Viruswatch - Evidence-Based COVID Medicine and Nursing

Today we're addressing a question that's been at the forefront of many of our minds as we've been caring for COVID patients: we're talking all about healthcare worker infections.  Despite an extensive review of the literature, there are still many unanswered questions; but here is what we know so far.

By the numbers

• What percentage of total cases are in HCW? The reported figures are highly variable, ranging from 2.5% (reported in California)1 to 20% (reported from Spain)2
  • Close to home in Ontario: 9.6% reported in one study3
• Some groups have tried to determine the occupational exposure-based excess risk. This is a highly relevant figure; it would tell us about the excess risk incurred from working in healthcare settings, above and beyond the general community risk. Here again, however, the data is inconsistent:
  • Minimal excess risk?
    • Observational data from Spain reported that HCW trends followed community infection rates very closely, arguing against significant occupational exposure4
    • A small case report from Switzerland detected no HCW infections after exposures of 15 minutes or less to confirmed positive cases, despite minimal PPE5
  • Significant excess risk?
    • One study identified a 7% increase in absolute risk of infection in HCW compared to non-HCW in a university hospital setting6
    • An interesting study using self-reporting via smartphone found that HCW had a HR of 11.6 (!) for reporting a positive result compared to the general population7
      • This figure was even higher in those reporting inadequate or re-used PPE
    • One reassuring point: there have been some case reports of situations where HCW were exposed with what would be considered inadequate PPE (AGMP without N95), with no subsequent cases in exposed HCW8
  • Mortality in HCW? Reports are highly variable. This is a difficult figure to determine as it really depends on the denominator (widespread availability of testing)
    • Data generally supports lower mortality rate in HCW, which is likely a reflection of more frequent testing (more detection of mild cases); plus potentially also lower age groups, and better access to healthcare9

Factors affecting HCW infections

• More frequent testing in HCW than the general population
  • 15% tested vs 3% of the general population in Alberta9
• Burden of COVID disease
  • For HCW in areas with low COVID numbers, infections are more likely to have arisen from a community setting9
  • In contrast, in areas with very high COVID prevalence, the workplace exposure is much greater (particularly if paired with PPE concerns and a generally overwhelmed system)2
• Type and location of care: there are conflicting reports about whether "high-risk" places like ICUs and EDs have higher rates of HCW infection
  • In the Chinese epidemic there seems to have been higher HCW infection rates in locations where AGMPs are carried out10
  • In contrast, an NHS survey did not find any difference in HCW infection rates in high vs moderate vs low-risk areas11
    • A few other studies also found no increased risk in groups involved in AGMP, perhaps due to very careful attention to PPE given the recognized risks of these situations12
  • What's more, one study actually found lower infection rates in ICU HCW (2.1%) compared to those on the general wards (4.9-9.7%)6
• HCW roles
  • Most sources seem to indicate higher risk of infection in nursing role compared to physicians – likely a reflection of providing much more direct patient care11,12
    • However, one study reported far more deaths in physicians: physicians accounted for 57% of deaths, despite representing only 22% of cases.13 This may be related to physician demographics, particularly in this Italian cohort.
  • HCW demographics: things that we know are risk factors for more severe disease such as older age and comorbidities14
    • This is particularly true in physicians who have come out of retirement to help with the pandemic15
    • In an analysis of just under 200 physicians deaths worldwide, 40% were in Italy, 90% were male, and the mean age of the cohort was 66 years old12
    • BAME (Black and minority ethnic) HCW seem to be disproportionately affected11
  • Availability of PPE
    • Compared to HCW with access to adequate PPE who were NOT caring for COVID patients, HCWs caring for patients with documented COVID-19 had aHRs for a positive test of 4.83 if they had adequate PPE, 5.06 for reused PPE, and 5.91 for inadequate PPE7
  • Systems factors may also play a role. There is no hard data on this, although some groups have published their protocols for trying to minimize HCW and nosocomial spread16
    • Many familiar measures: daily temperature monitoring, small segregated HCW teams, virtual teaching/meetings, no cross-institution work, etc.
  • Other factors may play a role in severity of disease, particularly in pandemic conditions: HCW sleep (or lack thereof), stress, adequate nutrition, etc17

What serology tells us

• There is a fascinating study out of Birmingham18 where they tested 554 HCW who were currently asymptomatic. They tested everyone for both current COVID (with PCR) and prior exposure (with serology). They also asked about viral symptoms in the past several months. They found that:
  • 4% of those tested were PCR positive (current asymptomatic COVID)
  • 24% (!) of those tested had positive serology – indicating previous COVID infection
    • Higher rate in those who endorsed viral symptoms recently (37.5%) vs those who had been totally asymptomatic (17%)
  • Highest rates of seroconversion (about 30%) amongst acute medicine/GIM, and housekeeping
    • Lower rates (13-14%) in EM and critical care
  • BUT: another group in Germany19 did a similar study, looking at seroconversion in 316 HCW with varying levels of contact with COVID patients; and that group only found a 1.6% seropositive rate

Secondary infections from HCW

• There is minimal data on secondary attack rate and infection of household contacts
• One recent publication in a general population cited a household attack rate of 4.7%, with no documented asymptomatic transmission20 -> this is reassuring as we expand our bubbles!

Sources

1. Heinzerling A, Stuckey MJ, Scheuer T et al. Transmission of COVID-19 to Health Care Personnel During Exposures to a Hospitalized Patient - Solano County, California, February 2020. MMWR, Apr 2020, 69(15), 472–476. doi:10.15585/mmwr.mm6915e5
2. Güell O. Spain ranks first for Covid-19 infections among healthcare workers. EL PAIS. Apr 25, 2020. https://english.elpais.com/spanish_news/2020-04-25/spain-ranks-first-for-covid-19-infections-amonghealthcare-workers.html
3. Pelley L. Health-care workers make up 1 in 10 known cases of COVID-19 in Ontario. CBC News (online), Apr 2020. https://www.cbc.ca/news/canada/toronto/health-care-workers-make-up-1-in-10-knowncases-of-covid-19-in-ontario-1.5518456
4. Folgueira MD, Munoz-Ruiperez C, Alonso-Lopez MA et al. SARS-CoV-2 infection in Health Care Workers in a large public hospital in Madrid, Spain, during March 2020. MedRxiv, March 2020. doi:10.1101/2020.04.07.20055723
5. Canova V, Lederer Schläpfer H, Piso RJ et al. Transmission risk of SARS-CoV-2 to healthcare workers -observational results of a primary care hospital contact tracing. Swiss Medical Weekly, Apr 2020,150, w20257–w20257. doi:10.4414/smw.2020.20257
6. Barrett ES, Horton DB, Roy J et al. Prevalence of SARS-CoV-2 infection in previously undiagnosed health care workers at the onset of the US COVID-19 epidemic. MedRxiv, Apr 2020. doi:10.1101/2020.04.20.20072470
7. Nguyen L, Drew D, Joshi A et al. Risk of COVID-19 among frontline healthcare workers and the general community: a prospective cohort study. MedRxiv, May 2020. doi:10.1101/2020.04.29.20084111
8. Ng K, Poon BH, Kiat Puar TH et al. COVID19 and the Risk to Health Care Workers: A Case Report. Ann Internal Med, Jun 2020. doi:10.7326/L20-0175
9. Alberta Health Services. COVID-19 scientific advisory group rapid response report. May 4, 2020. https://www.albertahealthservices.ca/assets/info/ppih/if-ppih-covid-19-hcw-risk-rapid-review.pdf
10. Ran L, Chen X, Wang Y et al. Risk Factors of Healthcare Workers with Corona Virus Disease 2019: A Retrospective Cohort Study in a Designated Hospital of Wuhan in China. Clin Infectious Dis, Mar 2020. doi:10.1093/cid/ciaa287
11. Cook T, Kursumovic E, Lennane S. Exclusive: deaths of NHS staff from covid-19 analysed. HSJ, Apr 2020. https://www.hsj.co.uk/exclusive-deaths-of-nhs-staff-from-covid-19-analysed/7027471.article
12. Kursumovic E, Lennane S, Cook T. Deaths in healthcare workers due to COVID‐19: the need for robust data and analysis. Anesthesia, May 2020. doi:10.1111/anae.15116
13. Lapolla P, Mingoli A, Lee R. Deaths from COVID-19 in healthcare workers in Italy—What can we learn? Infect Control Hosp Epidemiol, May 2020. doi:10.1017/ice.2020.241
14. Hume T. Italian Doctors Are Coming Out of Retirement to Treat Coronavirus — and Dying. Vice (online), Mar 2020. https://www.vice.com/en_us/article/v74jwm/italian-doctors-are-coming-out-of-retirement-to-treatcoronavirus-and-dying
15. Zhan M, Qin Y, Xue X et al. Death from Covid-19 of 23 Health Care Workers in China. New Eng J Med, Apr 2020. doi:10.1056/NEJMc2005696
16. Gan W, Lim J, Koh D. Preventing Intra-hospital Infection and Transmission of Coronavirus Disease 2019 in Health-care Workers. Safety and Health at Work, Mar 2020. doi:10.1016/j.shaw.2020.03.001
17. Wang J, Zhou M, Liu F. Reasons for healthcare workers becoming infected with novel coronavirus disease 2019 (COVID-19) in China. J Hosp Infect, Mar 2020. doi:10.1016/j.jhin.2020.03.002 0
18. Shields A, Faustini S, Perez-Toldeo M et al. SARS-CoV-2 seroconversion in health care workers. MedRxiv, May 2020. doi:10.1101/2020.05.18.20105197v1
19. Korth J, Wilde B, Dolff S et al. SARS-CoV-2-specific antibody detection in healthcare workers in Germany with direct contact to COVID-19 patients. J Clin Virology, May 2020. doi:10.1016/j.jcv.2020.104437
20. Cheng HY, Jian SW, Liu, DP et al. Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset. JAMA Internal Medicine, May 2020. doi:10.1001/jamainternmed.2020.2020

