.9 While this seems like promising information, further investigation in-vivo must be conducted to quanitify heparin’s therapeutic value.

References 1. Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS- CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. April 2020. doi:10.1007/s11239-020-02105-8 2. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140- 6736(20)30566-3 3. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847. doi:10.1111/jth.14768 4. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan,

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Melatonin also protects against lung fibrosis, and has been Possible Therapies for shown to attenuate bleomycin-induced lung fibrosis in Convalescent Pulmonary mice.[4] Post-ARDS fibrosis has been noted in SARS as well, and preventing progression to fibrosis could help improve Management of COVID-19 patient outcomes and pulmonary function.[5] Melatonin has By Austin Krebs been studied extensively in animal models of acute lung injury, and its safety in humans has been demonstrated Summary consistently, making it a potentially beneficial treatment for Current convalescent pulmonary management for COVID-19 COVID-19. patients is sparse. Melatonin is one possible option given its ARDS can also trigger persistent lung inflammation and anti-inflammatory, anti-oxidant, and anti-fibrotic effects. fibrosis through activation of the NLRP3 inflammasome and These mechanisms could attenuate lung injury in COVID-19 secretion of IL-1B. Pirfenidone, a federally approved anti- patients. Another option is pirfenidone, an anti-fibrotic fibrotic medication, has been shown to reduce LPS-induced medication that has shown efficacy in models of ARDS as lung inflammation and fibrosis by down-regulating NLRP3 well as advanced idiopathic pulmonary fibrosis. Clinical trials activity.[6] Pirfenidone has been shown to be efficacious even investigating pirfenidone are currently being conducted. A in advanced idiopathic pulmonary fibrosis, and could serve as final option is that of mesenchymal stem cells (MSCs). MSCs a potential adjunct in the treatment of lung injury in COVID- have been shown to home to damaged tissues and facilitate 19 patients.[7] A clinical trial examining the effects of their repair, and have been used in small samples of COVID- pirfenidone in COVID-19 patients is currently recruiting. 19 patients with good outcomes. Clinical trials in China are ongoing. These options are some of the current therapies being Another possible option is mesenchymal stem cells (MSCs). explored to address COVID-19 lung injury. MSCs have demonstrated immunosuppresive effects, but only when induced by inflammatory cytokines and nitric oxide.[8] Evidence to Date These stem cells have been shown to home to damaged tissue and integrate into the microenvironment, preparing it to Persistent hypoxemia is a problem in COVID-19 patients, facilitate tissue repair.[9] In fact, MSCs have already been sometimes requiring prolonged non-rebreather oxygenation. used in COVID-19 patients. Seven patients in Wuhan with The current literature is sparse regarding convalescent COVID-19 were treated with MSCs and within 2-4 days after pulmonary management of COVID-19 patients. Several treatment, showed resolution of symptoms, increase in O2 potentially beneficial medications have been proposed thus saturation, significant reduction in the pro-inflammatory TNF- far. The purpose of this review is to examine these proposals α, and significant increase in the anti-inflammatory IL-10.[10] and attempt to extrapolate existing clinical data and apply it to Clinical trials are currently enrolling in China to investigate the treatment of COVID-19. the effects of MSCs in the treatment of COVID-19 lung One potential therapy that has been proposed to treat COVID- disease. 19 is melatonin. Melatonin exerts an anti-inflammatory effect The current literature regarding convalescent pulmonary through Sirtuin-1(SIRT1), which has been shown to attenuate management is thin, but the above therapies are some of the lung injury and inflammation in sepsis-induced acute lung options currently being investigated to ameliorate lung disease injury.[1] Additionally, the anti-inflammatory effects of due to COVID-19. melatonin involve down-regulating NF-kB activation. It also stimulates NF-E2 related factor (Nrf2) which is an important References component in protecting the lungs from injury.[2] An anti- 1. Wang, Qian-Lu, et al. “Ginsenoside Rg1 Regulates SIRT1 oxidant effect has also been demonstrated in melatonin, which to Ameliorate Sepsis-Induced Lung Inflammation and might be helpful in countering the production of oxidized Injury via Inhibiting Endoplasmic Reticulum Stress and products of viral infections. SARS models of lung injury Inflammation.” Mediators of Inflammation, vol. 2019, demonstrated that oxidized low density lipoprotein activates Hindawi, 2019, p. e6453296. www.hindawi.com, doi: innate immune responses that lead to over-production of IL-6 10.1155/2019/6453296. via toll like receptor 4 (TLR4) and subsequent lung 2. Zhang, Rui, et al. “COVID-19: Melatonin as a Potential Adjuvant Treatment.” Life Sciences, vol. 250, June 2020, damage.[3] p. 117583. PubMed Central, doi:10.1016/j.lfs.2020.117583. 16

