COVID-19 Clinical Trials and Task Force Updates

Clinical Trials

UCSF, community based partners, departments of public health, and industry are planning, enrolling, and launching a variety of different clinical trials related to those diagnosed with and recovering from COVID:

UCSF-led trials are enrolling those living with and recovering from COVID-19.

A growing database of trials looking at a variety of factors related to COVID-19 and its impact was recently launched. You can now explore what options may be applicable.

-----------------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: May 7, 2020
 
EPIDEMIOLOGY STATISTICS -- AND A THANK YOU TO ALL NURSES

As of today there are 60,634 confirmed COVID-19 cases and 2,460 deaths in California. In San Francisco there are 1,806 cases and 32 deaths. Demands to re-open California have led to protesters at the state Capitol in Sacramento. While shelter-in-place restrictions are being eased in parts of California on Friday, the Bay Area and LA are taking a more cautious approach as concerns of a second wave of infections arise among health experts. The United States reached one million cases on Monday—as of today there are 1.23 million cases and over 73,000 deaths. Worldwide there are over 3.78 million reported cases of COVID-19 and 264,000 deaths as of this morning. National Nurse Appreciation Week began on Wednesday, now more than ever we would like to take a moment to reflect on the incredible work and sacrifices nurses make daily on the frontlines.


UP TO THE MINUTE DISPATCHES

Did hospitalizations and deaths vary across the New York City boroughs?
Authors conducted a cross-sectional analysis of COVID-19-related hospitalizations and deaths across the five New York City (NYC) boroughs which have known demographic differences. Hospitalizations and deaths per 100,000 population were highest in the Bronx (634 and 224 respectively) and lowest in Manhattan (331 and 122 respectively). Tests performed per 100,000 were also the highest in the Bronx (4599) compared to Manhattan (2844). The population density of Manhattan is more than double that of the Bronx (~71k vs ~34k per square mile, respectively), and both median age and proportion of population over age 65 is higher in Manhattan. However, the Bronx has a median household income half that of Manhattan and the proportion identifying as Black or Hispanic is double.
Conclusion: the NYC borough with the highest rate of poverty and the most racial/ethnic diversity had the highest COVID-19 hospitalization and death rates, while the borough with highest median income (despite highest population density, median age) had the lowest.

A rapidly developed scalable SARS-CoV-2 vaccine shows promise in non-human primates

A pre-print (non-peer reviewed) study reports the small-scale production of a purified, inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2-specific neutralizing antibodies against the S protein in mice, rats, and macaques. These antibodies were effective in neutralizing 10 representative SARS-CoV-2 strains. Vaccination of macaques provided partial to complete protection (as judged by viral loads from various tissues) and lack in clinical symptoms in animals inoculated with SARS-CoV-2 1 week after the 3rd vaccination. The vaccine appeared well-tolerated and safe without any signs of antibody-dependent enhancement of infection, one of the theoretical concerns in SARS-CoV-2 vaccine development. These studies bode well for the rapid clinical development of a SARS-CoV-2 vaccine in humans that would be ready to enter Phase I clinical trials. Conclusion: A purified inactivated SARS-CoV-2 virus vaccine candidate confers complete protection in non-human primates against SARS-CoV-2 strains circulating worldwide by eliciting potent humoral responses devoid of immunopathology.

Could human monoclonal antibiotics be effective in the prevention and/or treatment of COVID-19?

Like the antibodies found in sera of patients previously infected with COVID-19, human monoclonal antibodies (mAbs) that effectively neutralize SARS-CoV-2, could potentially be useful for treatment and/or prevention of COVID-19. Two groups have now reported isolating and developing highly promising human mAbs. The first study screened their previously developed collection of antibodies to SARS-CoV and identified an antibody against the Spike (S) protein adept at neutralizing SARS-CoV-2 in cell culture. A second study(pre-print, not peer-reviewed) isolated and developed two mAbs from memory B cells of patients that had recently recovered from COVID-19. These mAbs also bound to the S protein and were effective in neutralizing infectivity of a non-pathogenic virus that uses the S protein for binding and entry. Conclusion: Production of monoclonal, highly neutralizing antibodies to the S protein of SARS-CoV-2 may be a future strategy for prevention and treatment of COVID-19. Scaled-up production and clinical trials would be natural next steps.


FAQ

1. Are young adults with COVID-19 at risk for stroke?
A small case series in NEJM describes five young patients (ages 33-49 years) who were admitted to a New York City hospital over a two-week period with COVID-19 and large vessel ischemic stroke. Three of the patients had comorbidities such as hypertension or diabetes; only one had a history of prior stroke. Notably, two patients had no respiratory symptoms at presentation. Normally this hospital would treat an average of 0.73 patients <50 years with stroke per two-week period (compared to the five reported here). The authors postulate that stroke may be related to coagulopathy or vascular endothelial dysfunction in COVID-19. Conclusion: This study, although extremely small is concerning in light of the association of COVID-19 and disorders of coagulation. We need to be alert to and await more data on COVID-19 associated stroke in young patients.

2. What is our updated understanding of the impact of COVID-19 in organ transplant recipients?
Data on COVID-19 among organ transplant recipients are accumulating rapidly. Several case series, including the largest report of 90 organ transplant (kidney, lung, liver, heart, heart-kidney) recipients with COVID-19, suggest that these patients may be at increased risk for severe disease and mortality (range 7-30%). However, select subgroups, including patients earlier after transplant, may have more favorable outcomes. Organ transplant recipients seem to have typical clinical presentation with predominant symptoms of fever, dry cough, dyspnea, and diarrhea. Most have underlying comorbidities associated with COVID-19 such as hypertension, diabetes, obesity, and chronic kidney or lung disease. Decreasing immunosuppression has been a mainstay of treatment, though some patients have recovered without changes. Conclusion:Organ transplant recipients with COVID-19 may be at increased risk for complications of COVID-19 but it possible that their other comorbidities may be the driving risk factors for severe disease, not immunosuppression. Prospective studies are needed to guide the management of COVID-19 among organ transplant recipients.

3. Does the use of biologics for patients with autoimmune diseases increase risk for severe COVID-19?
It is unknown whether patients with autoimmune conditions are at increased risk for COVID-19 as a result of biologics, or whether these agents may have a protective effect against the cytokine storm seen in some patients. A recent case series describes 86 patients with immune mediated inflammatory diseases of which 62 (72%) were on biologics or JAK inhibitors. Only 14 (16%) required hospitalization. The percentage of patients on biologics and JAK inhibitors was higher among the ambulatory patients. In a multivariate analysis, hospitalized patients were more likely to be receiving steroids, methotrexate or hydroxychloroquine. Two deaths were reported, neither of these patients were on biologics or JAK inhibitors. When compared to the general population in NY, age-related hospitalization was not increased among this patient population. Conclusion: Use of biologics in patients with autoimmune disease and COVID-19 does not seem to be a risk factor for worse outcomes. The COVID-19 Global Rheumatology Alliance has been created with a registry for patients with rheumatologic conditions and COVID-19, an effort led by faculty from UCSF and ZSFG.

4. How is remdesivir going to be available given the FDA changes?
Remdesivir was approved under Emergency Use Authorization on 5/1/2020 for IV administration to hospitalized COVID-19 patients, based on preliminary data from the ACTT-1 study. Per the EUA factsheet, recommended adult dosing is 10 days for critically ill patients (intubated/ECMO) and 5 days for all others, with the ability to extend to 10 days if no clinical improvement. Gilead has donated RDV to the US federal government which will coordinate the distribution. Per the distribution website, hospitals identified by the U.S. government as a recipient for donated remdesivir will be proactively contacted; to find out if your hospital has been designated to receive donated remdesivir, you can email [email protected] and provide facility name, ship to address with zip code, Health Industry Number and DEA number.

 

FRONTLINE: Interviews with Leaders Responding to the COVID-19 Epidemic .

An interview with Joe Derisi, PhD and Steve Miller, MD, PhD on the UCSF and Chan Zuckerberg BioHub collaboration to provide a rapid scale up of COVID-19 testing to UCSF and the Bay Area.

At the beginning of the epidemic, at what point do you recognize that you were going to need significant support to ramp up testing?

Dr. Miller: In late January/early February, we became aware of the urgent need to develop and implement COVID-19 testing, but FDA regulations essentially precluded laboratories from developing their own assays. Fortunately, on March 2 the regulations were modified to allow academic laboratories to pursue emergency use authorization. On March 9, we went live with a modified version of the CDC assay for COVID-19 RNA detection. Given the increasing spread it became apparent we would need high-throughput testing, and we began exploring all potential options. Normally, commercial test manufacturers would take the lead in doing this, but since these were taking time and we were seeing shortages of supplies and reagents, we started looking at options to convert research testing facilities and resources into clinical use.

How did you conceive of the idea of using the CZ BioHub for testing and what were some barriers to creating this partnership between UCSF and CZ Biohub?

Dr. DeRisi: The question was "how can we mobilize a huge, and highly trained workforce (our graduate students and postdocs) that otherwise would be forced to stay at home?" Originally, the idea was to engage in "research only" activities - testing that would not return a result back the patient. The fact that results would not be returned to patients was inherently dissatisfying, since those who were asymptomatic and possibly positive for the virus would not be informed of their status. The barriers to actual clinical testing are significant. In this case, a key barrier, having to do with personnel requirements, was suspended by an Executive Order by the Governor on March 12th. This immediately cleared the way for us to consider utilizing volunteers and space UCSF had been leasing next to the Biohub as a "pop up" CLIA lab expansion, together with the Clinical Lab here at UCSF. That effort began in earnest on March 12th. With the help of a huge number of volunteers and Biohub staff, the SARS-CoV-2 real time assay was validated and "go live" on March 20th. This incredible speed would not have been possible without a close partnership with Ed Thornborrow and Steve Miller!