They may sound like superheroes, but they're more like the villains of these COVIDian times. We're talking all about superspreaders today!

What is a superspreader?

• Definition: an unusually contagious organism infected with a disease
• These are not new! Remember Typhoid Mary?1
  • Also described in recent pandemics and in other diseases: TB, measles, SARS, MERS, Ebola
• There is no numerical cutoff for what constitutes a superspreading event (SSE)
  • Large enough to be considered epidemiologically noteworthy

Reminder: R0

• R0: the basic reproductive number of a disease
  • to how many other people does one infected person transmit the virus
• The R0 is a dynamic parameter and varies among individuals!
  • Example: R0 on the Diamond Princess cruise ship went from 15 to 2 after strict isolation and quarantine measures were instituted2
• The goal of many public health measures is to push the average R0 below 1 – which is a good thing!
• BUT outliers matter!!
  • In many epidemics, the majority of individuals infect very few secondary contacts; BUT a small number of people have very high numbers of secondary contacts
  • The statistical way of describing this properly is called the fat tail of the degree distribution; the lay term is superspreaders
• In one mathematical model, over 80% of secondary infections were caused by 10% of infected cases3
• This group4 did some fancy and complicated statistical modelling – and came to the important conclusion that "even with an expectation of less than one new case per person, our model shows that exponential growth is still possible"

Factors affecting SSE1,5

• Virus factors: binding sites, virulence, infectious dose, mode of transmission
  • Interesting opinion piece theorizing that secondary infections caused by a superspreader are more likely themselves to be highly infectious (proposed mechanism due to high viral loads), and result in continued chain of superspreading events6
    • The author postulates that this may explain some of the heterogeneity of growth seen in different parts of the world
  • Host factors: duration of infection, location and burden of infection, symptoms
    • From previous pandemics: most superspreaders seem to have been symptomatic
  • Environmental factors: population density, public health guidelines, PPE, airflow dynamics, misdiagnosis or delayed diagnosis; inter-hospital transfers
  • Behavioural factors: cough/mask/hand hygiene, adherence to public health guidance
    • Also: activities such as singing, coughing, sneezing, yelling
      • The science of sneezing is incredibly complex, but one fascinating recent paper hypothesizes that large and small droplets may actually travel much further than we think: 7-8m!7
    • Response factors: timely intervention to prevent growth of outbreaks (both in community and in healthcare settings) – isolation, contact tracing, testing

SSEs in COVID

• Fascinating lay press article8 breaks down the patterns of reported SSEs in COVID so far
  • Most occurred between late February and late March – before a lot of travel restrictions and strict social distancing were in place
  • Many linked to intercontinental travel; and therefore higher among groups with higher socioeconomic status
  • Striking commonality of activities - over 70% involved one of:
    • Religious gatherings
    • Parties or "liquor-fueled mass attendance festivals" including weddings
    • Funerals
    • Conferences and face-to-face business networking
  • Almost all were indoors in crowded, socially intimate settings
  • High noise level seems to be a common feature – forcing close-range conversation or raised voices
• Interesting individual examples
  • Skagit choir example9
    • 61 individuals attended a 2.5hr choir practice with 1 symptomatic index patient
    • Secondary cases: 32 confirmed, 20 probable – secondary attack rate 53-87% (!)
    • Interesting because it took place under some precautions (some physical distancing of members), yet still resulted in a very high secondary attack rate
      • Prolonged singing with high velocity transmission of respiratory droplets in an enclosed space
    • The case of a symptomatic New Zealand flight attendant who spread infection primarily at a wedding reception he attended after a flight, NOT to passengers on the aircraft10
      • Seems to highlight social intimacy as a key in transmission, rather than shared airspace
    • Small community of Gangelt in Germany had an SSE originating from a town carnival; 15% of the town ended up becoming infected, with 22% of these being asymptomatic11
    • One paper12 looked at "mini SSEs" – shared meals where one index patient spread to multiple secondary contacts. From their data set, they found a secondary attack rate of 35% among close contacts sharing a meal with an index case patient
    • Religious gathering in Malaysia: SSE associated with attendees at the 4-day Tablighi Jama'at festival. Over 50% of the cases in Malaysia to date are linked to this single event13
    • Après-ski: SSE in Austria of 36 cases, where the barkeeper was later confirmed to be SARS-CoV-2 positive14
  • Nosocomial SSEs: case of an index patient who repeatedly visited a family member in hospital. The family member, as well as the other 3 people in the 4-person room, all became infected; as did 4 physicians and 1 nurse who had directed contact with the index patient. These secondary cases then went on to be the source of 11 tertiary cases15
  • Notable LACK of examples: movie theaters, symphony/opera, college lecture halls

 What SSEs tell us about mode of transmission

• Analysis of SSEs can give clues as to the dominant mode of transmission: large ballistic droplets, persistent concentrations of tiny airborne particles, or fomite transmission?
• From the documented SSEs, we see that almost all involve close contact, social intimacy, raised voices – people getting really up close and personal
  • This strongly supports large droplets as the primary mode of transmission
• This is hugely important as it will affect what public health measures to emphasize, and which ones may actually be causing harm
  • For example: case cluster in China of a restaurant operating with air conditioning – which would theoretically help decrease transmission if the virus were predominantly airborne. However, the authors of this paper actually found that the direction of airflow in the restaurant was crucial – being downstream from the index infected case was the strongest predictor of secondary infection16

What this means going forward

• Limiting SSEs is KEY à without this, other well-intentioned public health interventions may be of little value
  • "As most infected individuals do not contribute to the expansion of an epidemic, the effective reproduction number could be drastically reduced by preventing relatively rare superspreading events"3
• Controlling SSEs
  • Early recognition is paramount
    • Study in MERS showed that timely intervention (within 1 week) reduced size and duration of MERS transmission17
  • Rapid testing and contact tracing
  • Universal precautions in healthcare areas
• Analysis of SSE can help us re-open as we determine which activities are the highest risk
• The highest risk activities seem to involve indoor spaces (primarily), close physical contact and social intimacy, multiple social interactions
  • Things that may have to wait until a vaccine: traditional weddings, parties, conferences, funerals, networking events, clubs
• Activities that seem to pose less risk as may be safer to institute sooner:
  • Movie theaters, the symphony or the opera: quiet attendance, many people in a shared space but limited social interaction
  • Outdoor recreation activities like camping, hiking, swimming, tennis
  • Playgrounds? Fomite spread does not seem significant based on analysis of these events, but there are other factors to consider
• Bottom line: listen to your local public health guidance!

