Carlos Del Rio, MD Stuart Ray, MD Brian Hutler, Phd JD 5/19/2020 Clinical Cases

Carlos Del Rio, MD Stuart Ray, MD Brian Hutler, PhD JD 5/19/2020 Clinical Cases

• Patient 1 • 70 year old man presents to clinic for a scheduled video visit • Multiple medical problems • Immune compromising condition • Chronic lung disease • Chronic heart disease • Works in building maintenance • Chose to take FMLA, initially was paid, now not • Has option to return to work • Lives with someone with multiple medical problems • Does not want to return to work until cases in city steadily decline • Is unsure how he will pay for rent, groceries Clinical Cases

• Patient II • 35 year old man with no prior past medical history • Presents to ED with 5 days of progressive dyspnea upon exertion, fever (103), cough • O2 saturation in ED on room air = 82% • Admitted, intubated within 24 hours • Extubated after 7 days, transferred to floor • Worked in restaurant business, currently unemployed due to COVID-19 pandemic • Lives in a house with >5 other people, not related, some of whom have chronic medical problems • Able to defer rent 1 more month • Wants restaurants, other businesses to open now • Same opinion prior to developing COVID-19 Clinical Cases

• Patient I • Patient II • At risk for severe disease • Status post severe COVID-19 • Lives with someone at risk for severe • Lives with people who are at risk for disease severe disease • Keep city closed • Open city

Clinical Question: Should the United States ease restrictions? Sweden’s Approach

https://www.britannica.com/place/Scandinavia Restrictions in Sweden

• Gatherings of >50 people banned • High schools and colleges closed • Museums closed • Sporting events canceled • Visits to nursing homes banned (late March) • People encouraged and trusted to socially distance • Emphasis on hand washing and limiting contact with people >70y • Avoid unnecessary travel

https://www.nytimes.com/2020/04/28/world/europe/sweden-coronavirus-herd-immunity.html. https://www.nytimes.com/2020/03/28/world/europe/sweden-coronavirus.html. Sweden’s Decision to Stay Mostly Open

• Borders kept open • Restaurants and bars open • Preschools and grade schools in session • No limits on public transportation • No limits on public park outings • Hairdressers, yoga studios, malls, gyms, some cinemas open • Ski slopes open

https://www.nytimes.com/2020/04/28/world/europe/sweden-coronavirus-herd-immunity.html. https://www.nytimes.com/2020/03/28/world/europe/sweden-coronavirus.html Impact of Recommendations

https://www.nytimes.com/interactive/2020/05/15/world/europe/sweden-coronavirus-deaths.html Mortality Data Thus Far

https://www.nytimes.com/interactive/2020/05/15/world/europe/sweden-coronavirus-deaths.html. https://www.nytimes.com/interactive/2020/04/21/world/coronavirus-missing-deaths.html. More Mortality Statistics

• Sweden’s death rate is ~32/100,000 • 24/100,000 in the U.S. • 9/100,000 in Denmark • Stockholm: >200% increase in the usual number of deaths in April • More than Boston, Chicago; comparable to Paris • In Stockholm County through 4/17/20, there were almost 50% more deaths among men ≥80y than on average from 2015-2019 • Half of people >70y who died from COVID-19 lived in nursing homes

https://www.bloomberg.com/news/articles/2020-05-12/covid-infection-rate-drops-in-denmark-after-lockdown-relaxed?sref=q3TwEQDG. https://www.nytimes.com/interactive/2020/05/15/world/europe/sweden-coronavirus-deaths.html. https://www.scb.se/om-scb/nyheter-och- pressmeddelanden/stockholm-sticker-ut-i-statistik-over-dodsfall/ Relevant Data

Share of Single-Person Households Share of Population ≥65y Country Proportion Country Proportion Portugal 22.7% United States 16% Spain 25.6% Norway 17.1% United States 27% United Kingdom 18.3% United Kingdom 31.4% Switzerland 18.4% Italy 33.4% Netherlands 19% Netherlands 37.3% Spain 19.3% Switzerland 38.1% Sweden 19.9% Norway 45.8% Portugal 21.7% Sweden 56.6% Italy 22.7%

https://www.nytimes.com/interactive/2020/05/15/world/europe/sweden-coronavirus-deaths.html Relevant Data

Obesity Rate Share of Population with Diabetes Country Proportion Country Proportion Italy 9.8% Switzerland 5.6% Switzerland 10.3% Netherlands 6.1% Norway 12% Norway 6.6% Sweden 13% Sweden 6.9% Netherlands 13.6% United Kingdom 7.7% Spain 16.7% Italy 8.5% United Kingdom 26.2% United States 9.1% Portugal 28.7% Portugal 9.2% United States 40% Spain 9.4%

https://www.nytimes.com/interactive/2020/05/15/world/europe/sweden-coronavirus-deaths.html DEBATE: Distancing Vs. Herd Protection Embrace Herd Protection Why do I get to “defend Sweden”? The Global Response to COVID-19

• The major strategy has been lockdowns • This has resulted in an unprecedented economic recession globally • China placed ~ 50 million people under quarantine in Hubei Province for 77 days (January to April). • Despite lockdown there were over 67,000 cases and 3,200 deaths in Hubei. • After lifting the lockdown cases have occurred. • Are we to keep lockdowns until we have a vaccine? • Is this the only approach? Is this the right approach? Herd immunity is the only realistic option: the questions in how to get there safely Herd Immunity

• Herd immunity relies on the idea that as more individuals are infected and/or protected by a vaccine, there are less persons that are susceptible in the population.