What is the present testing capacity on what testing mechanisms are being used?

Dr. Miller: Currently the clinical laboratories at China Basin and the hospital sites have 5 different assay platforms running with a total potential throughput of > 1,000 samples per day. With the addition of the testing available at CZ Biohub, there is capacity to perform an additional 2,000 tests per day. We are overcoming several barriers to achieving that capacity, notably the shortage of swabs and tubes to collect samples, ability to handle and process large numbers of samples, and reporting of results through electronic means. Our partners have also had to ramp up their capacity to collect patient samples, and as all of this improves, we are increasing the utilization of that testing capacity. The Biohub's peak throughput for a 72-hour period was 3,245 samples tested during the COVID-19 Mission Study led by Diane Havlir.

How do you foresee this work enhancing the UCSF-CZBioHub partnership in the future?

Dr. Miller: We anticipate continuing to work closely together to support the clinical mission and perform research studies related to COVID-19 epidemiology, pathogenesis, tests development, and other areas. As commercial manufacturers and other laboratories build their testing capacity, there will be less of a need for Biohub to perform clinical testing, and eventually there will be an end declared to the COVID emergency, at which point the regulatory changes that enable clinical testing at Biohub will revert to their prior form. Currently, we are working to help our partners at other institutions and DPH to enable their testing, and much of this work can continue as needed. Over time, we will focus on other emerging infectious threats and use the experience gained to improve our ability to detect and respond to emerging agents.

Dr. DeRisi: Together with UCSF, the Biohub will dramatically ramp up our molecular epidemiology efforts, including full genome sequencing of positives from within San Francisco and throughout the State. In collaboration with CDPH, the Biohub and UCSF have a major role to play as a force to improve public health by providing surge testing capacity, advanced analytics, and genomics services.


--------------------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: April 30, 2020
EPIDEMIOLOGY

Local

As of today there are 46,506 confirmed COVID-19 cases and 1,873 deaths in California. In San Francisco there are 1,499 cases and 25 deaths. On Monday San Francisco and the other 6 Bay Area Counties announced the extension of shelter-in-place retrictions through the end of May.

National

The United States reached one million cases on Monday and as of today are 1.06 million cases and over 60,000 deaths. The epicenter in New York now reports over 300,000 confirmed cases, more than any other individual country, and over 23,000 deaths. However, in continued signs of improvement, new hospital admissions are down 70% and daily deaths down 50% from their peak earlier this month. Many states are starting to re-open their economies. Today we will highlight infection hotspots in food processing plants throughout the United States. Focal outbreaks have occurred at least 80 plants in 26 states, leading to over 4,400 infections and 18 deaths among workers and the death of an inspector for the USDA. The CDC and the Occupational Safety and Health Administration (OSHA) have issued new guidance for meat and poultry processing workers and employers advising increased distance between workers during work and break times, using physical barriers, improving ventilation, and increased handwashing/sanitizing stations. Yesterday President Trump issued an executive order compelling meat processing plants to stay open using the Defense Production Act and cited these plants as part of the critical infrastructure needed to keep people fed.

Global

Worldwide there are over 3.2 million reported cases of COVID-19 and 231,000 deaths as of this morning. In Spain, the hardest hit country behind the United States with over 230,000 reported infections, children are now allowed to play outside and adults will be able to exercise outside the home starting on May 2. France will start a gradual exit from lockdown on May 11, opening up shops and some business (but not bars or restaurants yet). Countries in Asia which initially oversaw effective responses now seeing a second wave. Singapore has seen a surge of coronavirus cases among migrant workers living in dormitories. As of Tuesday, coronavirus cases linked to migrant worker dormitories accounted for 88 percent of Singapore’s 14,446 cases. Japan was initially praised for its early and fast action to mitigate the outbreak, however after lifting restrictions the northern island of Hokkaido has seen an even larger second wave of infections and is now back in lockdown.

DAILY UPDATES

https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES

Remdesvir (RDV) Trifecta: There were three major updates from clinical trials of RDV released 4/29/2020.

Summary of studies:

ACTT-1 Study: Interim data was presented this fully enrolled, NIH-sponsored, randomized controlled trial evaluating 10 days of RDV vs. placebo in 1063 hospitalized patients. A preliminary DSMB analysis of about 400 patients found: a) 31% faster time to clinical recovery in those on RDV (11 vs 15 days, p <0.001) and b) a trend towards improved mortality with RDV, 8% vs. 11.6%, (p=0.059). Top-line analysis of the full data set is expected in several weeks.

RCT from China: A similarly designed RCT of RDV vs. placebo conducted in China found no difference in mortality, time to clinical recovery, or adverse events between arms; however, this study was underpowered as enrolled 237 out of 453 planned participants, due to declining COVID cases. Of note, there was no difference in quantitative PCR decline between arms; no viral cultures were done.

SIMPLE trial: This Gilead sponsored study, was an open label study of 5 vs 10 days of RDV in severe disease. They reported no difference in outcomes between arms, suggesting a shorter course of RDV may be possible, which would be welcome given current limitations in available RDV. Both the Chinese study and the SIMPLE trial reported a non-significant trend towards improvement in those treated with RDV within 10 days of symptom onset.

What do these studies tell us? ACTT-1 results are an important proof of concept that RDV can improve recovery from COVID-19 infection. We need more data to understand when and in whom RDV is most effective, what combination strategies are best, and what impact RDV is having on viral clearance.

Should we give RDV to all inpatients with COVID-19 if available? While these data are preliminary, they support use of RDV for hospitalized patients with COVID-19 infection, as more data is forthcoming. RDV has a good safety profile and is the only treatment thus far with a compelling signal for clinical improvement in a placebo controlled RCT.

Will the FDA allow easier access to RDV? RDV is not FDA approved and is only available through clinical trials or Expanded Access/compassionate use programs; an emergency use authorization (EUA) to expand pre-approval access in the US is anticipated.

Update on IL-6 receptor antibodies:

IL-6 blockers are an investigational strategy to dampen the heightened inflammatory response seen in COVID-19. A Phase 2/3 randomized controlled trial evaluated two different doses of the IL-6 receptor antibody sarulimab (“Kevzara”), vs placebo in hospitalized patients with severe disease (requiring oxygen) or critical disease (mechanical ventilation, high flow oxygen or ICU level care). Preliminary data from the Phase 2 portion indicated no difference overall in clinical outcome with IL-6R vs. placebo. In a subgroup analysis, those with severe disease did worse if assigned to sarulimab. However, those with critical disease assigned to the higher 400 mg sarulimab dose did better than placebo on a variety of metrics: clinical improvement (59% vs. 41%), off oxygen (58% vs 41%), persistent mechanical ventilation (9% vs 27%). As a result, the DSMB recommended that the Phase 3 study continue with only critically ill patients, at the higher dose of 400 mg vs. placebo. In an intriguing side note, a 4/27 twitter post states that positive data are forthcoming for another IL-6 blocker, tocilizumab; we look forward to the actual data! Conclusion: More information is needed to determine the role of IL-6 blockers—if any—for management of COVID-19. Definitive data to inform the safety and efficacy of these drugs is still needed. Use outside of a clinical trial setting is not recommended.

Is mass asymptomatic testing in nursing homes the key to controlling outbreaks?

In an article published in the NEJM last Friday by Arons M et al., the CDC reports on an outbreak of COVID-19 in a skilled nursing facility (SNF) in Washington State. Residents of the SNF were then offered two facility-wide point prevalence screenings for COVID-19 by RT-PCR of nasopharyngeal (NP) swabs a week apart, accompanied by symptom recall. Symptoms were classified into typical (fever, cough, shortness of breath), atypical, and none. Among 76 residents in the point-prevalence surveys, 48 (63%) had positive PCR results, with 27 (56%) essentially asymptomatic, although 24/27 (89%) subsequently developed symptoms, so were reclassified as pre-symptomatic. Quantitative viral loads were similarly high among those who were symptomatic, pre-symptomatic (with viable virus demonstrated by culture 1-6 days prior to symptom development) and those who remained asymptomatic. The mortality from COVID-19 in this setting was high; among 57 residents who tested positive, 26% died. Conclusion: More than half of SNF residents in a mass screening campaign were pre-symptomatic/asymptomatic and viral shedding was detected, at high concentrations, even prior to symptom onset. Effective prevention in SNFs (and other congregate settings like jails, homeless shelter, hospital inpatients, and health care workers) will likely require periodic asymptomatic mass COVID-19 testing to control spread.


FAQ

1. Should health care workers (HCWs) get universal COVID-19 screening?
It is not yet clear whether asymptomatic HCWs should get universal COVID-19 testing by RT-PCR in all settings. This process will likely involve serial testing (e.g. every 1 – 4 weeks), with self-collected nasal swabs being one option. Universal testing would provide important information about infection prevalence and could potentially decrease spread from asymptomatic or pre-symptomatic HCWs to their patients and co-workers. However, it is not clear how much this will add to other measures to combat COVID-19 spread, particularly in communities where the prevalence in HCWs is very low. We support universal testing in high-risk settings, such as skilled nursing facilities, as staff-to-patient and staff-to-staff transmission are well documented, and patient mortality is high. Testing HCWs for COVID-19 using serology should be limited to epidemiologic surveillance and research at this time, since these tests cannot yet be used for decisions regarding individual HCWs.