Sources

1. Frieden TR, Lee CT. Identifying and Interrupting Superspreading Events—Implications for Control of Severe Acute Respiratory Syndrome Coronavirus 2. Emerg Infect Dis. 2020;26(6):1059-1066. doi:10.3201/eid2606.200495
2. Rocklöv J, Sjödin H, Wilder-Smith A. COVID-19 outbreak on the Diamond Princess cruise ship: estimating the epidemic potential and effectiveness of public health countermeasures. J Travel Med. Apr 2020. doi:10.1093/jtm/taaa030
3. Endo A, Abbott S, Kucharski A et al. Estimating the overdispersion in COVID-19 transmission using outbreak sizes outside China. Wellcome Open Res, Apr 2020. doi:10.12688/wellcomeopenres.15842.1
4. Reich O, Shalev G, Kalvari T. Modeling COVID-19 on a network: super-spreaders, testing and containment. MedRxiv pre-print, May 2020. doi:10.1101/2020.04.30.20081828
5. Stein R. Super-spreaders in infectious disease. Int J Infect Dis. 2011, 15(8):e510-513. doi:10.1016/j.ijid.2010.06.020
6. Beldomenico P. Do superspreaders generate new superspreaders? a hypothesis to explain the propagation pattern of COVID-19. Int J Infect Dis, Mar 2020. doi:10.1016/j.ijid.2020.05.025
7. Bourouiba L. Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19. JAMA, Mar 2020. doi:10.1001/jama.2020.4756
8. Kay, J. COVID-19 Superspreader Events in 28 Countries: Critical Patterns and Lessons. Quilette (online). Apr 23, 2020. https://quillette.com/2020/04/23/covid-19-superspreader-events-in-28-countries-critical-patterns-and-lessons/
9. Hamner L, Dubbel P, Capron I et al. High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice - Skagit County, Washington, March 2020. CDC MMWR, May 2020, 69(19);606–610. doi:10.15585/mmwr.mm6919e6
10. Leahy, Ben. Covid 19 coronavirus: Air NZ steward 'deeply upset' by Bluff coronavirus outbreak. NZ Herald (online), Apr 16 2020. https://www.nzherald.co.nz/nz/news/article.cfm?c_id=1&objectid=12325198
11. Streeck H, Schulte B, Kuemmerer B et al. Infection fatality rate of SARS-CoV-2 infection in a German community with a super-spreading event. MedRxiv, May 2020. doi:10.1101/2020.05.04.20090076
12. Liu, Y, Eggo R, Kucharski A. Secondary attack rate and superspreading events for SARS-CoV-2. Lancet, Mar 2020. doi:10.1016/S0140-6736(20)30462-1
13. Chaw L, Koh W. Adli S et al. SARS-CoV-2 transmission in different settings: Analysis of cases and close contacts from the Tablighi cluster in Brunei Darussalam. MedRxiv, May 2020. doi:10.1101/2020.05.04.20090043
14. Correa-Martínez C, Kampmeier S, Kümperset S et al. A pandemic in times of global tourism: superspreading and exportation of COVID-19 cases from a ski area in Austria. J Clin Microbiol, Apr 2020. doi:10.1128/JCM.00588-20
15. Hu K, Zhao Y, Wand M et al. Identification of a super-spreading chain of transmission associated with COVID-19. MedRxiv, Mar 2020. doi:10.1101/2020.03.19.20026245
16. Lu J, Gu J, Li K et al. COVID-19 Outbreak Associated with Air Conditioning in Restaurant, Guangzhou, China, 2020. Emerg Infect Dis, Mar 2020. doi:10.3201/eid2607.200764
17. Lee J, Chowell G, Jung E et al. A dynamic compartmental model for the Middle East respiratory syndrome outbreak in the Republic of Korea: A retrospective analysis on control interventions and superspreading events. J Theor Biol. 2016;408:118–26. doi:10.1016/j.jtbi.2016.08.009

They teased us with a press release weeks ago, and Faucci has been promoting it ever since – and now, we finally have the data from the ACTT-1 trial on remdesivir. Here we take a closer look to see if this really is the "very promising result" it was sold as.

Reminder: background on remdesivir

• Antiviral with in-vitro promise
• Recent trial from Wang et al1 was negative for a difference in time to clinical improvement
  • Trial was underpowered as it was stopped early due to slow recruitment
  • They did note a trend towards faster improvement (18d vs 23d) in the subset of patients who received remdesivir within 10d of symptom onset

ACTT-1: Adaptive COVID-19 Treatment Trial2

• Randomized, double-blind, placebo-controlled trial of remdesivir for COVID-19
  • Enrollment for 3 weeks in Feb/March at 60 sites in the US, Europe, and Asia
  • Ended up being predominantly North American patients (about 80%)
• Methods
  • Patients: adults with PCR-confirmed COVID infection with at least one of the following: radiographic infiltrates, SpO2 < 94% on RA, need for supplemental oxygen, or MV/ECMO
    • Sub-stratified further into mild/moderate (SpO2 > 94% on RA, RR <24) vs severe disease; most patients (about 88%) had "severe" disease
    • Key exclusion: transaminitis (AST/ALT > 5x ULN), renal dysfunction (GFR < 30), pregnancy/breastfeeding
  • Intervention: remdesivir 200mg IV on day 1, then 100mg IV daily on days 2-10
  • Primary outcome: time to recovery, defined as the first day that the patient scored 1, 2, or 3 on an 8-point clinical scale
    • 1 = totally well; 3 = still hospitalized but not requiring oxygen or ongoing medical treatments
    • Primary outcome was actually changed near the start of the trial (previously designed as change in 8-point ordinal scale on day 15)
      • Changed due to evolving knowledge of the potentially protracted course of COVID-19
    • Secondary outcomes: 14d and 28d mortality; as well as adverse events
    • These results are actually an interim analysis: 1/3 of patients are still enrolled in the trial and have no documented final outcome yet
      • Because of the nature of the results, the data safety monitoring committee recommended the results be released while the trial is still ongoing
    • Results
      • Patient population
        • 1063 patients enrolled; though 301 are still continuing in the trial follow-up period (but their data to date was included in the analysis)
        • Relatively sick; most people were hospitalized requiring at least supplemental oxygen; about 25% of patient were mechanically ventilated or on ECMO
        • Most had at least one co-morbidity; most commonly hypertension (present in almost 50% of patients)
      • Primary outcome
        • Remdesivir group has faster time to clinical recovery: 11d vs 15d (rate ratio for recovery 1.32, CI 1.12-1.55)
        • Note that the sickest subgroups – those on non-invasive or invasive ventilation, or ECMO – did not demonstrate any benefit
          • Perhaps because in these groups there is a significant immune hyperactivation component?
        • No change in the significance of the outcome when they adjusted for those randomized <10d after symptom onset vs >10d
      • Secondary outcomes
        • Mortality at 14d was numerically lower in the remdesivir group, but not (quite) statistically significant – HR for death 0.70 (CI 0.47-1.04)
      • No significant difference in adverse events
    • Caveats
      • Change in primary outcome: we never like to see this in trials, but seems to have been done here for a fairly legitimate indication as our understanding of this disease evolved
        • Notably, the analysis for their original primary endpoint still shows a statistically significant benefit to remdesivir
      • Early unblinding and reporting of the trial: done when a planned interim analysis revealed a clinically significant benefit to remdesivir. The committee made the reasonable decision that in a pandemic situation, these were important results to be released as soon as possible.
        • The authors themselves note that it is important that the full trial period (with follow-up and monitoring) be completed, and these full results will be reported separately
      • It's interesting that they chose to report mortality at 14 days, when their change in primary outcome acknowledges that COVID often has a more protracted course and requires a longer time frame of study. Although the reported difference sounds numerically impressive, the Kaplan-Meyer curves appear to be converging, suggesting that the benefit is only transient
      • A lot of granular data is missing from this manuscript – hopefully will be included in the follow-up paper

Compared to the Wang trial

• Overall these trials are fairly congruent (though one was technically negative, and one was positive)
• Both show a reduced in time to clinical improvement with remdesivir
• Statistical significance of the ACTT-1 trial (in contrast to Wang) likely primarily due to higher numbers, more statistical power, and perhaps the use of an 8-point vs 6-point ordinal scale
• Not convincing effect on mortality in either trial
• The ACTT-1 group reports that they measured viral load (as did Wang, who found no difference), but it's not included in this paper

Where this leaves us

• This is potentially promising!
• Remdesivir appears to hasten time to recovery - even without any effect on mortality, this could have very significant implications from a resource utilization perspective, especially in a pandemic
  • BUT note that it is an IV drug - do we really need everyone hospitalized for 10 days to get the full treatment protocol?
• Mortality benefit is unclear; disappointingly, the curves seem to come together
• Remdesivir does appear safe
• We need the full data – stay tuned!