3. Imai, Yumiko, et al. “Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Can Nitric Oxide be used to treat Acute Lung Injury.” Cell, vol. 133, no. 2, Apr. 2008, pp. Covid-19? 235–49. ScienceDirect, doi:10.1016/j.cell.2008.02.043. 4. Zhao, Xiaoguang, et al. “Melatonin Protects against Lung By Helen Pozdniakova Fibrosis by Regulating the Hippo/YAP Pathway.” International Journal of Molecular Sciences, vol. 19, no. Summary 4, Apr. 2018. PubMed, doi:10.3390/ijms19041118. 5. Gralinski, Lisa E., et al. “Mechanisms of Severe Acute There is data that nitric oxide can inhibit viral replication of Respiratory Syndrome Coronavirus-Induced Acute Lung similar viruses (SARS) while also improving pulmonary Injury.” MBio, vol. 4, no. 4, Aug. 2013. PubMed, hypertension. If the respiratory illness caused by Covid-19 is doi:10.1128/mBio.00271-13. similar to HAPE, agents that increase nitric oxide such as 6. Li, Yi, et al. “Pirfenidone Ameliorates PDE5 inhibitors may show promise in treating severe disease. Lipopolysaccharide-Induced Pulmonary Inflammation and Fibrosis by Blocking NLRP3 Inflammasome Evidence to Date Activation.” Molecular Immunology, vol. 99, 2018, pp. Guidelines for severe illness in Covid-19 recommend 134–44. PubMed, doi:10.1016/j.molimm.2018.05.003. treatment based on ARDS protocol. ARDS is defined by the 7. Yoon, Hee-Young, et al. “Efficacy and Safety of Berlin Criteria. Despite using ARDS protocol, 50+% of Pirfenidone in Advanced Idiopathic Pulmonary Fibrosis.” patients who require invasive ventilation die. Dr. Gattinoni, an Respiration; International Review of Thoracic Diseases, anesthesiologist working in the epicenter in Italy, recently vol. 97, no. 3, 2019, pp. 242–51. PubMed, proposed that we think of Covid-19’s respiratory illness as an doi:10.1159/000492937. “atypical ARDS” and look at patients as having a biphasic 8. Ren, Guangwen, et al. “Mesenchymal Stem Cell- disease.[1] Initially, the hypoxemia begins with a Mediated Immunosuppression Occurs via Concerted dysregulation of pulmonary perfusion. Patients in this phase Action of Chemokines and Nitric Oxide.” Cell Stem Cell, are described as Type L and are characterized by: vol. 2, no. 2, Feb. 2008, pp. 141–50. PubMed, • Low elastance (i.e., high compliance) doi:10.1016/j.stem.2007.11.014. 9. Wang, Ying, et al. “Plasticity of Mesenchymal Stem Cells • Low V/Q ratio in Immunomodulation: Pathological and Therapeutic • Low lung weight Implications.” Nature Immunology, vol. 15, no. 11, 11, • Low recruitability Nature Publishing Group, Nov. 2014, pp. 1009–16. • Limited “PEEP response” www.nature.com, doi:10.1038/ni.3002. Later, patients go into pulmonary edema collapse or an 10. Zikuan L, Rongjia Z, Wei H, et al. “Transplantation of “ARDS” like state. These patients exhibit a phenotype ACE2- mesenchymal stem cells improves the outcome of described as type H and are characterized by: patients with COVID-19 pneumonia.” Aging Dis. • High elastance 2020;11:216- 228. • High right-to-left shunt http://www.aginganddisease.org/article/0000/2152- • High lung weight 5250/ad-0-0-216.shtml • Higher “PEEP response” • High recruitability. He cautions physicians that type L patients can progress to being type H depending on disease progression and our management. Because of this, many physicians compare the symptomatology of Covid-19 to high altitude pulmonary edema (HAPE) which is a pure hypoxemic disease leading to pulmonary hypertension. HAPE shares some similarities with Covid-19 such as: • A low PaO2/FiO2 ratio • Hypoxia/tachypnea • Hypocarbia • Ground glass opacities on chest CT or patchy infiltrates on chest x-ray • High levels of fibrin

• ARDS in severe disease[10]