2. Could saliva be an effective testing method for the diagnosis of COVID-19?
A new study, not yet peer reviewed, suggests that saliva testing for SARS-CoV-2 may have equal or better sensitivity compared to nasopharyngeal (NP) swab sampling. The study evaluated 44 inpatients with COVID-19, 28 of whom had matched NP swab and saliva samples. Saliva was self-collected by patients in sterile urine cups. While test positivity did not differ between sample types, SARS-CoV-2 viral load was consistently higher from saliva. In a subset of 12 patients with longitudinal sampling, saliva provided more consistent viral detection with less temporal variability in test positivity. Conclusion: Patient-collected saliva may offer a convenient method for self-collection that reduces healthcare worker exposures, allow for more judicious use of PPE, and provide a means for testing amidst a nationwide swab shortage. More studies are needed to confirm its utility.

3. What is the utility of chest CT scan in the diagnosis and care of patients with COVID-19?
The role of chest CT for diagnosis and care of COVID-19 remains unclear. Unlike RT-PCR, which tests for the presence of the virus itself, CT merely shows evidence of infection or lung injury and cannot be used as a confirmatory test for COVID-19. Currently we use CT mostly as a problem-solving tool in either a) symptomatic patients who have had multiple negative RT-PCR tests (is there some other lung disease we can diagnose?) or b) confirmed COVID-19 patients with fear of a complication (e.g. pulmonary embolism, superimposed bacterial infection). Some centers may consider CT as a “screening” tool but due to the lack of specificity this will likely result in many more false than true positives, especially in a region of relatively low prevalence.

4.Is SARS-CoV-2 causing distinct systemic inflammatory syndromes in children?
While children continue to suffer a lower burden of severe respiratory disease than adults globally, there is rising concern about distinct inflammatory manifestations of COVID-19. Reports of a toxic shock and Kawasaki Disease (KD)-like syndromes in children in the UK and Italy prompted this alert from the Pediatric Intensive Care Society in the UK. Three cases (6 months to 8 years old) in New York City were reported to have cardiac and GI involvement. These add to an already complex picture of cytokine release and thromboembolic inflammatory syndromes seen in adults. Providers should consider SARS-CoV-2 testing in children with toxic shock and KD-like presentations. However, more investigation will be needed to confirm this possible link.


FRONTLINE: Interviews with Leaders Responding to the COVID-19 Epidemic

This week we interviewed Dr. Lisa Winston—the Hospital Epidemiologist for Zuckerberg San Francisco General and Trauma Center.

When did you first recognize that an epidemic was a real possibility for us in San Francisco and what were the actions you recommended to ZSFG leadership?

During the fourth week of February, it became clear that community transmission was occurring in Washington and California in the absence of travel or contact with a known case. Some of the first issues that we had to address were (1) determine isolation precautions, (2) assess our PPE supply, and (3) identify a screening mechanism for patients coming to our healthcare settings. Patient screening was originally focused on symptoms and travel. Testing was very restricted, and we wanted to make sure we could test patients who were eligible.

What have been some of your biggest challenges in this role since the start of the COVID pandemic?

How to keep healthcare workers (HCWs) safe. Early on, we had little information about transmission mechanisms. Frontline HCWs were afraid, and we were afraid for them. Also, all plans we made were constantly changing. Every day, we were rewriting policies and procedures as we had more data and guidance. The pace of change was extraordinary.

What have been some of your biggest success in this role since start of the COVID pandemic?

None of the success have been mine alone and we have worked with amazing multidisciplinary teams. There has been an enormous sense of collegiality and the feeling that everyone working to find solutions together. SF DPH has also worked closely with us, and we partnered with them to help make the right decisions about shelter in place and other strategies to flatten the curve. Universal masking was controversial early on and our resources were limited but we worked with SF DPH leadership to help make that happen. We are very grateful to UCSF Medical Center for providing ZSFG with masks and other support.

How do you think this pandemic has changed the way we will approach infection prevention in the US health care system moving forward?

While I worry that our memories are short, I am optimistic we will be more prepared for future events with respect to the PPE supply chain and emergency reserves. Though the initial roll out of testing was centralized and slow, collaboration between academia and industry allowed the development of high throughput testing to occur at a faster pace than we have ever seen previously. I think we will be more prepared for widespread testing for the next novel pathogen.

 

UCSF Hospital Epidemiology and Infection Prevention COVID-19 webpage: https://infectioncontrol.ucsfmedicalcenter.org/ucsf-health-covid-19-resources

San Francisco DPH link: https://www.sfcdcp.org/infectious-diseases-a-to-z/coronavirus-2019-novel-coronavirus/

------------------------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: April 24, 2020
EPIDEMIOLOGY

Local

As of today, there are 40,812 confirmed COVID-19 cases and 1594 deaths in California. Today, California Governor Gavin Newsom announced a new program for local governments to provide restaurant delivery service to older Californians. In San Francisco, there are 1340 confirmed COVID-19 cases and 22 deaths. This week, San Francisco increased testing capacity for all essential workers and symptomatic residents. This weekend, UCSF investigators, the San Francisco DPH, and community partners will launch amassive testing project in the Mission district, one of the hardest hit neighborhoods in the municipality of San Francisco.

National

There are now over 924,402 cases reported and 52,168 deaths in the United States. New York State remains the epicenter of the epidemic, both in the United States and worldwide with New York continuing to report more coronavirus cases than any other country worldwide. New York State has 263,000 cases and 15,740 deaths to date. An early antibody testing project in New York City suggested that 20% of residents may have now had exposure to the virus, which would make the case fatality rate much lower than previously calculated. Today, we highlight the jail and prison system in the United States, where there have been many COVID-19 outbreaks. Earlier this week, a prison in Marion, Ohio, became the largest-known source of coronavirus cases in the country, with more than 1,800 inmates testing positive (with two inmates and one staff member now dead from the infection) during a mass testing campaign. In response, many jails around the country have initiated mass testing campaigns and have released prisoners to thin the population.

Global

There are currently 2,827,981 million cases of COVID-19 and 197,074 deaths reported around the world. The US continues to lead the world in the total numbers of infections. In brief updates from around the other regions, countries in Latin America are increasingly affected with Ecuador and Panama leading the region in terms of both infections and deaths, although both are likely underreported. Germany has opened up cautiously, but continue to be concerned that long-standing social distancing will be necessary. Coronavirus cases are increasing across the African continent, although testing capacity remains limited, and there is increasing concern about concomitant hunger and the rise of other infectious diseases-related deaths, such as from malaria, with the pandemic. Coronavirus cases are rising in Singapore, a region in which they were previously controlled, likely due to neglect of marginalized communities and migrant workers. And, although mortality rates in India are rising from coronavirus, the lockdown continues and the spread has been less than anticipated from earlier estimates.


UP TO THE MINUTE DISPATCHES

How do antibody-based tests perform in the lab or at the point-of-care for diagnosis of COVID-19?

Identification of viral nucleic acid via PCR has been the primary method for diagnosing COVID-19, but there is increasing interest in the use of antibody-based testing to assess exposure. Researchers in the UK (pre-print) evaluated a panel of antibody-based COVID-19 tests – a novel Enzyme-linked immunosorbent assay (ELISA) in the lab and 9 commercially-developed Lateral-Flow Assays (LFAs) to be used at the point of care. Serum of patients diagnosed with COVID-19 served as the positive controls and serum of patients in UK before December 2019 served as negative controls. ELISA identified COVID-19 IgM or IgG antibodies in 34/40 cases and 0/50 controls, yielding a sensitivity and specificity of 85% and 100%. The sensitivity of ELISA IgG improved to 100% when restricted to patients exhibiting symptoms for ≥10 days. No patients were IgM positive but IgG negative by ELISA. LFA had a sensitivity of 55-70% with a specificity of 95-100%. IgG titers rose for 3 weeks post symptom onset and began to fall by 8 weeks, but remained above the detection threshold. This small study was limited by small sample sizes and has not yet been peer reviewed. Bottom line: This study suggests ELISA is best used to identify COVID-19 exposure 10 or more days following symptoms. Despite being available at point of care, currently available LFAs have variable sensitivity. Whether a positive antibody test to COVID-19 by one of these tests correlates with immunity is not known.


Gaining insight into ARDS mechanisms in COVID-19:

Two recent papers seek to uncover the mechanisms behind the development of acute respiratory distress syndrome (ARDS) in a subset of COVID-19 patients often >7 days after onset of symptoms. Blanco-Mello et al compared the transcriptional response of SARS-CoV-2 to other respiratory viruses including Influenza A in a variety of immortalized tissue culture cells, infection of primary airways cells, in vivo samples derived from SARS-CoV-2 infected ferrets, and finally from post-mortem samples collected from the lungs of humans who died with SARS-CoV-2 or normal lung biopsies. These studies, together with serum profiling in the ferret model, revealed a unique and inappropriate inflammatory response characterized by low levels of type I and type III interferons, elevated chemokines, and elevated IL-6 expression. Giamarellos-Bourboulis et al compared 28 patients with COVID-19 and ARDS to 26 patients COVID-19 without ARDS. Control groups included patients with 2009 H1N1 Influenza A and patients with community acquired pneumonia-associated sepsis. Some patients with COVID-19 associated-ARDS had macrophage activation syndrome, and most had immune dysregulation characterized by low expression of HLA-DR on a subset of monocytes (CD14 positive) that is triggered by monocyte hyperactivation, excessive IL-6 release, and profound lymphopenia. This pattern is distinct from ARDS-associated bacterial sepsis or 2009 H1N1 influenza. Together, these studies suggest that COVID-19 associated ARDS may be characterized by both a reduced innate immune response coupled with an exaggerated inflammatory cytokine response.