Sources

1. Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, 2020;395: 1569-78. doi:10.1016/S0140-6736(20)31022-9
2. Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. New Eng J Med, May 2020. doi:10.1056/NEJMoa2007764

Today we're focused on POCUS! Here's what you need to know about point-of-care ultrasound in COVID-19.  

Potential advantages to POCUS in COVID

• Lack of ionizing radiation
• Superiority to CXR for common diagnoses1
• PPE conservation: performed by treating physician2
• Potential to reduce transmission by minimizing transport and healthcare worker contacts3
• Replace the use of the stethoscope?2

Safety and Infection Control

• Development of infection-control procedures (IPC) before using POCUS is imperative for these patients. This will vary by centre/machine, but considerations include:4
  • Equipment
    • Dedicated COVID-19 machine
    • Minimizing equipment brought into the room
    • Using sterile probe covers and single-use gel packets
    • Handheld devices may be ideal if available due to ease of cleaning3
  • Cleaning and disinfecting
    • Disinfect all machine surfaces with an appropriate product – see ipac-canada.org for choice of products
    • PRACTICE your IPC including incorporation donning and doffing of PPE before performing on patients!
  • Scanning personnel
    • Minimize scanners at the bedside

Scanning protocols

• Standard LUS: curvilinear or phased probe1
  • Linear to focus on the pleura
• How many zones to scan? More zones will be more sensitive
  • Some groups recommend 8 per side5
• Contrast-enhanced lung ultrasound?? See below

POCUS findings in COVID

• There are NO pathognomonic findings
• Findings may include6
  • "Inflammatory" B-lines: Patchy/asymmetrical B-lines with irregular pleura and subpleural consolidations
    • This pattern can be seen in ANY inflammatory/infectious cause of B-lines: Atypical pneumonia, other viral pneumonias, pulmonary hemorrhage, interstitial lung disease, etc.
  • Subpleural consolidations: could these actually be representative of peripheral pulmonary infarcts due to PE?
    • One group found PE in 3 of 3 ICU patients who had evidence of subpleural consolidations on POCUS7
    • Contrast-enhanced ultrasound (CEUS): a couple fascinating case reports demonstrating that subpleural consolidations were avascular and actually represented microinfarcts8,9
  • Bilateral dense consolidations
    • With development to acute respiratory distress syndrome (ARDS)
  • Cardiac findings10
    • May include pre-existing cardiac disease, LV involvement from COVID myocarditis, RV failure (due to PE, ARDS, mechanical ventilation)

Potential pitfalls11

• Cannot distinguish between other causes of "infectious/inflammatory" B-lines
• Cannot distinguish acute vs chronic changes (eg ILD)
• Will miss pathology that doesn't reach the pleura
• Limited scanning protocols (ie 3 zones per hemithorax) may miss early/localized disease

When to use POCUS

• Employ POCUS in confirmed or suspected COVID-19 patients if it will change management4
  • No educational scans; and no novice scans. Have an experienced operator scanning.
  • No scans in patients who are already have a confirmed diagnosis, in whom POCUS results won't change management
• Times to consider POCUS use
  • To look for other diagnoses
  • To look for compatible signs of COVID is suspected patients in whom PCR testing is imperfect*
  • To minimize use of other radiologic studies, especially CT scans
  • To monitor critically ill patients, especially those in shock or profound respiratory failure

From SoMe

An EM physician diagnosed with COVID-19 who shared the progression of his self-scanned POCUS clips throughout his disease course: https://twitter.com/yaletung

Sources

1. Volpicelli G, Elbarbary M, Blaivas M et al. International recommendations for evidence-based point of care lung ultrasound. Intensive Care Med, (2012) 38:577–591. doi:10.1007/s00134-012-2513-4
2. Buonseno D, Pata D, Chiaretti A. COVID-19 outbreak: less stethoscope, more ultrasound. Lancet Resp Med, Apr 2020. doi:10.1016/ S2213-2600(20)30120-X
3. Kiamanesh O, Harper L, Wiskar K et al. Lung Ultrasound for Cardiologists in the Time of COVID-19. Can J Cardiol, May 2020. doi: 10.1016/j.cjca.2020.05.008
4. Ma I, Somayaji R, Rennert-May E et al. Canadian Internal Medicine Ultrasound (CIMUS) Recommendations Regarding Internal Medicine Point-of-Care Ultrasound (POCUS) use during Coronavirus (COVID-19) Pandemic. Can J Gen Internal Med, Apr 2020. doi:10.22374/cjgim.v15i2.438
5. Soldati G, Smargiassi A, Inchingolo R et al. Is There a Role for Lung Ultrasound During the COVID‐19 Pandemic? J Ultrasound Med, Mar 2020. doi:10.1002/jum.15284
6. Peng QY, Wang XT, Zhang LN et al. Findings of lung ultrasonography of novel corona virus pneumonia during the 2019 – 2020 epidemic. Intensive Care Med, Mar 2020. doi:10.1007/s00134-020-05996-6
7. Zotzmann V, Lang C, Bamberg F et al. Are subpleural consolidations indicators for segmental pulmonary embolism in COVID-19? Intensive Care Med, Apr 2020. doi:10.1007/s00134-020-06044-z
8. Tee A, Wong A, Yusuff T et al. Contrast-enhanced ultrasound (CEUS) of the lung reveals multiple areas of microthrombi in a COVID-19 patient. Intensive Care Med, May 2020. doi:10.1007/s00134-020-06085-4
9. Soldati G, Giannasi G, Smarigiassi A et al. Contrast‐Enhanced Ultrasound in Patients With COVID‐19. J Ultrasound Med, May 2020. doi:10.1002/jum.15338
10. Johri A, Galen B, Kirpatrick J et al. ASE Statement on Point-of-Care Ultrasound (POCUS) During the 2019 Novel Coronavirus Pandemic. Apr 2020. https://www.asecho.org/wp-content/uploads/2020/04/POCUS-COVID_FINAL2_web.pdf.
11. Cheung JC, Lam KN. POCUS in COVID-19: pearls and pitfalls. Lancet Resp Med, Apr 2020. doi:10.1016/S2213-2600(20)30166-1

We're talking about the little adults today! In particular, we're diving into the reported Multi-System Inflammatory Syndrome/Kawasaki Disease that has been reported in association with COVID-19 in kids.

COVID in Peds: what we know

• Epidemiology
  • Infection rates are generally low: children seem to account for 1-5% of confirmed cases1
  • Only about 1% of cases in Canada seem to be in those < 19 years2 (though testing was previously not available to those with mild illness)
  • Seems to be distributed reasonably evenly among age groups3
• Presentations
  • Symptoms are similar to adults; cases are generally mild3,4,5
  • Fever and cough are most commonly reported3,4,5
  • Reports of causing isolated fever in young infants6
• Investigations
  • Lab data seems variable; only 3.5% had lymphopenia in one study7
  • CXR: similar to adults; may be normal or may demonstrate patchy consolidations4
  • POCUS: similar to adults à irregular pleura, patchy B-lines8
• Treatment
  • Supportive care!
  • Antivirals generally recommended only in the context of clinical trials9
    • For severe/critical disease, if used, panel recommends remdesivir over others9
  • Severity and outcomes
    • Most children have mild disease and do well: in one case series of over 700 pediatric cases from China, 55% were mild or asymptomatic, 40% were moderate, 5% were severe, and <1% were critical10
    • Small number of children have been identified who develop a significant systemic inflammatory response
      • This has features that overlap with other paediatric inflammatory conditions including Kawasaki disease, staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis and macrophage activation syndrome

Kawasaki Disease11

• KD: childhood vasculitis characterized by systemic inflammation and fever
• Classic KD
  • Fever for > 5 days PLUS
  • 4 of 5: conjunctival injection, peripheral extremity changes such as desquamation, edema, or erythema; mucous membrane changes such as strawberry tongue or injected pharynx; polymorphous rash; cervical lymphadenopathy
• Complications
  • Primarily cardiac, including coronary artery aneurysm
  • Can rarely be associated with macrophage activation syndrome and shock
• Treatment
  • IVIG and ASA
• Cause?
  • Association with respiratory viruses? A retrospective chart review of 222 patients with KD found that 42% tested positive for a viral respiratory infection; most commonly rhinovirus or enterovirus12
    • No differences in presenting features or clinical outcomes in this compared to those who did not test positive

MIS-C and COVID-associated KD?