• For COVID-19 it is estimated that 50-to-70 percent of the population would have to be infected to reach such a goal.

Herd immunity threshold estimation

# • Herd immunity threshold ≈ 1 − based on compartment model $% # • At R = 2.5, that would be 1 − = 0.6 or 60% (R = 2 or 3, 50% or 67%) 0 &.( 0 • Some argue that this threshold estimate is inflated, suggesting: • inhomogeneity in infectivity and susceptibility violate the assumptions of the simple compartment model • herd immunity threshold might be closer to 20%

Gomes MGM, et al. https://www.medrxiv.org/content/10.1101/2020.04.27.20081893v2 Herd immunity threshold estimation

Gomes MGM, et al. https://www.medrxiv.org/content/10.1101/2020.04.27.20081893v2 Scenarios

• Worst case scenario: the virus could infect thousands in a matter of months that would overwhelm hospitals and lead to high death rates.

• Best case scenario: we maintain current levels of infection—or even reduce these levels—until a vaccine becomes available. • This will take some level of continued physical distancing for an extended period, likely a year or longer, before a highly effective vaccine can be developed, tested, and mass produced. Sweden’s approach to COVID-19

• Sweden refused to lock down the country.

• The architect of the strategy was state epidemiologist Anders Tegnell.

• Sweden has chosen to rely on citizens’ sense of public duty and trust that they’ll practice social distancing even without a host of rules meant to keep people apart. Sweden

• Swedish authorities have not officially declared a goal of reaching herd immunity but “augmenting immunity” is no doubt part of the government’s strategy or at least a consequence of keeping schools, restaurants and most business open.

• Mathematical models suggest that if ~ 40% of the population in Stockholm is infected spread of SARS-CoV-2 will stop and this is likely to occur by mid-June Embrace Distancing COVID-19 Herd Immunity Strategy Requirements

1. Protect the vulnerable, informed by testing 2. Surveillance 3. Protective immunity COVID-19 Herd Immunity Strategy Requirement #1 – Protect the vulnerable, informed by testing • Diagnostic tests that guide key elements of decision-making • Who is infected with SARS-CoV-2, who isn’t • Who is infectious, who isn’t • Who is susceptible, who isn’t • Who is vulnerable to severe COVID-19, who isn’t We need: widespread, available, accurate testing vRNA

• viral RNA tests from NP swabs have ~70% sensitivity for COVID-19 • Biological: location of highest replication varies • Pre-analytical: Sample collection/handling • Analytical: Variability in assay sensitivity (relatively small source of error) • Logistical: Impact of time-to-result • Interpretation: PPV for current infection is high; NPV for subsequent positive is poor; NPV for infectivity unknown; PPV for infectivity unknown

• Fecal/anal samples can yield positive vRNA (yet culture neg, as a rule) results for weeks, possibly test for recent infection and a potential source of viral genomic sequence for molecular epidemiology Wu Y, et al. Lancet Gastr Hep 2020; 5(5):434-5 32235945

We need: widespread, available, accurate testing

Serological (antibody, Ab) tests positive by ~14 days from symptom onset • Biological: different hosts may have different seroconversion dynamics • Analytical: variable sensitivity and specificity • If test is 98% specific and prevalence is 2% then half of positives will be false positives

• Interpretation: best + Ab test indicates prior SARS-CoV-2 infection; however, • We do NOT know whether antibodies indicate lack of infectivity (many have positive respiratory vRNA while also being Ab positive) nor immunity (resistance to re- infection) • We do NOT know how long Ab positivity will last Wölfel R, et al. Nature 2020; PMID 32235945 COVID-19 Herd Immunity Strategy Requirement #1 – Protect the vulnerable, informed by testing • Diagnostic tests that guide key elements of decision-making • Who is infected with SARS-CoV-2, who isn’t • Who is infectious, who isn’t • Who is susceptible, who isn’t • Who is vulnerable to severe COVID-19, who isn’t

• Answer to all of these: • We don’t know whether we have the right tools COVID-19 Herd Immunity Strategy Requirement #2 - Surveillance • Do we know when it’s safe to relax versus when we must “strap in”? • Are we equipped to perform meaningful contact tracing? We need: Rapid response if rates rise

• Problems: • Reporting lags in multiple forms, including mid-week catch-up • Noisy data make increases harder to recognize • Rise in deaths lags cases by 1-2 weeks COVID-19 Herd Immunity Strategy Requirement #2 - Surveillance

• Do we know when it’s safe to relax versus when we must “strap in”? • Are we equipped to perform meaningful contact tracing?