FAQ

1. Is hepatic injury common in patients with COVID-19?
Elevated transaminases (AST and/or ALT) are relatively common in COVID-19. Multiple studies from China showed that transaminases were elevated in up to 35% of patients with COVID-19. Two recent large studies from New York City show that this number may be even higher (up to 39% for ALT and 58% for ALT). One study form China showed that transaminase elevations were mild in the majority of cases, although more significant elevations were associated with a higher risk of severe COVID-19 disease. It is not clear if liver injury is related to direct infection in the hepatobiliary system versus indirect effects of inflammation. Conclusion: Mild transaminitis is common in patients with COVID; more significant elevations are unusual but associated with more severe disease.

2. What do we know seasonal spread of common human coronaviruses and how might that influence our predictions of future spread of COVID-19 in future seasons?
Prior outbreaks of animal coronaviruses (SARS-CoV, MERS-CoV) did not result in prolonged and sustained human spread as we are seeing with SARS-CoV-2. It is possible that spread of SARS-CoV-2 may ultimately follow a similar pattern as the four human coronaviruses (OC43, 229E, HKU1, NL63). A longitudinal study of respiratory illnesses in Michigan explored the transmission dynamics of human coronaviruses. Spread began in December, with a peak incidence in January/February followed by a decline in March. Transmission in June to September represented only 2.5% of total cases. Household transmission was confirmed in a quarter of cases and children < 5 years had the most disease. Conclusion: It is unknown if SARS-CoV-2 will follow the same seasonal transmission pattern as common human coronaviruses and we should prepare for that. However, this is a new virus with its own unique transmissibility, and only time will tell.

3. Are patients on ACE-Inhibitors (ACE-I) or Angiotensin-Receptor Blockers (ARBs) at increased risk for severe COVID-19?
As mentioned in an earlier digest, SARS-CoV-2 binds to cells via the ACE-II receptor, therefore there has been speculation that the use of an ACE-Is or ARBs might impact the course of disease in COVID-19. Researchers at a large hospital in Wuhan, China, performed a retrospective study of 1178 patients admitted with COVID-19 between January-March 2020. 362 (31%) admitted patients had hypertension with an in-hospital mortality rate of 21% (vs. 6.5% non-hypertension). Among patients with hypertension on ACE-I/ARBs, there was no difference in rates of severe/non-severe disease nor any difference in mortality, when compared to those with hypertension not on ACE-I/ARBs. Differences were not seen between ACE-Is and ARBs either. Conclusion: Use of ACE-I/ARBs does not seem to increase risk for poor outcomes in patients with hypertension and COVID-19. This data supports present guidelines that patients with ACE-I/ARBs should continue treatment during COVID-19 epidemic.


FRONTLINE: Interviews with Leaders Responding to the COVID-19 Epidemic:

This week we interviewed Dr. Becky Martinez—an anesthesiologist on the front line at New York Presbyterian- Columbia University Irving Medical Center in New York City. We asked her about the Obstetric Intensive Care Unit “OBICU” (O-BIK-U). Editorial disclosure: She is Diane Havlir’s daughter and starting critical care fellowship at UCSF in the summer.

Why did the OBICU start? Let me start a step back from that. In March, one of our OB patients requiring intrapartum intubation unexpectedly tested COVID positive. The number of exposures was enormous, and this served as a wake-up call for us. We tested 210 pregnant women presenting for delivery and to our surprise found 13.7 % women PCR positive, 88% of which had no symptoms. As a result, on March 22, we starting COVID screening all labor and delivery patients. The practice of care for OB patients requiring intensive care at that time was to transfer them to the main medical or surgical ICU. It was imminently clear that capacity in these units was going to be a challenge so we decided to establish an OB ICU for any peripartum patient with critical care needs on labor ward of the hospital.

How does the OBICU work? The unit is led by OB anesthesia. We have a multi-disciplinary team that rounds multiple times a day and includes OB physicians, nurses, pharmacists and ancillary services. Although a family member can be present at delivery, only medical personnel are allowed in the unit. We still have over 250 patients with a primary diagnosis of COVID19 in various ICUs at our hospital. We are in communication and always sharing updates and insights. Every day we learn something new.

What are some of the complications you are seeing? We are seeing most of the same complications in the OBICU as we find in the other ICUs—hypoxia, hypotension, and high fevers. We are aggressively managing respiratory distress and have avoided invasive ventilation to date. Clots are a big concern, in particular because of the increased susceptibility of our OB population. We have not seen a dramatic increase in pre-eclampsia. I am happy to say we have not had any deaths.

Any final comments? I am proud to be a member of the medical community. Any support we can give each other during this time, no matter how small or big can really make a difference. One night when I was on call, a dinner food delivery arrived from the UCSF residents. You should have seen the smile on everyone’s faces! Thank you so much.

UCSF Hospital Epidemiology and Infection Prevention COVID-19 webpage: https://infectioncontrol.ucsfmedicalcenter.org/ucsf-health-covid-19-resources

San Francisco DPH link: https://www.sfcdcp.org/infectious-diseases-a-to-z/coronavirus-2019-novel-coronavirus/

----------------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: April 21, 2020
EPIDEMIOLOGY

Local

As of today there are 34,001 confirmed COVID-19 cases and 1,227 deaths in California. In San Francisco there are 1,231 cases and 20 deaths. Across the UCSF/ZSFG/VA system, 41 patients with COVID-19 are hospitalized. Data on infection rates by zip code released on Monday by the San Francisco Department of Public Health show neighborhoods which experience economic and health disparities are the hardest hit by COVID-19, including SOMA where the MSC South Homeless shelter is located, the Mission District with a high proportion of Latinx residents, and Bayview-Hunters Point.

National

There are now over 820,000 confirmed cases and 43,921 deaths in the United States. Over half of the deaths are in New York and New Jersey. On Monday, NY Governor Cuomo, announced that 478 people had died in New York, the first time the daily death toll has been below 500 since April 2. There are currently over 27,000 cases and 800 deaths in Florida, which was one of the later states to issue a stay-at-home order on April 3. Modeling data project that the peak deaths had occurred on April 2, when 77 deaths occurred, and the peak hospital usage occurred on April 14. Beaches in Duval County and St. Johns County re-opened over the weekend. However, hotspots of infections are ongoing throughout the state, particularly in nursing homes. Currently over a quarter of all deaths statewide are among residents of nursing homes and long-term care facilities.

Global

Worldwide there are now over 2.5 million cases of COVID-19 and 175,812 deaths reported in 185 countries and regions. The United States continues to lead the world in number of cases, with almost 4 times as many cases as Spain, which has 200,210 cases and the second-most number of reported cases globally. Turkey reached 90,000 cases and 2,140 deaths on Monday, but the number of deaths in Istanbul alone was over 2,100 greater during the last month than expected based on historical data suggesting the outbreak is much wider spread than the official statistics suggest.
 

DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES
Remdesivir ameliorates COVID-19 in a macaque model of acute respiratory infection:

Researchers developed a macaque model of respiratory SARS-CoV-2 infection that recapitulates important aspects of human infections. Investigators from the NIH studied the effect of remdesivir treatment starting near the peak of viral replication. Remdesivir was administered with a loading dose 12 hours after respiratory and ocular inoculation, followed by a daily IV dose for 6 days, similar to protocols for humans. At 12 hours after the initial treatment, the remdesivir-treated monkeys had fewer symptoms and less radiologic evidence of pneumonia compared to the control-treated monkeys, a trend which continued during the 7-day study. The remdesivir-treated monkeys had lower viral loads and titers of infectious virus in the lungs and less damage, but interestingly, drug treatment did not decrease viral shedding in the nose, throat, or rectal swabs. While the Gilead remdesivir clinical trial results are not yet known, this primate model suggests that early treatment of COVID-19 with remdesivir may prevent progression to severe pneumonia and sterilize viral cultures in the upper and lower airways. Upper airway viral shedding was still detectable; however, the significance of PCR detectable virus in the absence of viral growth is not known.
 

What proportion of Santa Clara County residents have been infected with COVID-19?

True prevalence of people who have ever been infected with COVID-19 in different US communities is unknown. Researchers sought to determine the prevalence COVID-19 infection antibodies among Santa Clara County residents and recruited adults and their children via targeted Facebook ads. Using drive-through testing sites, participants underwent serologic testing using a point-of-care test on a fingerstick blood sample to detect the presence of antibodies against COVID-19 infection (IgM [recent infection] and/or IgG [more distant infection]). The researchers reported an independent validation of the assay and estimated its sensitivity and specificity to be 80.3% (95%CI: 72.1-87.0) and 99.5% (95%CI: 98.3-99.9%), respectively. Among 2,718 adults and 612 children tested between April 3rd and 4th, the total number who had detectable antibodies against COVID-19 infection was 50/3,330 for an unadjusted prevalence of 1.5% (95%CI: 1.1-2.0). After adjusting for local population and test performance characteristics, the revised prevalence was estimated to be 2.5-4.2%; the estimated number of cases (48,000-81,000) was 50-85 times higher than the number of confirmed cases to-date. There are a number of methodologic concerns scientists have expressed related to the sampling strategy, statistical analyses, and the true performance characteristics of the antibody test utilized. We can probably safely say from this study that the true number people ever infected with COVID-19 is likely much higher than “reported cases” which have been skewed by “symptom based” testing requirements. We can also say that overall prevalence in this sample is relatively low.