• There is very little published research on this topic
  • One case report of a 6-month old girl presenting with classic KD, without respiratory symptoms, whose swab was positive for COVID. She was treated with IVIG and high-dose ASA (standard KD Tx)13
  • One series of infographics from out of NYC14
  • A couple guideline statements and media releases on the basis on expert anecdotal experience15,16
  • A couple recent case series: one from the UK, one from Bergamo17,18
• This is what we seem to know from guideline statements:
  • There has been a small rise in the number of cases of critically ill children presenting with an unusual clinical picture
    • Many of these children had tested positive for COVID-19 previously, and are now presenting with common overlapping features of toxic shock syndrome, Kawasaki disease, and MAS
  • Presenting symptoms
    • Prolonged fever (>5 days, >38.5 degrees)
    • GI symptoms: severe abdominal pain, nausea, diarrhea, vomiting
    • Conjunctival injection
    • Maculopapular rash
    • Other: cyanosis or pallor, dysphagia, dyspnea, palpitations, tachycardia, chest pain, lethargy, irritability, confusion
  • Lab abnormalities
    • Inflammatory markers: high CRP, ESR, ferritin; hypoalbuminemia
      • High IL-6 and IL-10 (if available)
    • Lymphopenia
    • Coagulopathy: high D-dimer, high fibrinogen
    • Cardiac involvement: elevated troponin/BNP (sometimes)
    • May be present: AKI, high CK, transaminitis, high trigs
  • Imaging features (may be present in some cases)
    • EKG: changes consistent with myopericarditis
    • Echo: coronary artery dilation; pericardial effusion
    • CXR: patchy symmetrical infiltrates; may have pleural effusion
    • Abdo US: HSMG, ileitis, colitis, ascites
  • Treatment recommendations
    • Early consultation with multiple specialists (peds ID, Rheum, Cardio, Crit Care)
    • Early antibiotics if appropriate in accordance with sepsis protocols
    • IVIG if meets KD or toxic shock criteria
    • ASA if meets KD criteria
    • COVID-specific:
      • Supportive care
      • Antivirals only in the context of clinical trials
      • Immunomodulatory therapy in discussion with subspecialists
    • More details from the NYC media releases: 82 cases on day of release (May 13)14
      • Relationship to COVID
        • 60% of kids test positive for COVID PCR, 40% test positive for COVID antibodies (and 14% are positive for both)
      • Severity of illness: 71% admitted to ICU, 19% intubated
        • 71% admitted to ICU
        • 19% intubated
      • Seen in most age groups: few cases < 1yr; most in age 5-9 and 10-14
    • UK series17
      • 8 children with overlapping features of KD/KD shock syndrome/TSS
        • 1 death from a large cerebral infarct while on ECMO; others discharged
      • All previously well
      • All had no respiratory symptoms, but 7 required mechanical ventilation for cardiovascular stabilization
      • All initially tested negative for COVID; 2 tested positive post-discharge
    • Bergamo series18
      • Retrospective review of KD cases before vs after COVID
      • Found that the monthly incidence was 30x greater than the historical average since the COVID pandemic (0.3 vs 10 cases per month)
      • 10 cases identified; compared to historical cases (19 in previous 5-year period)
        • Older on average (7yrs vs 3.5yrs)
        • More cardiac involvement (60% vs 10%)
        • More severe disease: 50% met criteria for KD-shock syndrome or MAS (compared to 0% of controls)
        • More were treated with adjunctive steroid therapy (80% vs 16%)
      • Relationship to COVID
        • 2 had positive RT-PCR, but 8 had positive IgG to COVID – previous exposure
      • Overall, there have still been very few cases of critically unwell children with COVID-19

Sources

1. Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(6):1088. doi:10.1111/apa.15270
2. Canada COVID-19 situational awareness dashboard. Ottawa, ON: Public Health Agency of Canada; 2020. Available from: https://phac-aspc.maps.arcgis.com/apps/opsdashboard/index.html#/e968bf79f4694b5ab290205e05cfcda6. Accessed 2020 May 17.
3. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):422. Apr 2020. doi:10.15585/mmwr.mm6914e4
4. Lu X, Zhang L, Du H et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663. Mar 2020. doi:10.1056/NEJMc2005073
5. Parri N, Lenge M, Buonsenso D et al. Children with Covid-19 in Pediatric Emergency Departments in Italy. New Eng J Med, May 2020. doi:10.1056/NEJMc2007617
6. Paret M, Lighter J, Pellett Madan R et al. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress. Clin Infect Dis, Apr 2020. doi:10.1093/cid/ciaa452
7. Jiang M, Guo Y, Luo Q et al. T cell subset counts in peripheral blood can be used as discriminatory biomarkers for diagnosis and severity prediction of COVID-19. J Infect Dis, May 2020. doi:10.1093/infdis/jiaa252
8. Denina M, Scolfaro C, Silvestro E et al. Lung Ultrasound in Children With COVID-19. Pediatrics, May 2020. doi:10.1542/peds.2020-1157
9. Chiotos K, Hayes M, Kimberlin DW et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc, Apr 2020. doi:10.1093/jpids/piaa045
10. Dong Y, Mo X, Hu Y et al. Epidemiology of COVID-19 Among Children in China. Pediatrics, Mar 2020. doi:10.1542/peds.2020-0702
11. Kawasaki disease: clinical features and diagnosis. UpToDate. Updated Dec 2019.
12. Turnier JL, Anderson MS, Heizer HR et al. Concurrent Respiratory Viruses and Kawasaki Disease. Pediatrics, 2015 Sep;136(3):e609-14. doi:10.1542/peds.2015-0950
13. Jones VG, Mills M, Suarez D et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020; doi:10.1542/hpeds.2020-0123
14. Twitter, @MarkLevineNYC. May 13 2020. https://twitter.com/MarkLevineNYC/status/1260579970138636289
15. Paediatric Intensive Care Society (PICS) Statement. Increased number of reported cases of novel presentation of multisystem inflammatory disease. Apr 2020. https://picsociety.uk/news/pics-statement-regarding-novel-presentation-of-multi-system-inflammatory-disease/
16. Royal College of Paediatrics and Child Health (RCPH). Paediatric multisystem inflammatory syndrome temporally associated with COVID-19. May 2020. https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19
17. Riphagen S, Gomez X, Gonzalez-Martinez C et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet, May 2020. doi:10.1016/S0140-6736(20)31094-1
18. Verdoni, L., Mazza, A., Gervasoni A et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet, May 2020. doi:10.1016/ S0140-6736(20)31129-6

Today we're talking about something that has been on the mind of many mothers and mothers-to-be: the impact of COVID-19 on pregnancy and breastfeeding.