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This begs the question: if this theory is true, can we use HAPE Coronavirus.” Journal of Virology, vol. 79, no. 3, Feb. treatments for severe Covid-19? Treatment options for HAPE 2005, pp. 1966–69. PubMed Central, includes supplemental oxygen, nifedipine, phosphodiesterase doi:10.1128/JVI.79.3.1966-1969.2005. type 5 inhibitors (PDE5-i), and dexamethasone. Relieving 4. Chen, H. I., et al. “Nitric Oxide in Systemic and hypoxemia is the most effective method of reducing Pulmonary Hypertension.” Journal of Biomedical pulmonary artery pressure and protecting other organs. Science, vol. 4, no. 5, 1997, pp. 244–48. PubMed, Preliminary treatment for hospitalized Covid-19 patients doi:10.1007/bf02253424. currently is noninvasive ventilation with high oxygen settings. 5. Dominiczak Anna F., and Bohr David F. “Nitric Oxide Out of the above choices, there may be a role for adjunct and Its Putative Role in Hypertension.” Hypertension, vol. PDE5 inhibitors. In SARS, the literature shows that nitric 25, no. 6, American Heart Association, June 1995, pp. oxide inhibits the replication cycle of the virus in-vitro in a 1202–11. ahajournals.org (Atypon), dose dependent fashion. Induction of iNOS reduced the yield doi:10.1161/01.HYP.25.6.1202. of virus by about 82%.[3] In a separate study with the same 6. “Effects of Phosphodiesterase 5 Inhibitor Sildenafil on the methodology, they found the survival rate of SARS infected Respiratory Parameters, Inflammation and Apoptosis in a cells was greatly increased with treatment with NO. [7] Saline Lavage-Induced Model of Acute Lung Injury.” Because SARS shares a lot of similarities to Covid-19, these Journal of Physiology and Pharmacology, 2018. DOI.org results may be applicable in the current pandemic. (CSL JSON), doi:10.26402/jpp.2018.5.15. In the context of acute lung injury, a study using a rabbit 7. Keyaerts, Els, et al. “Inhibition of SARS-Coronavirus model demonstrated reduced markers of lung inflammation Infection in Vitro by S-Nitroso-N-Acetylpenicillamine, a using 1mg/kg IBW of IV sildenafil. Markers that were Nitric Oxide Donor Compound.” International Journal of reduced included release of TNF-alpha/IL-8/IL-6, lung edema Infectious Diseases: IJID: Official Publication of the formation, protein content in bronchoalveolar lavage, and International Society for Infectious Diseases, vol. 8, no. 4, apoptosis of epithelial cells with an improvement in July 2004, pp. 223–26. PubMed, respiratory parameters. [6] doi:10.1016/j.ijid.2004.04.012. 8. Maggiorini, Marco. “Prevention and Treatment of High- Clinically, studies have shown that nitric oxide production is Altitude Pulmonary Edema.” Progress in Cardiovascular impaired in patients with HAPE which is probably the Diseases, vol. 52, no. 6, May 2010, pp. 500–06. underlying mechanism for the elevated pulmonary artery ScienceDirect, doi:10.1016/j.pcad.2010.03.001. pressures. [8] [11] Likewise, studies have shown a correlation 9. Moro, Fabrizio Dal, and Ugolino Livi. “Any Possible between hypertension and depletion of nitric oxide, likely due Role of Phosphodiesterase Type 5 Inhibitors in the to endothelial dysfunction. [4] Some authors postulate that the Treatment of Severe COVID19 Infections? A Lesson depletion of nitric oxide may be the reason that we are seeing from Urology.” Clinical Immunology (Orlando, Fla.), Covid-19 patients having a higher susceptibility to than Apr. 2020. PubMed Central, healthy patients. [9] One benefit of using PDE5 inhibitors is doi:10.1016/j.clim.2020.108414. that they are primarily a pulmonary vasodilator and not 10. Solaimanzadeh, Isaac. “Acetazolamide, Nifedipine and systemic like nifedipine. The current treatment of HAPE is 20- Phosphodiesterase Inhibitors: Rationale for Their 50mg q8 of sildenafil or 10mg q12 of tadalafil. [8] Utilization as Adjunctive Countermeasures in the Treatment of Coronavirus Disease 2019 (COVID-19).” Given this information, the data looks promising. However, Cureus, vol. 12, no. 3. PubMed Central, we know that nitric oxide can be a double-edged sword and doi:10.7759/cureus.7343. Accessed 8 Apr. 2020. actually be detrimental in high quantities. Some postulate 11. Tooba, Rubabin, et al. “Is There Value in Repeating increased nitric oxide may be an early marker of lung Inhaled Nitric Oxide Vasoreactivity Tests in Patients with inflammation. Therefore, studies done on this topic should pay Pulmonary Arterial Hypertension?” Lung, vol. 198, no. 1, attention to dosages and effect on nitric oxide levels in vivo. Feb. 2020, pp. 87–94. Springer Link, doi:10.1007/s00408- 019-00318-0. References 12. Wright, Christine E., et al. “Protective and Pathological Roles of Nitric Oxide in Endotoxin Shock.” 1. Gattinoni, Luciano, et al. “Covid-19 Does Not Lead to a Cardiovascular Research, vol. 26, no. 1, Oxford ‘Typical’ Acute Respiratory Distress Syndrome.” Academic, Jan. 1992, pp. 48–57. academic.oup.com, American Journal of Respiratory and Critical Care doi:10.1093/cvr/26.1.48. Medicine, Mar. 2020. doi:10.1164/rccm.202003-0817LE. 2. 2018 - Effects of Phosphodiesterase 5 Inhibitor

Sildenafi.Pdf.

http://jpp.krakow.pl/journal/archive/10_18/pdf/10.26402/j

pp.2018.5.15.pdf. Accessed 8 Apr. 2020.

3. Åkerström, Sara, et al. “Nitric Oxide Inhibits the Replication Cycle of Severe Acute Respiratory Syndrome 18

of hemoglobin leading to dissociation of the iron from the Does O2 Saturation Speak to the protoporphyrin. [5] This may explain severe hypoxemia out of Severity of Covid-19? proportion to lung pathology. Since it is likely that this is a By Helen Pozdniakova vascular issue, this may explain why ARDS protocol ventilation may lead to high mortality in ventilated patients; it involves high PEEP pressures to keep the alveoli open at the Summary expense of compressing the pulmonary vasculature. High Anecdotal evidence and recent literature may suggest the enough PEEP pressures can also lead to hypotension. ARDS protocol for treating Covid-19 may be inappropriate. Oxygen saturation may not be a reliable indicator of Perhaps it is time for a change in the way we are treating these respiratory status in Covid-19 patients. high-risk patients. The physicians who spoke in the podcasts used in this study recommend using the O2 saturation in Evidence to Date addition to the patient’s appearance to decide when to Patients triaged in the emergency room are monitored by their intubate. They recommend starting conservatively with high vital signs. A decrease in oxygen saturation measured by pulse flow nasal cannula in combination with self-pronation and [3][4][6] oximetry is used as an indication of worsening respiratory restriction of maintenance fluids. High flow nasal function in Covid-19 patients and an indication for cannula has been shown to improve outcomes in ARDS and endotracheal intubation. With the growing concern over the may contribute a small amount of PEEP to maintain lung [8] shortage of ventilators, we are trying to prevent or delay inflation which may be all these patients need. The ROTH intubation in as many patients as possible. However, we also score, which involves asking a patient to count from 1 to 30 know that Covid-19 patients on invasive ventilation have a using one signal breath, may be useful as a screening tool [1] mortality between 50-80% despite using the acute respiratory (sensitivity 91% and specificity 93% for pulse ox < 95%). distress syndrome (ARDS) protocol. This report discusses the Some physicians have even asked their patients to walk to sit efficacy of the current management of Covid-19 as ARDS. up and down in their chair as a measurement of hypoxia.