FAQ

1. What is known about COVID-19 in patients with cancer?
Patients with cancer are more susceptible to infections given anticancer treatment and the disease itself. In one retrospective study from England, patients with cancer admitted for COVID-19 had a similar mortality rate to those without cancer (6%). However, a nationwide analysis of COVID-19 patients in China of patients found that those with cancer had higher rates of infection and those receiving chemotherapy or recent cancer-related surgery were more likely to have severe disease. Another study found a strong association between recent of anti-cancer therapy (chemotherapy, radiotherapy, targeted therapy, and/or immunomodulatory therapy) within 14 days and COVID-19 complications. Conclusion: Patients with cancer, particularly those receiving anti-cancer treatment, may be at higher risk for severe COVID-19. More work is needed to understand which cancer therapies pose most risk of poor COVID-19 outcomes and how this risk can be mitigated.

2. Are there cutaneous manifestations of COVID-19?
We are unsure. Cutaneous findings were rarely reported (<1%) in large studies from China. A recent study from Italy found that 18 of 88 (20%) hospitalized patients had skin findings: erythematous rash (78%), diffuse urticaria (17%), and vesicles resembling varicella (5%). Another report from Italy described 22 patients with papulovesicular eruption resembling varicella. In both reports, the trunk was most commonly involved, and itching was uncommon. Individual case reports of patients with COVID-19 and a diffuse erythematous rash, diffuse urticaria, petechial rash, and violaceous lesions in the toes have been described as well. The American Academy of Dermatology has launched a COVID-19 dermatology registry to better understand the cutaneous manifestations of COVID-19. Conclusion: Cutaneous findings with COVID-19 seem uncommon and work is underway to better characterize dermatologic manifestations.

3. What does a negative RT-PCR test mean?
The negative predictive value [(true negatives)/(true negatives + false negatives)] allows us to understand the significance of a negative test, which differs depending on the prevalence of disease in the population being tested. In asymptomatic patients, the prevalence of SARS-CoV-2 in the Bay Area and in the U.S. is not yet known. If we assume that the prevalence in the Bay Area is 1% and the sensitivity/specificity of a NP swab test is estimated at 75%/98%, then the negative predictive value of the test is 99.7%. In symptomatic patients or those with known exposures, the prevalence rate may be 10% or higher. In this case, the negative predictive value would be lower at 97.2%. Conclusion: When interpreting a negative test one must take into account both the sensitivity of the test and the prevalence of disease.

 

Further questions, please feel free to reach out.

UCSF Hospital Epidemiology and Infection Prevention COVID-19 webpage: https://infectioncontrol.ucsfmedicalcenter.org/ucsf-health-covid-19-resources

-----------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: April 17, 2020
EPIDEMIOLOGY

Local

As of today, there are 28,899 confirmed COVID-19 cases and 1,021 deaths in California. Today, California Governor Gavin Newsom announced the creation of a 80-member task force to advise on reopening the state, but did not give any dates or deadlines for reopening. In San Francisco, there are 1,058 confirmed COVID-19 cases and 20 deaths. An update on the MSC South Shelter outbreak is provided below in the interview of Dr. Liz Imbert from the containment team. Today, Mayor London Breed announced a new mandate that San Franciscans will be required to wear face coverings while running essential errands, seeking healthcare, waiting for or taking transit. People who are exercising outdoors with proper social distancing precautions (running, biking, etc.) are not required to wear face coverings but should carry one with them.

National

There are now over 708,297 cases reported and 36,959 deaths in the United States. New York State remains the epicenter of the epidemic, both in the United States and worldwide with New York continuing to report more coronavirus cases than any other country worldwide. New York State has 222,284 cases and 7844 deaths to date. Rates of hospitalizations and infections have slowed and Governor Cuomo announced yesterday that the New York State shutdown will be extended to May 15th. On Wednesday, the NY Governor also mandated the wearing of face masks in public for all New York residents. Today we make note of the eight states in the United States where the governors have resisted issuing statewide “shut down” orders despite the ongoing U.S. coronavirus pandemic: Arkansas, Nebraska, North Dakota, Oklahoma, South Dakota, South Carolina, Utah, and Wyoming. Over the past week, Oklahoma saw a 53% increase in cases, Arkansas saw a 60% jump in cases, and Nebraska reported a 74% increase in cases. South Dakota saw an alarming 205% increase in coronavirus cases. Today in the national scene, President Trump called for “liberation” of states where protestors gathered (mainly without masks) to protest stay-at-home restrictions, including Michigan and Minnesota. President Trump this week also halted U.S. funding to the World Health Organization, with Ireland deciding to quadruple funding to the international public health organization as a result.

Global

There are currently 2,248,029 million cases of COVID-19 and 154,108 deaths reported around the world. The US continues to lead the world in the total numbers of infections. Germany has been reporting falling numbers of infections, deaths, hospitalizations and ICU admissions and has announced a plan to reopen the country, stating a statistic that, on average, each infected person is spreading the virus to 0.7 other people at this point (with an Ro of >2 reported as the number predicting exponential growth). Chancellor Angela Merkel announced this week the first steps to ease restrictions, allowing some stores to reopen this coming Monday and high school students to return to classrooms to prepare for or take exams. Yesterday came with dire warnings from the United Nations on the impact of the COVID-19 pandemic on children. While children are largely spared severe disease from SARS-CoV-2, the United Nations has warned that the social and economic fallout of the pandemic “risk being catastrophic and amongst the most lasting consequences” for children. As schools remain closed, families lose income and the ability to procure food. Moreover, the health needs of children go unmet, with the threat of thousand or even millions of children worldwide being plunged into greater poverty as a result of the pandemic.
 

DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES
Iceland conducts widespread population screening resulting in early response and containment of COVID-19
Iceland conducted an extensive testing campaign which included both targeted testing (symptoms plus travel risk) and population screening (random invitations) to 13,080 individuals. In this study, ~7% of Iceland’s population (n=24,562) was tested via these two strategies. With targeted testing, 13% tested positive with 0.7% testing positive in the general population, a proportion which remained stable 20 days later. In the population-screening group, 0/848 children <10 years of age tested positive vs. 100/12,232 persons (0.8%) among those ≥10 years of age. 43% of those who tested via population screening were asymptomatic. Travel and work contacts were identified as a key risk factor early in the epidemic, while exposure to infected family members became most important later in the epidemic. After viral sequence analysis, later cases in Iceland were found to represent new introductions rather than persistent community spread. Conclusions: A widespread testing and contact tracing campaign following by isolation helped to curb the epidemic in Iceland. Children were largely spared from infection and asymptomatic infection was common.

COVID-19 among US Healthcare Workers

This week, several studies highlight COVID-19 among US healthcare workers (HCWs). The first study examines 121 HCWs in unknowingly exposed to a COVID-19 patient during a 4-day admission in mid-February Northern California hospital. The patient was on standard precautions and underwent multiple aerosol-generating procedures (AGPs). Of 121 exposed HCWs, 43 (35.5%) developed potential COVID-19 symptoms but only 3 (2.5%) had a positive COVID-19 PCR result. Risk factors for acquisition were prolonged patient contact and exposure to AGPs. The second study examined all COVID-19 cases reported to the CDC between February 12 and April 9, 2020. They identified 9,282 HCWs with COVID-19 accounting for at least 2.9% of all cases in the US. Healthcare occupational status was only available for 15.6% of all COVID-19 cases suggesting that this represents a substantial underestimation. Only 10% of HCW with COVID-19 required hospitalization and amongst those 184 (8-10%) required ICU admission and 27 (0.3%-0.6%) died. A recentreport found that as of April 15, 2020, there have been 2,789 confirmed COVID-19 cases among HCWs in California.
Conclusion: HCWs are at increased risk for acquisition of COVID-19 infection and it remains crucial to make all possible efforts to ensure their health and safety.


FAQ

1. What neurological manifestations are seen in patients with COVID-19?
Several reports were published this week on neurological findings in patients with COVID-19. A Chinese study described 214 patients and found that 36.4% had neurologic manifestations which included dizziness (16.8%), headache (13.1%), myopathy (10.7%), impaired consciousness (7.5%), taste impairment (5.6%), smell impairment (5.1%), acute stroke (2.8%), and seizure (0.5%). A second French study of 58 ICU patients found agitation (69%), corticospinal tract signs such as clonus (67%), and confusion (65%). 13 patients had MRIs which revealed leptomeningeal enhancement in 62% and acute stroke in 15%. 7 patients had an LP – all were normal and negative for COVID-19 by PCR.Conclusion: Neurologic finding are common in patients with severe COVID-19. Possible mechanisms include hypercoagulability, inflammation, exacerbation of underlying vascular comorbidities, or direct CNS infection. However, only a single case of meningoencephalitis with a positive CSF PCR has been published to date.

2. Where do we stand in the development of a COVID-19 vaccine?
In response to the global COVID-19 pandemic, the global vaccine R&D effort has moved at an unprecedented speed. Just over two months after the genetic sequence of SARS-CoV-2 was published (Jan 11), the first vaccine candidate entered human clinical testing (mRNA-1273, Moderna). As of last week, there are 78 confirmed exploratory vaccine candidates. Most of the vaccine candidates aim to induce neutralizing antibodies to the spike (S) protein which mediates attachment of the virus to the host cell and facilitates cell entry. A diverse array of technologies is being used to develop candidates. 7 have moved into clinical development, 5 of which have early phase clinical trials, which have opened for recruitment. Conclusion: Based on the scale and speed at which vaccine development is proceeding, there is an indication that a vaccine could be available by early 2021 under emergency use protocols.