COVID-19 and pregnancy

• The national obstetrical and gynecologic societies of Canada, the USA, and UK have all issued guidance on COVID-19 and pregnancy1-3
• There is no strong evidence that pregnant women are at increased risk of contracting COVID-19 compared to the general population4
• Symptoms in pregnant patients are typically similar to the general population: malaise, cough, dyspnea, fever5,6
• Pregnant patients are not at increased risk of severe disease; however critically ill mothers have a high risk of intrauterine fetal demise and neonatal mortality4
  • The most frequently documented adverse outcome in pregnant patients with COVID-19 is spontaneous or iatrogenic preterm labour7,8
• There is no strong evidence for vertical transmission of COVID-191
  • One study reported no presence of SARS-CoV-2 in samples of amniotic fluid, placenta, neonatal throat swab, anal swab and breastmilk9
  • Most neonates test negative on RT- PCR, however, IgM and IgG antibodies and elevated IL-6 were found in the sera of 6 neonates born to mothers with COVID-19, despite the neonates themselves having negative RT-PCR tests7
• C-sections, preferably with epidural anesthesia, have been considered safe for both the health care workers and the patients, with appropriate airborne precautions and safety measures10
• FIGO guideline highlights11
  • Antepartum care
    • Suggest treatment in tertiary care hospitals with effective isolation facilities and PPE 
    • CT chest may be considered in addition to the diagnostic algorithm 
    • Close fetal monitoring
  • Delivery
    • COVID-19 itself not an indication for delivery unless there is need for improving maternal oxygenation
    • Negative pressure room for suspected/confirmed cases
    • Vaginal delivery or C-section, but short procedure time
  • Postpartum care
    • Separation if mother is critically ill
    • Co-rooming if mild disease or asymptomatic: washing hands, respiratory hygiene

COVID-19 and breastfeeding

• The WHO provides balanced, practical guidelines on breastfeeding for patients with COVID-19, which weigh the enormous benefits of close physical contact between newborn babies and their mothers with the potential risks of COVID transmission12
  • Mothers with confirmed COVID-19 are encouraged to breastfeed, if they wish to do so. Mothers should use excellent respiratory hygiene, wear a mask if one is available, and routinely clean and disinfect high-touch surfaces
  • Mothers with confirmed COVID-19 are encouraged to have close contact with their newborns, including skin-to-skin and room sharing. Mothers should use excellent respiratory hygiene, wash hands frequently, and regularly clean surfaces.
• For working mothers pumping while working on the front lines: there is no good evidence around this
  • It is our personal feeling that this can certainly be done safely – weighing the benefits of breast milk with the theoretical risks of transmission
  • Use excellent hand-hygiene and regular thorough cleaning practices

Sources

1. Elwood C, Boucoiran I, VanSchalkwyk J et al. Updated SOGC Committee Opinion – COVID-19 in Pregnancy. Updated Mar 13 2020. https://www.sogc.org/en/content/featured-news/Updated-SOGC-Committee-Opinion__COVID-19-in-Pregnancy.aspx
2. Novel Coronavirus 2019 (COVID-19): Practice Advisory. American College of Obstetricians and Gynecologists (Immunization, Infectious Disease, Public Health Preparedness Expert Work Group). Updated Apr 23 2020. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/novel-coronavirus-2019
3. Coronavirus (COVID-19) Infection in Pregnancy: Information for healthcare professionals. Royal College of Obstetrics and Gynaecologists (UK). May 13 2020. https://www.rcog.org.uk/en/guidelines-research-services/guidelines/coronavirus-pregnancy/
4. Qiao J. What are the risks of COVID-19 infection in Pregnant Women? Lancet, Mar 2020. doi:10.1016/S0140-6736(20)30365-2
5. Beslin N, Baptiste C, Gyamfi-Bannerman C et al. COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of New York City hospitals. Am J Obstet Gynecol MFM,Apr 2020. doi:10.1016/j.ajogmf.2020.100118
6. Chen L, Li Q, Zheng D et al. Clinical Characteristics of Pregnant Women with Covid-19 in Wuhan, China. New Eng J Med, Apr 2020. doi:10.1056/NEJMc2009226
7. Parazzini F, Bortolus R, Mauri PA et al. Delivery in pregnant women infected with SARS-CoV-2: A fast review. Int J Obstet Gynecol, Apr 2020. doi:10.1002/ijgo.13166
8. Gajbhiye R, Modi D, Mahale S. Pregnancy outcomes, Newborn complications and Maternal-Fetal Transmission of SARS-CoV- 2 in women with COVID-19: A systematic review. MedRxiv, pre-print, Apr 2020. doi:10.1101/2020.04.11.20062356v1
9. Yin M, Zhang L, Deng G et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection During Pregnancy In China: A Retrospective Cohort Study. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.04.07.20053744
10. Chen R, Zhang Y, Huang L et al. Safety and efficacy of different anesthetic regimens for parturients with COVID-19 undergoing Cesarean delivery: a case series of 17 patients. Can J Anesth, Mar 2020. doi:10.1007/s12630-020-01630-7
11. Poon LC, Yang H, Kapur A et al. Global interim guidance on coronavirus disease 2019 (COVID-19) during pregnancy and puerperium from FIGO and allied partners: Information for healthcare professionals. Int J Gynaecol Obstet, Apr 2020. doi:10.1002/ijgo.13156
12. World Health Organization. Q&A on COVID-19 , pregnancy, childbirth, and breastfeeding. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-and-answers-hub/q-a-detail/q-a-on-covid-19-and-breastfeeding. Updated May 7 2020.

Like Voldemort at the end of The Goblet of Fire, lopinavir/ritonavir seems to have come back from the dead…maybe?

The background

• SARS
  • Open-label study showed improved clinical outcomes (combo of ARDS or death) with ribavirin plus lopinavir/ritonavir compared to ribavirin alone1
• MERS
  • Case reports suggest that triple-therapy with ribavirin, lopinavir/ritonavir, and interferon led to improved survival and viral clearance2
  • There is an ongoing clinical trial of combination therapy – stay tuned!3

LOTUS China trial4

• Randomized open-label trial (no placebo) at a single hospital in China
• Methods
  • 199 patients hospitalized with PCR-confirmed COVID-19
    • Had to have pulmonary involvement: positive chest imaging and hypoxia on room air: sats < 94% or P/F ratio < 300mmHg
  • Randomized to lopinavir/ritonavir plus standard care vs standard care alone
  • Primary endpoint: time to clinical improvement (7-point scale)
• Results
  • No difference in the primary outcome of time to clinical improvement
    • No difference in subgroup receiving treatment within 12 days of symptom onset
  • No difference in 28-day mortality
    • Note high mortality in both groups (19-25%)
  • No difference in detectable viral RNA at various time points
  • GI side effects were more common in the treatment group

Hung et al5

• Multi-center prospective open-label phase II RCT at 6 hospitals in Hong Kong
• Methods
  • Patients: 127 adults (>18yrs) with PCR-confirmed COVID, within 14 days of symptom onset, with NEWS2 scores of at least 1
  • Treatment:
    • 14 days of lopinavir/ritonavir (BID) and ribavirin (BID)
      • Plus up to 3 doses of interferon beta-1b every other day if within 7d of symptom onset*
    • Control: lopinavir/ritonavir alone
  • Primary outcome: time to a negative RT-PCR NP swab
    • Secondary: time to resolution of symptoms, SOFA scores, hospital length of stay, 30-day mortality
  • Interestingly, their power calculation was based on an estimated 26.4% (!!) improvement in mortality with triple-Tx group based on a prior study1
• Results
  • Patients: only very mildly ill
    • Only 11% had dyspnea; and twice as many in control group as Tx group (sicker?)
    • Only 13% required oxygen therapy during their admission
      • Most of these people would NOT have been admitted to hospital here in Canada!
    • Baseline viral load similar between groups
  • Primary outcome: faster time to negative swab in the triple-therapy group (7 vs 12d)
  • Secondary outcomes: many were also improved in the triple-therapy group
    • Improved time to NEWS 0 (4 vs 8 days)
    • Improved time to SOFA score 0 (3 vs 9 days)
    • Shorter hospital length of stay (9 vs 14.5 days)
    • No change in 30 day mortality (0% mortality in both groups)

Why the difference? Possible explanations:

• Timing of medication administration: randomization occurred at median 13 days after symptom onset in LOTUS China
  • Hung: 60% of patients presented within 7 days of symptom onset
    • Subgroup who presented after 7 days: no difference
  • Sicker patients in LOTUS China?
    • Required to be hypoxemic on room air; vs only a small percentage of patients in Hung et al needed oxygen
  • It's the drugs!
    • Maybe ribavirin or interferon are actually the effective agents?
    • Is there something synergistic and magical about combination therapy?