On March 30th, 2020 Dr. Luciano Gattinoni, an It is important to remember that we cannot become too lax in anesthesiologist on the front lines in Italy, wrote his viewpoint our criteria to intubate. In a study from California with 54 discussing that patients with severe Covid-19 exhibit an Covid-19 patients showed that low oxygen saturation at initial atypical form of ARDS. [2] This has since gained support by examination were significantly associated with admission to many physicians, especially those working in NYC. These the ICU, diagnosis of pneumonia, and progression to ARDS. [7] physicians speculate Covid-19 patients behave more like For now, we do not know at what oxygen saturation people with high altitude pulmonary edema (HAPE) rather someone will decompensate, but it likely depends on the than your typical ARDS patient. This is because many patients patient. Because of the high mortality of ventilation, maybe it is time for us to use other measures including respiratory seem to exhibit a lower-than-tolerable O2 saturation but without all the symptoms one would expect with hypoxia such effort and mental status to determine treatment, focusing on as altered mental status or lethargy. In HAPE, high altitudes delaying intubation. This differs from the current dogma of cause an increase in pulmonary artery pressure leading to early intubation is best, so the sources used in this paper argue pulmonary artery vasoconstriction in a patchy and diffuse more information is needed on proper ventilation protocol in pattern, similar to Covid-19. HAPE patients initially these patients. compensate for the low oxygen in high altitudes by References tachycardia in the presence of a low oxygen saturation. [3][4] As the disease worsens, Dr. Gattinoni reports these patients 1. Chorin, Ehud, et al. “Assessment of Respiratory Distress seem to have a dissociation between well-preserved lung by the Roth Score.” Clinical Cardiology, vol. 39, no. 11, mechanics and the severity of hypoxemia shown by a large Oct. 2016, pp. 636–39. PubMed Central, discrepancy in compliance vs shunt fraction. [2] doi:10.1002/clc.22586. 2. Gattinoni, Luciano, et al. “Covid-19 Does Not Lead to a Given this evidence it seems that Covid-19 is primarily a ‘Typical’ Acute Respiratory Distress Syndrome.” hypoxemic disease, unlike ARDS, which involves alveolar American Journal of Respiratory and Critical Care collapse and exhaustion of respiratory muscles. The reason for Medicine, Mar. 2020. Crossref, doi:10.1164/rccm.202003-0817LE. the hypoxemia is proposed in a pre-print article showing in vivo that Covid-19 proteins exhibit binding to the 1-beta chain 19

3. Scott Weingart, an ED Intensivist from NY No conflicts of. “EMCrit Wee - Stop Kneejerk Intubation with the What is the Role of ECMO for EMCrit Crew.” EMCrit Project, 30 Mar. 2020. emcrit.org, https://emcrit.org/emcrit/stop-kneejerk- Severe Covid-19? intubation/. By Helen Pozdniakova 4. Kyle-Sidell, Cameron. FROM NYC ICU: IS COVID REALLY ARDS?!!! 2020. Vimeo, https://vimeo.com/402537849. Summary 5. wenzhong, liu, and Li hualan. COVID-19: Attacks the 1- ECMO is a limited resource that seems to have a high Beta Chain of Hemoglobin and Captures the Porphyrin to mortality in Covid-19 but Japan is seeing good results. Right Inhibit Human Heme Metabolism. preprint, 30 Mar. 2020. now, there is no Covid-19 specific inclusion criteria for DOI.org (Crossref), doi:10.26434/chemrxiv.11938173.v5. ECMO. There is a theoretical risk of bloodborne Covid-19 6. “REBEL Cast Ep79: COVID-19 - Trying Not to Intubate transmission on ECMO but it is probably more of a concern Early & Why ARDSnet May Be the Wrong Ventilator during long runs. We are unsure about how to address the Paradigm.” REBEL EM - Emergency Medicine Blog, 5 coagulopathies of Covid-19 for patients on ECMO. Apr. 2020. rebelem.com, https://rebelem.com/rebel-cast- ep79-covid-19-trying-not-to-intubate-early-why-ardsnet- may-be-the-wrong-ventilator-paradigm/. Evidence to Date 7. Rubin, Samuel J. S., et al. Clinical Characteristics Extracorporeal membrane oxygenation (ECMO) is a form of Associated with COVID-19 Severity in California. last resort support for critically ill patients whose heart or preprint, Infectious Diseases (except HIV/AIDS), 30 Mar. lungs cannot provide adequate perfusion for the body. In 2020. DOI.org (Crossref), dedicated ECMO centers, it has been an invaluable resource doi:10.1101/2020.03.27.20043661. for those critically ill who meet criteria. It has also been used 8. Frat, Jean-Pierre, et al. “High-Flow Oxygen through successful in the past during the H1N1 to improve survival. Nasal Cannula in Acute Hypoxemic Respiratory Failure.” [5] With the high mortality of Covid-19 and the surge of New England Journal of Medicine, vol. 372, no. 23, cases worldwide, does ECMO has a role now? Massachusetts Medical Society, June 2015, pp. 2185–96. Taylor and Francis+NEJM, doi:10.1056/NEJMoa1503326. Is ECMO available? WHO interim guidelines recommend offering EMCO to eligible patients with ARDS due to Covid-19. Right now, we do not know how many patients with Covid-19 will develop ARDS that is refractory to maximal medical management. The use of ECMO globally is overall low and generally restricted to specialized centers. Therefore, the ELSO (the foundation overseeing ECMO) acknowledges that widespread ECMO use in this pandemic may be unrealistic. ECMO is resource intensive and limited in availability. The need for specially trained staff and transportation to specific facilities may not be feasible during a severe surge.