FRONTLINE: Interviews with Leaders Responding to the COVID-19 Epidemic
From the editors: We are starting a new feature of conversations with faculty working on the front line.

Dr. Elizabeth Imbert was seconded to temporarily work for the Department of Public Health to assist in their efforts at our City’s Shelters and is our featured guest interviewee today.
 

What is your role title at UCSF/ZSFG and how did you start working full time for the SFDPH during the COVID-19 epidemic?

I am an Assistant Professor in the Division of HIV, ID and Global Medicine at ZSFG and the Director of the POP-UP Program at Ward 86, a program that aims to reduce health inequities among people living with HIV who experience homelessness and unstable housing. Two weeks ago, I started to work in the San Francisco Department of Public Health (SFPDH) Departmental Operations Centers (DOC) Containment Branch on the shelter health response
Can you describe the outbreak of COVID-19 at the homeless shelter in San Francisco?

From the time SFDPH opened its emergency operations on Jan. 21, protecting vulnerable populations including people experiencing homelessness (PEH) and preparing our response has been one of the top priorities of the department. When the first two cases were confirmed at Multi-Service Center (MSC) South, which is San Francisco's largest shelter, we were able to immediately launch contact tracing investigations and test symptomatic patients. We quickly found several cases in close proximity in the shelter, at which point we decided to deploy mass testing and offer all patients an isolation and quarantine hotel room. Of the 225 residents and 65 staff at risk for infection, we tested 147 residents and 62 staff. 65% (95/147) of residents and 16% (10/62) tested positive for COVID-19. We learned two important things: the prevalence rate was extremely high, and most of the people testing positive did not yet have symptoms.

What strategies are you taking to provide care for and help prevent further spread and mitigate morbidity and mortality of COVID-19 in patients experiencing homelessness?

The entire city is working together to protect the most vulnerable, including PEH, on a population level. DPH is working with Department of Homelessness and Supportive Housing (HSH) on strategies to improve social distancing, implement universal masking, enact heightened infection control practices and train shelter staff to do symptom screening. DPH in partnership with the Human Services Agency has created isolation and quarantine hotels, and DPH is developing medical shelters and recovery centers with wraparound services for patients. DPH and UCSF are trying every approach to expand testing to this population. Other departments have leased hotel rooms and are offering these to PEH who are over 60 or have co-morbidities. The City is adding toilets and hand-washing stations. The COVID-19 situation is rapidly evolving and we are learning every day and making progress. We are united in our commitment to protect those most in need.

Further questions, please feel free to reach out.

UCSF Hospital Epidemiology and Infection Prevention COVID-19 webpage: https://infectioncontrol.ucsfmedicalcenter.org/ucsf-health-covid-19-resources

----------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: April 14, 2020
EPIDEMIOLOGY

Local

As of today there are 24,329 confirmed COVID-19 cases and 725 deaths in California. In San Francisco, there are 987 cases and 15 deaths. Across the UCSF/ZSFG/VA system, 49 patients with COVID-19 are hospitalized (18 ICU). On Friday the city announced an outbreak at the MSC South homeless shelter and by the end of the weekend 92 people, 82 residents and 10 staff members had tested positive.

National

There are now over 600,000 confirmed cases and 25,000 deaths in the United States. New York, which has been a national and global epicenter, may have reached its peak with decreases in the number of hospitalized and intubated patients over the last few days and a steady number of deaths since the end of last week. The number of daily deaths across the United States has also decreased daily, since a peak of 2,108 deaths was reported on April 10. Today we will highlight South Dakota, which remains one of the few states to resist a state-wide shelter-in-place order. Last week a meat processing plant in Sioux Falls announced an outbreak at its facility which has now increased to more than 300 confirmed cases and over a third of the state’s reported cases and one of the county’s largest clusters of infections linked to a single facility. Smithfield Foods, which produces more than 5% of the nation’s pork announced shutdown on Sunday due to the rate of COVID-19 infections among employees. While the total case count in rural America is lower, there is concern the number of cases may quickly overwhelm health resources as more than half of counties in America, where more than 7 million people over the age of 60 live, have no hospital ICU beds.

Global

Worldwide there are now over 1.9 million cases of COVID-19 and 121,726 deaths reported in 185 countries. Spain, Italy, France and Germany are still the only other countries reporting over 100,000 infections. Russia, which had previously stated COVID-19 infections were “under control,” now acknowledges the pandemic is spreading rapidly and straining the healthcare system. On Monday, Russia reported more than 2,700 new cases and 22 new deaths bringing the total number of infections to 21,102 and 170 deaths.

PUBLIC HEALTH ACTION

Governors on the East and West coasts of the United States formed coalitions to coordinate eventual easing of COVID-19 restrictions and re-opening of the economy. California Governor Gavin Newsom announced a “West Coast reopen pact” between California, Washington and Oregon. In the Northeast, New York, New Jersey, Connecticut, Pennsylvania, Delaware, Rhode Island, and Massachussetts have formed a multi-state regional effort to cooperate on re-opening. Italy and Spain, who have been on lockdown since March 9 and 15 respectively, are slowly re-opening, while France has announced the country’s strict lockdown will be extended until May 11.

DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES
Outcomes from compassionate use of remdesivir in patients with severe COVID-19

Remdesivir is an intravenous antiviral with broad activity against several RNA viruses. In vitro and animal model studies were encouraging of its efficacy against COVID-19. This first human study using remdesivir for treatment of patients with COVID-19 is a description of 53 patients who received it for compassionate use. At baseline, the patients had varying degree of disease severity—34 (64%) requiring invasive ventilation which included 4 patients on ECMO, 17 (32%) requiring non-invasive oxygen support, and 2 (4%) not requiring oxygen. Among those requiring invasive ventilation upon enrollment, 6 died (18%), 9 remained on invasive ventilation (26%), and 19 clinically improved (56%) after a median 18 days of follow-up. Data on viral load change was not provided. 4 patients discontinued remdesivir prematurely—1 with worsening pre-existing renal failure, 1 with multiple organ failure, and 2 with elevated aminotransferases, including one patient with a maculopapular rash. Conclusion: This non-randomized study does little to inform our understanding of the efficacy of remdesivir treatment for COVID-19. Results of remdesivir randomized control trials are eagerly awaited.

New York City cases of COVID-19 likely originated from Europe
We previously reported on how COVID-19 was introduced to California. This study reports the genome sequencing and likely origins of 84 SARS-CoV-2 isolates in New York City (NYC) from patients who sought medical care at the Mt. Sinai Health System between February 29th and March 18th 2020. They revealed multiple, independent isolated introductions from Europe (Italy, Spain, France, Finland, UK) and some from US and Canada during the first 2 weeks of March. Evidence for community transmission is also provided as suggested by clusters of related viruses found in patients living in different neighborhoods of the city. Cases with a history of travel exposure showed no further evidence of community transmission, supporting efficacy of self-quarantine measure. Conclusion: Like in California, introduction of COVID-19 into NYC occurred from multiple independent events, not a single event with mass spread. Early introduction of COVID-19 in NYC was predominately from travel to Europe.

Studies demonstrate safety concerns when chloroquine and hydroxychloroquine are given for COVID-19
Chloroquine and hydroxychloroquine have been used as a treatment for COVID-19 despite very limited data in poorly designed studies. Two new studies call-out risks of treatment. One study of low-dose vs. high-dose chloroquine both with azithromycin for severe COVID-19 was stopped early after a safety analysis showed increased mortality in the high-dose arm. Mortality rate of 17.5% in the high-dose arm vs. 9.7% in the low dose arm. Ventricular tachycardia prior to death seen in 2 patients. There was no placebo-arm but investigators report a mortality rate in treated patients similar to untreated historical controls. Another recent observational study of patients treated with hydroxychloroquine and azithromycin found that 11% of patients developed new severe QTc prolongation (>500ms) on therapy. Conclusion: These studies call on providers to use caution when considering these treatments, given lack of efficacy data and increasing data on possible harm.


FAQ

1.When can inpatients with COVID-19 come off isolation precautions?
Discontinuation of isolation precautions may be done using clinical criteria or a test-based strategy. Approach depends on clinical scenario and test availability. At UCSF and ZSFG, hospitalized patients can come off precautions when they have met the following: (1) ≥14 days from symptom onset and (2) ≥72 hours fever-free without anti-pyretic and (3) improving respiratory symptoms (e.g. cough, dyspnea) and (4) 2 consecutive negative RNA swabs (nasopharyngeal/mid-nasal turbinate plus oropharyngeal) collected ≥24 hours apart. For patients returning home, we recommend following the CDC criteria for discontinuation of home isolation. All 3 criteria must be met: (1) ≥72 hours fever-free without anti-pyretic and (2) improving respiratory symptoms (e.g. cough, dyspnea) and (3) ≥7 days since 1st symptoms appeared. For patients with immunosuppression or who have protracted symptoms, a test-based approach should be considered if testing supplies are available.

2. Does any country have herd immunity?
No. Herd immunity refers to a type of community protection against transmission of an infectious disease that occurs when most people in a population—usually 70% or more—have immunity against the infectious agent. With respect to COVID-19, herd immunity will occur when either a large proportion of the population gets infected or vaccinated. Since a vaccine for SARS-CoV-2 does not yet exist, only the former is the relevant. While robust seroprevalence studies have not yet been conducted, assumptions based on models estimating the ratio of undiagnosed cases to diagnosed cases (~6:1 in China) suggest that the prevalence of SARS-CoV-2 in China—which presumably is amongst the highest in the world—is less than 5%, far from herd immunity.