The bottom line

• This is promising! But…
• We need more studies
  • With sicker patients: do these actually improve endpoints that we care about?
  • To help tease out the effect of each drug
• If early administration is the key, we really need to think about how we might deploy this from a public health perspective

Sources

1. Chu CM. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. March 2004:252-256. doi:10.1136/thorax.2003.012658
2. Kim UJ, Won E-J, Kee S-J, Jung S-I, Jang H-C. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-α for Middle East respiratory syndrome. Antivir Ther, 2016; 21: 455-9. doi:10.3851/IMP3002
3. Arabi YM, Alothman A, Balkhy HH et al. Treatment of Middle East Respiratory Syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials 2018; 19: 81. doi:10.1186/s13063-019-3846-x
4. Cao B, Wang Y, Wen D et al. A trial of lopinaviar/ritonavir in adults hospitalized with severe COVID-19. New Eng J Med, March 2020. doi:10.1056/NEJMoa2001282
5. Hung IF-N, Lung K-C, Tso EY-K et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet. May 2020. doi:10.1016/s0140-6736(20)31042-4

Today we're exploring a COVID-complication that has caught a lot of attention on social media: hypercoagulability.

Clinical features

• Part of the syndrome of immune hyperactivity seen in severe SARS-CoV-2 infection is activation of complement pathways involved in coagulation
  • Termed COVID-associated coagulopathy (CAC) or thromboinflammation
  • Appears distinct from DIC
    • Hallmark is clotting, NOT bleeding!
  • Clinical features include
    • VTE1
      • Incidence of VTE appears very high in critically ill patients: 25% to 43%, often despite prophylactic anticoagulation2-4
      • Much lower incidence in ward patients, but data limited2
      • Outpatients: unknown
    • Arterial thrombosis
      • The incidence of arterial thrombosis in COVID is unknown
        • Two single-center studies of admitted inpatients with COVID report an incidence of 5% and 3.7% respectively4,5
      • Lay press reports describe the experience of one American physician, who notes that they have seen young patient presenting with stroke (large-vessel occlusions)6,7
      • Clinical antiphospholipid antibody syndrome (APS) has also been described in case reports, with patients presenting with limb ischemia, cerebral infarcts, and positive antiphospholipid antibodies8,9
    • Microvascular thrombosis
      • Some studies suggest that multiorgan failure secondary to microvascular damage may be an important cause of death in COVID patients

Lab evaluation

• Patients with severe COVID-19 infections and non-survivors (compared to those with less severe infection) have been found to have:
  • Markedly elevated D-dimer10-12
    • Patients with D-dimer > 1000 had 20x increased risk of mortality in one study!11
  • Higher PTT levels11,12
  • Platelets: typically N/high (unlike DIC); but may be low13
  • High fibrinogen and factor VIII activity (unlike DIC)14

Potential therapies

• Anticoagulation
  • It's been suggested that heparin may be beneficial in COVID-19, given its anticoagulant, anti-inflammatory, endothelial-protective, and antiviral properties
  • In retrospective observational studies, there is a signal for heparin for reduced mortality with heparin, particularly in critically ill patients15,16
    • Excessive bleeding was low in one study (about 1%)16
    • Note the potential for bias with these studies!
  • This group has published a nice decision algorithm that may help inform anticoagulation use in COVID patients, taking into consideration risk of VTE, D-dimer levels, and POCUS findings17
  • Bottom line: still need more evidence here!
    • While awaiting that: individualized decisions in accordance with your group/hospital/health authority policy
  • Prophylactic-dose anticoagulation is strongly recommended in all patients in the absence of very compelling contraindications18
• Antiplatelet agents
  • Some of these reports describe therapy for arterial thrombosis with ASA5
    • No high-quality data; no data on prospective use
  • One group looked at the administration of dipyridamole and its effects on in-vitro cell lines, as well as laboratory coagulation/inflammatory parameters, and on clinical outcomes19
    • The group cites effects of dipyridamole on viral replication, as well as its antiplatelet and "immune-enhancing" properties
    • Very small size and methodological issues prevent drawing any conclusions from this paper, but it's hypothesis-generating
  • Thrombolysis
    • tPA has also been trialed in select cases in patients with COVID-19 and ARDS, leading to transient improved oxygenation20
  • Management of hemorrhage/DIC
    • Bleeding does not seem as common in these patients. Opinion-only (not evidence-based) guidelines have suggestions for management of coagulation parameters in bleeding patients18
      • If bleeding: target plts > 50, fibrinogen > 2, PT ratio < 1.5 (similar to general management of pts in DIC)

Future directions

• Ongoing trials are looking at the safety and efficacy of anti-platelets and anti-coagulation, including aspirin, clopidogrel, rivaroxaban, tirofiban, fondaparinux and dipyridamole

Sources

1. Cui S, Chen S, Li X et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. Apr 2020; doi:10.1111/jth.14830
2. Middeldorp S, Coppens M, van Haaps TF et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. May 2020; doi: 10.1111/jth.14888
3. Helms J, Tacquard C, Severac F et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. May 2020; doi:10.1007/s00134-020-06062-x
4. Klok F, Kruip M, van der Meer N et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Res, Apr 2020; doi:10.1016/j.thromres.2020.04.013
5. Li Y, Zhou Y, Wang M et al. Acute Cerebrovascular Disease Following COVID-19: A Single Center, Retrospective, Observational Study. SSRN, Mar 2020; doi: 10.2139/ssrn.3550025
6. Cha, A. Young and middle-aged people, barely sick with COVID-19, are dying of strokes. Washington Post online, Apr 25 2020. https://www.washingtonpost.com/health/2020/04/24/strokes-coronavirus-young-patients/
7. Fox, M. Covid-19 causes sudden strokes in young adults, doctors say. CNN Health (online), Apr 23 2020. https://www.cnn.com/2020/04/22/health/strokes-coronavirus-young-adults/index.html?fbclid=IwAR2s8aUzUcA9N6Vcy02J9eNjYpkkQ2sZUqjmat-00dQpOwEtHcmgUU4eA30
8. Ma J, Xia P, Li X et al. Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19. Clin Immunol, Apr 2020; doi:10.1016/j.clim.2020.108408
9. Zhang Y, Xiao M, Zhang S et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. New Eng J Med, Apr 2020; doi:10.1056/NEJMc2007575
10. Guan W, Ni Z, Hu Y et al. Clinical characteristics of coronavirus disease 2019 in China. New Eng J Med, Feb 2020; doi:10.1056/NEJMoa2002032
11. 11. 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. Lancet, Mar 2020; doi:1016/S0140-6736(20)30566-3
12. Tang N, Li D, Wang X et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost, Mar 2020; doi:10.1111/jth.14768
13. Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clinica Chimica Acta, Mar 2020; doi:10.1016/j.cca.2020.03.022
14. Panigada M, Bottino N, Tagliabue P et al. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis. J Thromb Haemost. Mar 2020; doi: 10.1111/jth.14850
15. Tang N, Bai H, Chen X et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy. J Thromb Haemost, Mar 2020; doi:10.1111/jth.14817
16. Paranjpe I, Fuster V, Lala A, et al. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19. Journal of the American College of Cardiology. May 2020. doi:10.1016/j.jacc.2020.05.001
17. Atallah B, Mallah SI, Al Mahmeed W. Anticoagulation in COVID-19. European Heart Journal – Cardiovascular Pharmacotherapy. April 2020. doi:10.1093/ehjcvp/pvaa036
18. Thachil J, Tang N, Gando S et al. ISTH interim guidance on recognition and management of coagulopathy in COVID‐19. J Thromb Haemost, Mar 2020; doi: 10.1111/jth.14810
19. Liu X, Li Z, Liu S et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta Pharmaceutica Sinica B, Apr 2020. doi:10.1016/j.apsb.2020.04.008
20. Wang J, Hajizadeh N, Moore E et al. Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series. J Thromb Haemost, Apr 2020; doi:10.1111/jth.14828

We're looking optimistically to the future today and talking about the development of potential vaccines for COVID. All the information below has been amalgamated from the review pieces cited.