Is ECMO indicated? ECMO has been used already for severe Covid-19 ARDS. The ECMO registry has 122 patients who received ECMO for Covid-19. Of those, 34 have completed their ECMO run but only 1 was discharged alive. [3] Similarly, recommendations from China cite high mortality of patients on ECMO, with a 50% mortality in a study of 28 patients. [7] Because of this, ELSO recommends judicious selection of patients for ECMO therapy. Hospitals continue to use conventional inclusion/exclusion criteria and they do not provide specific guidelines for Covid-19. [8] It is hypothesized that because Covid-19 is primarily a lung pathology, that V-V ECMO is the best choice for treatment. Exclusion criteria includes prolonged mechanical ventilation, severe uncontrollable infection, terminal illness, lack of cerebral function, or contraindication to anticoagulation. One important relative exclusion criterion is age. Many centers do not recommend patients over 65 receive ECMO as their risk of death is 20 considerably high. We know that Covid-19 infection is References deadlier in those who are older, so many favor ECMO use only in young patients. Another common exclusion criteria is 1. COVID-19 Protocols. https://www.covidprotocols.org/. multi-organ dysfunction which is a common complication of Accessed 3 Apr. 2020. those critically ill with Covid-19. We need more data before 2. “ELSO Extracorporeal Life Support Organization.” we can identify Covid-19 patients who are older or with multi- YouTube. www.youtube.com, organ dysfunction that will benefit from ECMO. https://www.youtube.com/watch?v=Kuq-YS5A5Hk. Accessed 3 Apr. 2020. However, data from Japan seems to be different. Statistics as 3. Extracorporeal Life Support Organization - ECMO and of March 30th, 2020 from the Japanese Society of Intensive ECLS > Registry > Full COVID-19 Registry Dashboard. Care Medicine show a total of 40 patients on ECMO, of which https://www.elso.org/Registry/FullCOVID19RegistryDas 14 recovered (35%) and 6 died (15%). We also know that hboard.aspx. Accessed 3 Apr. 2020. ECMO is being utilized at a higher rate in Japan compared to 4. Liu, Keibun. An Assessment of Aerosolization via the US. More information is needed but we may be seeing a Membranous Oxygenator and Coagulopathy in COVID- large difference in ECMO mortality between the US and 19. p. 19. Japan. https://ecmoedblog.files.wordpress.com/2020/03/elso- webinar-slides-keibun-liu.pdf 5. Ramanathan, Kollengode, et al. “Planning and Provision Can ECMO spread Covid-19? of ECMO Services for Severe ARDS during the COVID- Due to limited information, ELSO recommends proper PPE 19 Pandemic and Other Outbreaks of Emerging Infectious during any ECMO related procedures. In addition to PPE, Diseases.” The Lancet Respiratory Medicine, vol. 0, no. sterile attire must be worn when performing cannulation and 0, Elsevier, Mar. 2020. www.thelancet.com, decannulation. Because of all these layers, performing a doi:10.1016/S2213-2600(20)30121-1. proper procedure may be challenging and therefore extensive 6. Tang, Ning, et al. “Abnormal Coagulation Parameters Are training must be done beforehand to decrease risk of Associated with Poor Prognosis in Patients with Novel contamination and procedural error. Coronavirus Pneumonia.” Journal of Thrombosis and In regard to blood transmission, the diameter of an ECMO Haemostasis, vol. 18, no. 4, 2020, pp. 844–47. Wiley membrane is 0.04 – 0.10 m and the diameter of Covid-19 is Online Library, doi:10.1111/jth.14768. 0.06 – 0.14 m. It is theoretically possible that Covid-19 7. Xie, Jianfeng, et al. “Critical Care Crisis and Some could pass through. However, it is thought that the charge Recommendations during the COVID-19 Epidemic in created by the coating material of the membrane is likely China.” Intensive Care Medicine, Mar. 2020. Crossref, enough to block Covid-19 transmission and that the risk of doi:10.1007/s00134-020-05979-7. transmission is likely lower than the risk of respiratory tract 8. Zangrillo, A. “The Criteria of Eligibility to the transmission through mechanical ventilation. There is one Extracorporeal Treatment.” HSR Proceedings in Intensive caveat: with long ECMO runs the membrane can deteriorate Care & Cardiovascular Anesthesia, vol. 4, no. 4, 2012, pp. causing a plasma leak. A hospital in Japan had a positive PCR 271–73. https://www.ncbi.nlm.nih.gov/pubmed/23441290 swab from the exhalation port from an ECMO machine during 9. Zhou, Fei, et al. “Clinical Course and Risk Factors for a plasma leak. [2][4] Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study.” The Lancet, vol. 395, no. 10229, Mar. 2020, pp. 1054–62. Crossref, What is the concern for coagulopathy on doi:10.1016/S0140-6736(20)30566-3. ECMO? Patients on ECMO for any reason are given unfractionated heparin at the time of cannulation and by continuous infusion during the course of treatment. This is to prevent thrombosis within the system so a target aPTT of 40-60 is recommended. This may be beneficial for Covid-19 patients who are thought to be in a hypercoagulable state, evidenced by the increased reports of VTE and elevated d-dimer levels. However, we have seen that patients who exhibit coagulopathy (elevation of PT or aPTT) are at higher risk for severe illness and may be a late complication of Covid-19. [6] Based on experience in Japan, they believe bleeding is actually a more common complication of severe Covid-19 than thrombosis. However, they did not make any specific recommendations on changing the anticoagulant protocol for Covid-19 ECMO patients. Instead, they suggested monitoring the PT/aPTT every 6 hours for bleeding risk. [2]