3. What is new in the overlap of COVID-19 and HIV epidemics?
There is emerging data on the overlap of the COVID-19 and HIV epidemics over the past month since we first covered this topic. Increasing concerns about the impact of shut-down of HIV clinics to in-person visits countrywide has been voiced in the HIV community around antiretroviral therapy (ART) refills. Community members are calling for both commercial insurers and ADAP to allow 90-day ART refills via mail order to avoid running out of ART in the midst of the pandemic. In other news, since the phosphorylated form of tenofovir (breakdown product of both TDF and TAF) may have activity against the SARS-CoV-2 RNA-dependent RNA polymerase and serve as immunomodulators, there has been speculation on whether tenofovir-based ART or PrEP decrease the severity or frequency of COVID-19. Based on anecdotal reports from Spain and Italy – in the setting of their large COVID-19 epidemics—of patients with HIV presenting with less severe COVID-19 disease than those without HIV, a clinical trial has just launched in Madrid to see if Truvada protects healthcare workers against contracting COVID-19 called the Randomized Clinical Trial for the Prevention of SARS-CoV-2 Infection (COVID-19) in Healthcare Personnel (EPICOS). We expect more data on the interaction of COVID-19 and HIV to be forthcoming in coming months. This topic will also be covered in an upcoming city-wide Town Hall.

Additional questions, feel free to reach out.

Further UCSF resources, including ways to help, can be found here.

---------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: April 10, 2020
EPIDEMIOLOGY

Local

As of today, there are 21,101 confirmed COVID-19 cases and 584 deaths in California. In San Francisco, there are 797 confirmed COVID-19 cases and 13 deaths. Across the UCSF/ZSFG/VA system, 43 patients with COVID-19 are hospitalized (19 ICU). San Francisco had its first coronavirus case in a homeless shelter (Division Circle Navigation Center) on April 2, with containment efforts in place since then, moving residents out to hotels for quarantining.

National

There are now over 492,962 cases reported and 18, 466 deaths in the United States. New York State remains the epicenter of the epidemic, both in the United States and worldwide with New York reporting more coronavirus cases than any other country worldwide. New York State has 170,512 cases and 7,844 deaths to date, although Governor Cuomo announced today that the number of patients on ventilators and in the ICU decreased for the first time in NY over the last day, providing more hopeful signs of a “flattening of the curve”. Deaths remain high, however, with 777 new deaths in the state over the past 24 hours. The number of deaths in New York and New York City from coronavirus is widely thought to be underestimated given that paramedic calls on deaths occurring at home have increased substantially. On the final tally after the pandemic subsides, these deaths are likely to be counted as COVID-19-related.

Today we will spotlight Massachusetts, which is reporting 20,974 cases and 599 deaths. Boston reported 310 new coronavirus cases Thursday marking the biggest single-day increase in the city in the outbreak so far. Boston is currently reporting 2812 cases and 34 deaths and, yesterday, at a press conference, the COVID-19 Task Force at the White House stated that ““We’re watching the Chicago metro area. We’re watching the Boston metro area” due to concern of increasing rates in both cities. New data released by Boston officials Thursday indicate that, just like other cities reporting such data, African-American and Latino residents have contracted SARS-CoV-2 at substantially higher rates than whites. With very limited data from Boston, African-Americans represented 40% of known cases, despite representing about one quarter of Boston residents. Whites make up roughly half of Boston’s population, but represent about 28% of known cases. Latinos, about 20% of residents, made up 14% of known cases.

Global

There are currently over 1.69 million cases of COVID-19 and 102,525 deaths reported in 185 countries around the world. The US continues to lead the world in the total numbers of infections by approaching a half-million. The second-most affected country in the world is Spain at 157,053 cases and only Italy, France and Germany, among all countries worldwide, are reporting over 100,000 infections. Spain and Italy continue to report reduced deaths, ICU admissions, and hospitalizations. Japan emerged on the world scene this week, declaring a state of emergency on Tuesday, with rapidly increasing rates of coronavirus cases (now reporting 5,347 with 88 deaths). Japan’s government had been criticized for their handling of the quarantine situation on the Diamond Princess cruise ship and there is variation in Prime Minister Shinzo Abe’s and the Tokyo governor’s guidelines on “lockdowns” –including whether restaurants should close and sheltering-in-place. Moreover, testing capability in Japan still remains low as of this writing and US citizens in Japan were encouraged by their Embassy to return home to the US (although many, understandably, demurred).

PUBLIC HEALTH ACTION

With improvements in case counts across Europe, a few countries have started to discuss easing of sheltering-in-place guidelines. Denmark and Austria have become the first countries in Europe to announce easing of lockdown restrictions, with both countries shutting down early (March 11 in Denmark; March 16 in Austria) with low numbers of cases and deaths. In Austria, small stores are slated to reopen April 14, with larger stores to follow on May 1. Restaurants, hotels and schools may reopen in mid-May, although this decision will be made firmly closer to the end of April in Austria. Denmark will also begin opening up, but slowly in terms of shop openings; border controls will remain in place, and gatherings of more than 10 people will remain banned. Strict rules about masks, social distancing and the number of people allowed into a store at any one time will remain in place. In the US, more than 95% of the population is now under shelter-in-place/stay-at-home orders. Ecuador, a country of 17 million, emerged in the news this week as it now has the highest official rate of coronavirus infection and deaths per capita in Latin America. Poignantly, the number of deaths and bodies led to companies that usually package bananas and shrimp to begin converting boxes into cardboard coffins for funeral homes. Although most of the Latin America countries reacted early and prophylactically to the spread of the epidemic in Europe in March, Ecuador was the latest country in the region to shut down. Moreover, some experts believe that the virus may have traveled into Ecuador from Spain and Italy in late February—early March, both hard-hit, given the frequency of travel between these regions.

DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES
Early cases of COVID-19 outbreak in San Francisco are associated with travel to New York and Europe

A study by UCSF researchers analyzed the first 46 consecutive COVID cases testing positive (COVID+) by PCR from the inpatient and outpatient setting between March 10-22. 102 randomly-selected patients with acute respiratory infection, from same time period, who tested negative for COVID-19 served as controls. Of the COVID-19 cases, 37% were classified as travel-associated, 26% as community-acquired transmission, 13% as close contacts of known COVID-19 patient, and 13% as health care workers (HCWs). Travel to New York or Europe was significantly enriched in the 20 COVID-19 cases as compared to the controls. In contrast, travel to Asia, close contact with COVID-19 patients, and being a HCW were not enriched in the COVID-19 cases. The association with travel to New York at that time suggests that COVID-19 was circulating in New York in early March. This study is consistent with another report that suggests that COVID-19 was introduced into California multiple times by travelers from outside of the state. Notably, it has also recently been shown that the New York COVID-19 outbreak most likely originated in Europe. The authors conclude that interstate and international travel was as important as community transmission for California cases.

Do school closures increase COVID-19 mortality in the US by increasing child care obligations among health care workers?

School closures were amongst the first actions taken by many governments around the world, including local and state governments in the United States, in an attempt to slow the spread of COVID-19. However, such social distancing policies could have a deleterious impact on patient outcomes by contributing to healthcare worker (HCW) absenteeism due to increased child-care obligations. Researchers constructed a model using data from the US Current Population Survey to estimate childcare obligations for US HCWs arising from school closures and to identify the level at which the importance of HCW availability in increasing COVID-19 patients’ survival probabilities would be undone due to absenteeism and could actually increase cumulative COVID-19 mortality. They found that US HCWs have extremely high childcare obligations and that at least 15% would have unmet child care needs due to school closures (approximately 2.3 million children); this varied substantially by healthcare profession and from state-to-state. Their model estimated that if a 15% decline in the healthcare labor workforce resulted in a small increase in the COVID-19 mortality rate (from 2.0% to 2.4%), then school closures could contribute to more deaths than they prevent. This study shows that implementing school closures to slow the spread of COVID-19 and other emerging infections must be carefully considered and should be combined with alternative childcare arrangements for HCWs in order to minimize unintended harm.


FAQ

1. What is the role of ECMO in severe COVID-19 infection?
Extracorporeal membrane oxygenation (ECMO) has been used as a rescue therapy for severe ARDS, however its role in COVID-19 remains unclear. Data on its use with respiratory viral infections is encouraging. In the H1N1 influenza epidemic, ECMO reduced hospital mortality rate (23.7% ECMO-referred vs. 52.5% non-ECMO referred) and a retrospective study of 35 patients with severe MERS showed decreased in-hospital mortality, 65% with ECMO vs 100% without. To date, ECMO has been used infrequently for the care of COVID-19 patients in intensive care units (only 1% largest study from Italy) and outcomes are largely unknown. Interim guidance: the WHO and ELSO (Extracorporeal Life Support Organization) recommend administering venovenous ECMO to eligible patients not improving by conventional methods at experienced ECMO centers.

2. Which types of PPE can have extended-use or re-use?
Given the present shortage of PPE, strategies for extended (wearing PPE continuously without doffing between multiple patient interactions) and reuse (doffing PPE and storing in a clean dry place such as a paper bag labelled with the user’s name) have been developed. Regularly updated guidelines on extended and reuse of PPE at UCSF Medical Center can be found here. Extended wear of masks and face shields in areas where COVID-19 patients are cohorted is easiest to implement. N95 masks can be reused if contaminated hands have not touched inside of the mask, the mask is not wet/soiled/damaged, and appropriate fit maintained (a fit check should be performed each time the N95 is donned). If a face shield is worn over the N95 mask during aerosol generating procedures, reuse is also acceptable. If masks become contaminated, they must be discarded. Some institutions are decontaminating N95 respirators using UV germicidal irradiation, vaporous hydrogen peroxide, or moist heat, and UCSF Medical Center is investigating these options. Extended use and reuse guidance is also available for goggles and face shields.