• Answer: We have partial answers Embrace Herd Protection Sweden

• Sweden’s response has not been perfect, but it has succeeded in bolstering immunity among the young and the healthy—those at the lowest risk of serious complications from COVID-19—while also flattening the curve. What has happened as a result?

• The country’s intensive care units have not been overrun

• Hospital staffs, although under strain, have at least not had to juggle additional childcare responsibilities because daycares and lower schools continue to operate.

• As a result is estimated that 15% to 20% of people in Stockholm had reached a level of immunity that would "slow down the spread" of a second wave of the virus. Sweden’s Coronavirus Strategy Will soon Be the World’s Sverige har rätt (Sweden is right) Embrace Distancing COVID-19 Herd Immunity Strategy Requirement #3 – Protective immunity

• Does resolving SARS-CoV-2 infection lead to immunity? • If so, will that last more than a few months? (is it durable?) Is COVID-19 immunity achievable in individuals?

• Upper respiratory coronavirus (“common cold”) infections do not tend to generate lasting immunity, leading to repeated infections • Measures of immunity (neutralizing antibody levels, cellular immunity) suggest responses are neither robust nor sustained

• For multiple vaccine successes, natural infection was not protective: • Tetanus (antigen insufficient in natural infection) • HiB (conjugate design augments T cell help) • There is plenty of reason for hope Short-term immunity in macaques against homologous rechallenge

• A medRxiv preprint by Bao L, et al. describes a study of Rhesus macaques in which 4 animals in the early recovery phase (d28) from primary infection 6 were re-challenged with the same inoculum (10 TCID50 of WH-09 strain in 1 mL, intratracheally). No animal was reinfected based on clinical markers, swabs (nasal, throat, anal), or necropsy tissue analysis. COVID-19 Clinical and Microbiologic Relapse Is this repeat infection, or recrudescence?

• Clinical and virologic relapse in one 46 yo woman in China (Chen D, et al. Int JID 2020 [online Mar 5]; 93:297-9) • USS Theodore Roosevelt: • In March an outbreak of COVID-19 resulted in at least 585 sailors testing positive, one of whom died on April 13 (ref) • On May 16, the Navy reported that 5 of the sailors who had recovered fully, had tested negative for SARS-CoV-2 viral RNA (vRNA), then recently reported influenza- like illnesses and tested positive again for vRNA; testing of other sailors then revealed 8 more positives for a total of 13 at this time. (ref) • Relapses in other populations • S. Korea https://www.npr.org/sections/coronavirus-live-updates/2020/04/17/836747242/in-south-korea-a- growing-number-of-covid-19-patients-test-positive-after-recover COVID-19 Herd Immunity Strategy Requirement #3 – Protective immunity

• Does resolving SARS-CoV-2 infection lead to immunity? • If so, will that last more than a few months? (is it durable?)

• Answer to both questions: We don’t know COVID-19 Herd Immunity Strategy Requirements

1. Protect the vulnerable, informed by testing 2. Surveillance 3. Protective immunity

Many promising leads just 6 months in, but all are works in progress. Embrace Distancing? • Sweden’s strategy is unlikely to work in the US because: • We have less people in single person households • Higher obesity and diabetes rates • More individualistic approach • Less trust in government and others • However as the country reopens this will be the path we end up taking anyway. • While President Trump has bashed the Swedish model this is the path he is pushing the country into. What is the herd immunity threshold in the US? The picture will be much rosier if:

Not likely: • SARS-CoV-2 dissipates this summer, never to return • COVID-19 becomes milder spontaneously

Possible: • Convalescent plasma, or IVIg, is found to be protective, effective • We develop safe, effective, accessible antiviral drugs for SARS-CoV-2 • We develop safe, effective, accessible immunomodulatory drugs for COVID-19 • We develop a safe, effective, accessible vaccine for SARS-CoV-2 SARS-CoV-2 seems vaccine feasible antigenically

hominoids G 2 E F 1 1a 1c D A 1b C B 0.1 7 HBV 3181 sites

SARS-CoV-2 5 F K (pinpoint, D C ~ 1/1000 size of HBV) 4 B H 0.1 27,000 sites G 0.1 AEA J HCV (whole genome sequences, all on HIV 9198 sites same scale [ML GTR+I+G]) 8316 sites 6 3 Ray SC and Thomas DL. Mandell’s PPID 7th ed, 2009: chap 154 S. Ray 2020 Distancing Vs. Herd Protection: An Ethics Perspective “Evaluating the Ethics of Social Distancing and Reopening Plans”

• Ruth Faden • Hahrie Han • Travis N. Rieder • Anne Barnhill • Justin Bernstein • Brian Hutler

Public health goals Scale and uncertainty of the crisis Relevant ethical values Importance of democratic participation SLIDES & RECORDINGS ARCHIVED ONLINE https://bit.ly/2Y2DIDj