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distress syndrome (ARDS) [3]. The patients, 2 women and 3 Convalescent Plasma as a men aged 36-65, were receiving mechanical ventilation at the Treatment Option for Patients with time of transfusion, and had received antiviral agents and methylprednisolone. Following the transfusion with COVID-19 convalescent plasma, all of the patients showed improvement in clinical status approximately one week after transfusion [2]. By Katherine Veltri Additionally, ARDS resolved in 4 of the patients within 12 days and viral loads became zero in all 5 patients within 12 Summary days of transfusion [3]. This study was limited by a lack of a control group [2]. Convalescent plasma provides passive immunization to critically ill patients with COVID-19. Studies assessing the Another study assessed four case reports of critically ill benefit of convalescent plasma treatment in patients with patients with COVID-19 who were treated with supportive SARS-CoV, influenza, and COVID-19 show improvement of care and convalescent plasma. In the first case, the viral load clinical status, decreased mortality and decreased viral load. dropped from 55 × 105 to 3.9 × 104 to 180 copies per While these results seem promising, high-quality control trials milliliter after the administration of convalescent plasma. The are needed to truly assess the benefits of convalescent plasma. time from transfusion to negative RT-PCT testing in all four patients ranged from 3-22 days. They reported no serious Background adverse reactions. Three out of the four patients were discharged from the hospital and are recovering, one remained Plasma is a component of blood composed of many proteins, in the ICU. The limitations of this study are that the including antibodies. Treatment with convalescent plasma contributions of convalescent plasma versus supportive care provides immediate, passive immunization to different and the patient’s immune-response cannot be determined. [6] diseases. It is especially helpful when there are no immunization for a disease, or when a disease carries significant morbidity and mortality [5]. Convalescent plasma Conclusion has been used in the past to treat SARS-CoV, H1N1, and other We need well-designed clinical trials to truly assess the benefit viral infections with promising results [4] and it is currently of convalescent plasma as a treatment option for COVID-19. being investigated as a treatment option for patients with However the improvement in clinical status seen in these COVID-19. studies is compelling and we should continue investigating this treatment option in critically ill patients with COVID-19. Evidence to Date Due to the possibility of adverse outcomes and the lack of References consistent, high-quality research, convalescent plasma is being 1. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. used as a last resort option for patients who are critically ill The effectiveness of convalescent plasma and [6]. Possible adverse reactions to convalescent plasma include hyperimmune immunoglobulin for the treatment of severe a small but nonzero risk of infectious disease transmission, acute respiratory infections of viral etiology: a systematic fever, life threatening bronchospasm, and transfusion related review and exploratory meta-analysis. J Infect Dis. acute lung injury (TRALI) [2]. 2015;211(1):80-90. doi:10.1093/infdis/jiu396 2. Roback JD, Guarner J. Convalescent Plasma to Treat In 2014, a systemic review and exploratory meta-analysis COVID-19: Possibilities and Challenges. JAMA. March assessed 32 studies that administered convalescent plasma to 2020. doi:10.1001/jama.2020.4940 critically ill patients with SARS-CoV and influenza. They 3. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically found consistent evidence for reduction in mortality, Ill Patients With COVID-19 With Convalescent Plasma. especially when given early on in the disease. Some of the JAMA. March 2020. doi:10.1001/jama.2020.4783 studies in the review also showed significant decrease in viral 4. Tiberghien P, Lambalerie X de, Morel P, Gallian P, load in the respiratory tracts of patients with both SARS-CoV Lacombe K, Yazdanpanah Y. Collecting and evaluating and influenza. None of the studies reported adverse effects convalescent plasma for COVID-19 treatment: why and from treatment. The overall significance of the results found in how. Vox Sanguinis. n/a(n/a). doi:10.1111/vox.12926 this review is limited by the lack of high-quality studies and 5. Wong HK, Lee CK. Pivotal Role of Convalescent Plasma risk of bias. [1] in Managing Emerging Infectious Diseases. Vox Sang. April 2020. doi:10.1111/vox.12927 Treatment with convalescent plasma is currently being in 6. Zhang B, Liu S, Tan T, et al. Treatment with convalescent investigated in critically ill patients with COVID-19. In an plasma for critically ill patients with SARS-CoV-2 uncontrolled case series from China, convalescent plasma infection. Chest. March 2020. containing neutralizing antibody was administered to 5 doi:10.1016/j.chest.2020.03.039 critically ill patients with COVID-19 and acute respiratory 22

Who Can Receive or Donate titers > 1:80 to be used in treatment. Donors should weigh more than 110lbs and be in general good health. Convalescent Plasma? By Katherine Veltri Possible Adverse Reactions Although serious adverse reactions are not reported in many studies assessing the benefits of convalescent plasma Background treatment, there still is risk associated with the transfusion. Convalescent plasma treatment is a way to provide critically Possible adverse reactions include mild fever, allergic ill patients with antibodies to fight COVID-19. People who reactions, life threatening bronchospasm, transfusion related recovered from the disease may be eligible to donate their acute lung injury (TRALI), and circulatory overload [5]. plasma to patients with severe or life-threatening illness. Whole Blood Donation: Criteria Typically, when someone donates plasma, the rest of the blood Patient Eligibility: [4] components are returned to their body. This differs from whole blood donation, when all four components of blood are - Patients with laboratory confirmed, severe or immediately taken: red blood cells, white blood cells, platelets, and plasma. life-threatening COVID-19 infection are eligible for Currently, blood centers are being challenged to maintain their treatment. inventory due to blood drive cancellations, social distancing, o Criteria for severe disease: and decreased number of eligible donors [6]. As we ▪ Dyspnea ▪ Respiratory rate >30 BPM implement convalescent plasma treatment and recruit plasma donors, it could be beneficial to collect whole blood from ▪ SpO2 less than or equal to 93% donors since plasma can be extracted from the whole blood ▪ PaO2/FiO2 ratio of <300 and/or ▪ Lung infiltrates >50% within 24-48 hours donation. This could help replenish the inventory of the other o Criteria for life-threatening disease: components of blood in blood centers and hospitals. However, ▪ Respiratory failure the downside of whole blood donation versus plasma donation ▪ Septic shock and/or is that we get approximately 2-3 times more plasma per ▪ Multiple organ dysfunction or failure donation when someone solely donates plasma [3].