Vaccine development landscape

• Researchers across the country are devoting huge amounts of time and energy to the development of a coronavirus vaccine
• Currently there are 115 vaccine candidates
  • 78 are confirmed active trials
    • Majority (73) are in exploratory or pre-clinical testing phase
    • First vaccine candidate entered human testing on March 16 2020
  • Majority are in the private/industrial sector (>70%)
• Many different vaccine types are being investigated, each with advantages and disadvantages
  • mRNA, DNA, viral vector, live attenuated virus, inactivated virus, peptide-based, recombinant protein, etc
  • Trials of vaccine adjuvants are also underway
• Current phase 1 clinical trials
  • Moderna: mRNA vaccine
  • CanSino Biologicals: recombinant protein
  • Inovio Pharmaceuticals: DNA vaccine
  • Shenzhen Geno-Immune Medical Institute: viral vector (2)

Vaccine safety

• Vaccine safety remains to be a major consideration
  • This is a new viral target with some novel vaccine technology and developmental paradigms
  • There were documented adverse vaccine responses with SARS (ADE)
    • Some concerns in particular about liver damage
  • To combat this, rigorous animal model safety assessment is being undertaken
    • Mouse and macaques (monkeys) have proven to be reliable models for vaccine study
  • Mutations?
    • The virus may mutate and necessitate vaccine reformulations; however, this would be a much shorter process (similar to the yearly flu vaccine)
    • Some research is also underway to create a pan-coronavirus vaccine

Timeline

• Timeline for completion of the clinical trials varies from 2021 to 2023 and beyond
• The most optimistic estimates are that a vaccine may be ready by early 2021
  • That does not account for the time it would take to mass-produce the vaccine; nor for any hiccups along the way!!

Global perspective

• Moving forward, there is also a need to ensure that vaccines will be manufactured in sufficient quantities and equitably supplied to all affected areas, particularly low-resourced

Sources

1. Le T, Andreadakis Z, Kumar A et al. The COVID-19 vaccine development landscape. Nature Reviews, April 2020. doi:10.1038/d41573-020-00073-5

1. Zhang J, Zeng H, Gu J et al. Progress and Prospects on Vaccine Development against SARS-CoV-2. Vaccines,2020, 8(2), 153. doi:10.3390/vaccines8020153

1. Weber B. A look at research being done in Canada for a coronavirus vaccine. Global News, Mar 30 2020. https://globalnews.ca/news/6749536/coronavirus-canada-vaccine-research/

Today we're tackling a question with a lot of public health implications as we consider how to move forward in this pandemic (and potentially being to loosen restrictions). A huge part of that equation is the question of immunity: are people who have previously been infected immune to COVID; or could they become re-infected and continue to transmit the virus? And could antibody tests help us determine who has already been infected (perhaps asymptomatically)?

Antibody tests for COVID-19

• Several different types of tests available1
  • GICA: gold immunochromatographic assay
  • CLIA: chemiluminescent immunoassay
  • ELISA: enzyme-linked immunosorbent assay
  • Point-of care lateral flow tests
• ELISA tests are the most common (most studies below use ELISA assays)
  • Plate-based technique for detecting and quantifying peptides, proteins, antibodies, etc
  • May have slightly different targets
• Several assays available each with slightly varying test characteristics
  • Generally sensitivity is good (>90% for most tests)2
  • False positives are rare but have been reported3
• Some assays show cross-reactivity with other coronaviruses4

Initial antibody response and seroconversion

• Most studies support a high rate of seroconversion after acute illness
  • One study found 50% of pts had detectable antibodies by day 7 post-Sx onset5
  • Most pts who seroconvert do so by day 10-156
  • Seroconversion rates varied but are generally high: 83% to 100% by day 21-353,5,7-11
• However -
  • One study classified patients as "strong responders" vs "weak responders" vs "non-responders"12
    • Strong responders: >2x the cutoff value; weak responders: 1-2x the cutoff value; non-responders: below assay cutoff value
      • The clinical implications of this stratification system have NOT been determined
    • A significant portion of patients were non- or weak-responders by the end of the follow-up period (1 month)
      • 7% (IgM) and 16.7% (IgG) were non-responders
      • 2% (IgM) and 61.1% (IgG) were weak responders
    • Another group found that 30% of patients had very low titers at day 10-15 post-symptom onset – again, the clinical implications of these low levels are unclear13
  • Patients with more severe disease seem to mount a stronger antibody response (IgG in particular)12,14
    • Weak antibody responders had a higher rate of viral clearance in one study12

Lasting immunity?  

• IgM levels decline over time, as expected
  • 33% of pts had no detectable IgM by week 7 in one study15
• Some evidence that IgG levels also fall with time
  • One group did weekly serial testing of IgG levels and found that levels decreased with time16
  • Adams et al reported that IgG levels decreased by 8 weeks (but remained above detection threshold)17
  • In contrast, another group found stable IgG levels up to 7 weeks after symptom onset15
• No one has looked beyond 2 months post-Sx onset yet à we don't know how long immunity might last!

UPDATE – May 18/20

• An interesting new basic science study has come out looking at the role of T-cells in COVID-1918
  • Reminder: T-cells are key players in cell-mediated immunity (vs B-cells in humoral immunity discussed above)
• This group found that SARS-CoV2-reactive CD4+ T cell were detected in 40-60% of healthy historical controls who had never been exposed to COVID
• They theorize that this may reflect a degree of cross-reactivity between SARS-CoV-2 and other coronaviruses
  • BUT the clinical implications of this re: immunity are not known
• This is a potentially hopeful study – if there is some degree of cross-reactivity, we may be closer to herd immunity than previously suspected

Sources

1. Gao HX, Li YN, Xu ZG et al. Detection of serum immunoglobulin M and immunoglobulin G antibodies in 2019-nCoV-infected cases from different stages. Chinese Medical Journal, Mar 2020. doi:10.1097/CM9.0000000000000820

1. Lassauniere R, Frische A, Harboe ZB et al. Evaluation of nine commercial SARS-CoV-2 immunoassays. MedRxiv pre-print, Apr 2020. doi: 10.1101/2020.04.09.20056325

1. Xiang F, Wang X, He X et al. Antibody detection and dynamic characteristics in patients with COVID-19. Clin Infect Dis, Apr 2020. doi: 10.1093/cid/ciaa461/5822173

1. Okba N, Muller M, Li W et al. Severe Acute Respiratory Syndrome Coronavirus 2−Specific Antibody Responses in Coronavirus Disease 2019 Patients. Emerg Infect Dis, Apr 2020. doi:10.3201/eid2607.200841

1. Wölfel, R., Corman, V.M., Guggemos, W. et al. Virological assessment of hospitalized patients with COVID-19. Nature, Apr 2020. doi:10.1038/s41586-020-2196-x

1. Wu F, Wang A, Liu M et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.03.30.20047365

1. Zhang B, Zhou X, Zhu C et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.12.20035048

1. Zhao J, Yuan Q, Wang H et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis, Mar 2020. doi:10.1093/cid/ciaa344

1. Lou B, Li T, Zheng S et al. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.23.20041707

1. Long Q, Deng H, Chen J et al. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.18.20038018v1

1. To K, Tsang O, Leung W et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infec Dis, Mar 2020. doi:10.1016/S1473-3099(20)30196-1

1. Tan W, Lu Y, Zhang J et al. Viral kinetics and antibody responses in patients with COVID-19. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.24.20042382v1

1. Wu F, Wang A, Liu M et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.03.30.20047365

1. Huang A, Garcia-Carreras B, Hitchings M et al. A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.04.14.20065771

1. Xiao A, Gao C, Zhang S. Profile of specific antibodies to SARS-CoV-2: The first report. J Infect, Mar 2020. doi:10.1016/j.jinf.2020.03.012

1. Du Z, Zhu F, Guo F et al. Detection of antibodies against SARS‐CoV‐2 in patients with COVID‐19. J Med Virol, Apr 2020. doi: 10.1002/jmv.25820

1. Adams E, Ainsworth M, Anand R et al. Evaluation of antibody testing for SARS-CoV-2 using ELISA and lateral flow immunoassays. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.04.15.20066407

1. Grifoni A, Weiskopf D, Ramirez SI et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals, Cell, May 2020, doi:10.1016/j.cell.2020.05.015