Donor Eligibility: [4] References: - Who: 1. Frequently Asked Questions. o Males, females who have not been pregnant, or https://www.redcrossblood.org/faq.html#donating-blood- females who have been pregnant but who have covid-19-convalescent-plasma. Accessed April 7, 2020. negative HLA antibodies who have been infected 2. Nguyen TC, Kiss JE, Goldman JR, Carcillo JA. The Role with COVID-19. of Plasmapheresis in Critical Illness. Crit Care Clin. o Infection must be confirmed with a diagnostic test at 2012;28(3):453-468. doi:10.1016/j.ccc.2012.04.009 time of illness or with positive antibodies after 3. Plasma Donations | New York Blood Center. recovery. https://nybloodcenter.org/donate-blood/become- - When: donor/types-donations/about-plasma-donations/. o Complete resolution of symptoms for 28 days prior to Accessed April 7, 2020. donation or complete resolution of symptoms for 14 4. Research C for BE and. Investigational COVID-19 days with a negative test (e.g. nasopharyngeal swab) Convalescent Plasma - Emergency INDs. FDA. April 2020. https://www.fda.gov/vaccines-blood- biologics/investigational-new-drug-ind-or-device- Details of Donating Plasma [1], [2] exemption-ide-process-cber/investigational-covid-19- convalescent-plasma-emergency-inds. Accessed April 7, Whole blood has four components: red blood cells, white 2020. blood cells, platelets, and plasma. Plasmapheresis is the 5. Roback JD, Guarner J. Convalescent Plasma to Treat process of separating plasma from the rest of the blood and COVID-19: Possibilities and Challenges. JAMA. March can be performed by two different techniques. Centrifugation 2020. doi:10.1001/jama.2020.4940 spins whole blood so that the components are separated based 6. Shander A, Goobie SM, Warne MA, et al. The Essential on density. Filtration is when whole blood passes through a Role of Patient Blood Management in a Pandemic: A Call filter that separates plasma from the other components. Most for Action. Anesth Analg. March 2020. blood centers use the centrifugation technique: blood gets doi:10.1213/ANE.0000000000004844 drawn from the body and spun in a machine, plasma is separated, and the rest of the blood is returned to the body. Donated plasma must have COVID-19 neutralizing antibody 23

Anticoagulation in Coivd-19 anticoagulation in the treatment of Coivd-19 coagulopathies. The sepsis-induced coagulopathy (SIC) scoring system was By Kevin Brandecker used which factored in PT, platelet count, and sequential organ failure assessment (SOFA). They found that there was no difference in 28-day mortality in heparin vs non-heparin Summary patients. But there was a decrease in 28-day mortality between Elevated D-dimers have been a lab finding seen in several heparin and non-heparin patients when both groups had a SIC patients hospitalized with Covid-19. Lung dissection of a ≥4 or a D-dimer > 6 times the upper limit of normal. Given the critically ill patient found the evidence of microthrombi which design of the study, they acknowledge that patients may have has raised the question of the role of anticoagulation in the been started on Heparin for a specific symptom or past treatment of Covid-19. A team out of China, citing medical condition, the influence of other therapies cannot be unpublished data on DIC in Covid-19, recommends the use of excluded and was conducted early in the outbreak. A lung LMWH, 100 U/kg every 12 hours for 3-5 days when the D- dissection of a critically ill patient found microthrombi on the dimer is > 4 times upper limit of normal. One member of this exam which may have led to the use of anticoagulation after team published his account of working in Wuhan and noted these results were released.3,4 that some patients between days 7 and 14 seemed to develop a worsening of their clinical state which was associated with a They conclude that anticoagulation mainly with LMWH may hypercoagulable state and thus recommend the use of LMWH benefit patients with a SIC ≥4 or a markedly elevated D- and IVIG. A retrospective study showed that in patients with dimer. Regarding dosing, there is no specific dose endorsed sepsis-induced coagulopathy score (SIC) ≥ 4 or a D-dimer > 6 but most patients were on prophylactic doses. They do times the upper limit of normal there was decrease mortality in acknowledge that there are lower rates of venous the group treated with LMWH or Heparin mostly given at thromboembolism in the Asian population so the dose may prophylactic dosing. A commentary on this article echoed the need to be increased in non-Asian populations. Recombinant use of LMWH citing anecdotal accounts out of Italy that soluble thrombomodulin or antithrombin is not currently showed an increased risk of venous thromboembolism in available in China and thus was not able to be used.3 Covid-19 hospitalized patients. A commentary on this paper also in the Journal of Thrombosis Background and hemostasis was written by Dr. Jecko Thachil who is the chairman of the DIC subcommittee of the International A team out of China reported that they have noticed Covid-19 Society of Thrombosis and Hemostasis. He mentions patients with severe disease often develop DIC, citing anecdotal accounts in Italy that showed an increased risk of unpublished data. Because of this, they recommend the venous thromboembolism in patients admitted to the hospital anticoagulation of patients when their D-dimer is four times with Covid-19. The severe lung inflammation seen in Covid- the upper limit of normal and there are no contraindications to 19 triggers the upregulation of pro-inflammatory cytokines anticoagulation. They used LMWH at a dose of 100 U/kg which could lead to increased fibrinogen lysis. Also every 12 hours for 3-5 days. In addition to LMWH, they are mentioned is a systematic review that concluded in the clinical also endorsing the use of high-dose IVIG at 0.3–0.5 g/kg per environment heparin decreased levels of inflammatory day for 5 days with the thought that it will disrupt the cytokine biomarkers and a meta-analysis that showed LMWH reduced storm due to its efficacy in the treatment of patients with 7- and 28-day mortality and increased oxygen index among 1 influenza and SARS-CoV. ALI/ARDS patients. The immediate question raised is determining what the dose of LMWH is effective to treat One of the authors on this paper is Taisheng LI M.D. Ph.D. patients. Prophylactic dosing may be appropriate in most who published on March 25th, 2020 his observation on Covid- patients but may need to increase the dose in higher body mass 19 patients since arriving in Wuhan on February 7th, 2020. patients.5 He notes that often between days 7-14 of the infection some patients develop a worsening of their clinical condition which he calls the “second phase.” As part of this, they developed a Reference hypercoagulable state and D-dimer coagulation becomes 1. Lin L, Lu L, Cao W, Li T. Hypothesis for potential abnormal. He notes that with the elevated D-dimer there is pathogenesis of SARS-CoV-2 infection–a review of often an increase in the PT and decrease in fibrinogen. immune changes in patients with viral pneumonia. Because of this his colleagues at the Department of Emerging Microbes & Infections. 2020;9(1):727-732. Hematology, Peking Union Medical College Hospital doi:10.1080/22221751.2020.1746199 recommend the use of LMWH as well as IVIG at this stage of 2. Li T, Lu H, Zhang W. Clinical observation and the disease.2 management of COVID-19 patients. Emerging Microbes & Infections. 2020;9(1):687-690. A retrospective review of hospitalized Covid-19 patients in doi:10.1080/22221751.2020.1741327 Wuhan, China was performed to look at the role of 24

3. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Update on QT monitoring in Covid-19 Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with when treated with Hydroxychloroquine coagulopathy. Journal of Thrombosis and Haemostasis. n/a(n/a). doi:10.1111/jth.14817 and/or Azithromycin 4. Luo W, Yu H, Gou J, et al. Clinical Pathology of Critical By Kevin Brandecker Patient with Novel Coronavirus Pneumonia (COVID-19). February 2020. https://www.preprints.org/manuscript/202002.0407/v2. Summary Accessed April 8, 2020 The use of either Hydroxychloroquine alone or paired with 5. Thachil J. The versatile heparin in COVID-19. Journal of Azithromycin has garnished much interest as a possible Thrombosis and Haemostasis. n/a(n/a). treatment for Covid-19. Both medications are associated with doi:10.1111/jth.14821 QTc prolongation which increases the risk of drug induced Torsades de pointes and sudden cardiac death. A retrospective study performed at NYU Langone medical center with 84 patients found that the average QTc increased from 435 ± 24 ms to a maximum of 463 ± 32 ms after the initiation of treatment with Hydroxychloroquine and Azithromycin. The increase QTc peaked on day 3.6 ± 1.6 of therapy1. A paper in Mayo Clinical Proceeding provided guidelines about the use of QTc prolonging drug in Covid-19 by creating a “green light, yellow light, red light” system to classify patients by their pre-treatment and post-treatment QTc. This scheme was then used to create a flow chart to help guide clinical decision making. They recommend the use of repeat ECG 2-4 hours after the initiation of treatment in patients with a QTc ≥500 ms. They state that those patient with a QTc ≥ 500 ms should only be started on QTc prolonging medications if they have significant benefit compared to the risk. And then for all patients to have a repeat ECG 48-96 hours after initiation of treatment2. Given the results out of NYU Langone it may be worth expanding the window recommended from the paper in Mayo Clinical Proceeding, 48-96 hours after initiation of treament, in order to better assess the maximum QTc interval if Azithromycin is also being used.

Evidence to Date There was a preprint paper released on April 3, 2020 out of NYU Langone medical center that looked at 84 patients that were treated with Hydroxychloroquine and Azithromycin (HY/AZ) combo therapy and its effect on the QTc interval. Prior to initiation of HY/AZ treatment the average QTc was 435 ± 24 ms which lengthen to a maximum of 463 ± 32 ms on day 3.6 ± 1.6 of therapy. During this time 11 % of patients were found to develop a QTc > 500 ms and 30 % had their QTc increase by greater than 40 ms. The development of acute renal failure was found to be a significant predictor of QTc elongation. They concluded that pretreatment QTc measurement is unable to predict QTc elongation and that repeat testing needs to be performed after the initiation of treatment1.

An article out of the Mayo Clinical Preceding focused on the creation of precautions that should be taken to decrease the risk of drug induced Torsades de pointes and sudden cardiac death in those with Covid-19 being treated with QTc prolonging agents. They endorse an approach of using pre- treatment EKG or smartphone enabled mobile QTC meter to 25 screen patients for a prolonged QTc interval and to stratify them into varying groups.

“Green light” patients are those who are pre-puberty with QTc < 460 ms, post-puberty males QTc <470 ms, or post-puberty females < 480 ms and thus can be prescribed the Hydroxychloroquine if indicated2.

“Yellow light” patients are pre-puberty with QTc ≥ 460 ms, post-puberty males QTc ≥470 ms, or post-puberty females ≥ 480 ms but less then 500 ms. These patients should have any unnecessary QTc prolonging medications stopped and their potassium and magnesium checked and then can start Hydroxychloroquine if indicated 2.

“Red light” is considered those with a QTc ≥ 500 ms and they recommend carefully weighing the risk and benefits of Hydroxychloroquine. If there is initiation of treatment, they recommend a repeat EKG 2-4 hours after the first dose of Hydroxychloroquine 2.

All patients should then have a repeat EKG 48 to 96 hours after initiation to evaluate for changes in QTc which may change management. Their decision making progress is found in figure 1 of their paper2. A limitation discussed is that repeat testing is going to result in increased personal exposure, use of limited PPE, and contamination of ECG machine/wires. An alternative discussed is the use of FDA-approved consumer mobile ECG devices or telemetry systems that are equipped with real time QTc monitoring2.

These two studies in combination can provide guidance on the use of QTc prolonging drugs like Hydroxychloroquine and Azithromycin in the treatment of Covid-19. Applying the data from the study performed at NYU to the guidelines released in the article from Mayo Clinical Preceding it may be worth increasing the time frame recommended from the article in Mayo Clinical Preceding, 48-96 hours, to factor in that maximum QTc found at NYU Langone was on day 3.6 ± 1.61,2. It’s important to note that this article did not include the use of Azithromycin in their algorytheme2.

Reference 1. Chorin E, Dai M, Shulman E, et al. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin. medRxiv. April 2020:2020.04.02.20047050. doi:10.1101/2020.04.02.20047050 2. Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19 [published online ahead of print March 25, 2020]. Mayo Clin Proc. https://doi.org/10.1016/j.mayocp.2020.03.024

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