3. What treatments are currently available for severely ill COVID-19 patients on our campuses?
The following treatments are available through clinical trials, expanded access programs (EAP) or compassionate use for intensive care unit (ICU) patients at UCSF and ZSFG: 1) Remdesivir (blocks viral replication) 2) Mesenchymal Stromal Cells (for ARDS) 3) Convalescent COVID-19 Plasma (coming soon). We will be reporting on additional studies in upcoming digests.

4. Do tigers get COVID-19?
In late March, four tigers and three lions at the Bronx Zoo developed dry cough and decreased appetite. One of the cats—Nadia, a 4-year old Malayan tiger—was sedated and tested positive for COVID-19. Nadia and the 6 other big cats are believed to have been infected by an asymptomatic zoo keeper. Early research also suggests that domesticated cats can get infected and spread SARS-CoV-2: A study in Wuhan tested 102 cats for antibodies to SARS-CoV-2 and found that 15% tested positive (3 had been living with people who were diagnosed with COVID-19 and the rest were strays or had been in pet hospitals). A second studydeliberately infected cats and other animals with SARS-CoV-2 and found replication in the respiratory tracts of both cats and ferrets, but not in dogs, pigs, chickens, or ducks. Hong Kong has reported three dogswho tested positive for COVID-19; all three dogs had owners with confirmed COVID-19 infections and all three were asymptomatic. Human to human transmission is driving the current COVID-19 pandemic.Summary: Coronaviruses have vast animal reservoirs and understanding the transmissibility of COVID-19 within and between animal species is important as we look towards a future vaccine as animals may be a continuing source of spread.

Further questions, feel free to reach out.

UCSF Hospital Epidemiology and Infection Prevention COVID-19 webpage: https://infectioncontrol.ucsfmedicalcenter.org/ucsf-health-covid-19-resources

San Francisco DPH link: https://www.sfcdcp.org/infectious-diseases-a-to-z/coronavirus-2019-novel-coronavirus/

--------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: April 7, 2020
EPIDEMIOLOGY

Local

As of today, there are 17,216 confirmed COVID-19 cases and 426 deaths in California. In San Francisco, there are 622 confirmed COVID-19 cases and 9 deaths. Across the UCSF/ZSFG/VA system, 50 patients with COVID-19 are hospitalized (23 ICU). Laguna Honda remains a concern with 11 staff and 3 residents currently infected; to date 290 staff members and 98 residents have been tested.

National

There are now over 395,000 cases reported in the United States. New York continues to be hard hit, with over 130,000 cases and 5,489 deaths statewide, over half of which are in New York City. This morning Governor Cuomo announced 731 new deaths, the largest single-day increase. These numbers are staggering, and time will tell if projections that cases are starting to stabilize are true. Some very stark and alarming disparities are emerging in places that are reporting COVID-19 data by race: In Chicago 52% of COVID-19 cases and 69% of deaths are among Black residents, who make up 30% of the city’s population. Only 14% of Michigan’s population is Black but represent 33% of COVID-19 cases and 41% of deaths in the state. In Louisiana, 70% of the deaths statewide are among black residents who make up 32% of the state’s population. North Carolina, Washington DC, and Milwaukee are also reporting disproportionate infections and death among black residents. Less access to healthcare, higher rates of comorbidities, and inability to work from home are likely contributing to these disparities. Today we will spotlight Michigan, which is emerging as a new epicenter in the US: on Monday, total COVID-19 cases reached 17,221 and 727 deaths, with 1,503 new confirmed cases and 110 new deaths in the preceding 24 hours. Infections among health care workers is a significant concern with 1,500 workers at Beaumont Health, the state’s largest hospital system, experiencing symptoms and over 700 employees at Henry Ford Health System in Detroit testing positive for COVID-19.

Global

There are currently over 1.36 million cases of COVID-19 and 76,315 deaths reported in 184 countries around the world. The US continues to lead the world in the total numbers of infections and Italy, Spain, and Germany are all reporting over 100,000 infections. There is hope for Italy and Spain as their curves seem to be flattening. Daily deaths in Spain have decreased daily from a peak of 900 on April 2 and on April 4 Italy reported the number of patient’s hospitalized in intensive care had declined for the first time since the beginning of the outbreak. Boris Johnson, who announced he had tested positive for COVID-19 on March 27, was admitted to the hospital on April 5 and is currently in the intensive care unit. On Monday, China reported no new deaths from COVID-19 in Hubei for the first time since January.

PUBLIC HEALTH ACTION

Lockdowns continue across Europe. In the US, an estimated 90% of the population is under shelter-in-place/stay at home orders. Iran, which has been a regional epicenter with 60,500 confirmed cases of the coronavirus and 3,739 deaths as of Monday, announced that “low-risk” economic activities will resume April 11. Iran. Access to testing in San Francisco continues to improve. Yesterday, Mayor London Breed announced a new drive through/walk through COVID-19 testing facility for frontline workers. This dedicated COVID-19 testing facility is located at Pier 30-32 began testing workers on April 6 and by the end of the week is expected to be able to conduct 200 tests/day. By the end of the week the city will also launch an online system for eligible employees to sign themselves up for testing directly. More population health data is now available to inform public health action in California through the UCSF Health Atlas, an interactive map that aggregates publicly available data on COVID-19 infections, population demographics, and social determinants of health.


DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES
Are public health interventions working? The mathematical modelers’ answers for Europe

Given the enormous economic and social costs of large-scale public health interventions such as social distancing, closures, and travel restrictions to control the COVID-19 epidemic, it is imperative to try to understand if they are working. Researchers from Imperial College London constructed a model using the observed number of deaths in 11 European countries to assess whether these public health interventions have reduced the “effective reproduction number” (‘Re’; the expected number of cases directly generated by one COVID-19 case in a population) and how many deaths may have been averted to-date. Across 11 countries through March 28th, they estimate that 1.9-11.4% of the population had been infected (7-43 million), and that there has been a 64% reduction in the average Re compared to pre-intervention values (3.9 vs. 1.4). The number of deaths averted due to implementation of the interventions was estimated to be 59,000 (95%CI: 21,000-120,000). While there is a high level of uncertainty in these estimates, they suggest that large-scale interventions have had a substantial impact on transmission. Nonetheless, the estimates also imply that because Europe may not even be close to herd immunity (at least 50-75% of the population infected), and because Re remains > 1, the virus causing COVID-19 will continue to spread if public health interventions are lifted.

Getting serious about serologies—COVID-19 antibody testing

This study reports 535 serial plasma levels tested for serology (total antibody, IgM, and IgG) from 173 COVID-19+ patients hospitalized in Wuhan. The samples were analyzed for dynamics during disease progression in conjunction with PCR testing nasal/pharyngeal swabs for viral load. The mean time to antibody seroconversion was day 11, day 12, and day 14, respectively. Less than 40% of patients seroconverted during first week of symptoms, but increased to 100%, 94.3%, and 79.8% by day 15 after onset. At the same time, PCR positivity decreased from 66.7% to 45.5%. Combining RNA and serologies improved sensitivity of diagnosis, even within early times (7 days) after symptom onset, suggesting a role of combined serologic and PCR testing for diagnosis of COVID-19 disease. Much more work is being done in the area of optimizing diagnosis tools and use of serologies at UCSF and elsewhere. See our FAQ below—we will keep readers updated on this rapidly moving field.


FAQ

1. Is asymptomatic shedding from children an important driver in the spread of COVID-19?
This remains an area of uncertainty. Several reports of children shedding SARS-CoV-2 have raised concern about the potential impact of asymptomatic shedding from children in the spread of COVID-19. In one study of 36 children admitted with COVID-19 in China, 28% were asymptomatic and 19% had only mild URI symptoms. A report from the US CDC found that children were less likely (73%) to have symptoms of fever, cough, or shortness of breath compared to adults (93%). A recent report documented contamination in the hospital room of an asymptomatic infected 6-month old. A pre-print release of a study from Singapore suggests that children represented the source in ~ 10% (3/31) of household transmission clusters; this is lower than the 54% (30/56) for H5N1. More testing of children with little or no symptoms and investigations of transmission events in the US and the San Francisco Bay area are needed to answer this question.

2. What type of ocular findings are seen in patients with COVID-19?
The main ocular manifestation of COVID-19 is conjunctivitis. A recent report described the ocular findings in a cohort of 38 patients from China: 12 patients (38%) had chemosis, conjunctival hyperemia, and epiphora (watery eyes). All 12 patients had moderate, severe, or critical illness, suggesting that ocular findings may be found in more severe disease. Notably, one patient had epiphora (“watery eyes”) as the first symptom of COVID-19. Two out of the 12 patients had a positive conjunctival swab for COVID-19, suggesting the possibility of transmission directly from the eye. Prior to this report, there were also a few case reports where conjunctivitis was described as part of the clinical syndrome of COVID-19.

3. What is status of serological testing to measure COVID-19 immunity and who should be getting this test?
Serologic testing is now available in the US, although only one company to date has received FDA Emergency Use Authorization to market their product. Serologic testing may be useful for: 1) measuring the true prevalence of COVID-19 in the population, 2) determining the presence and duration of protective immunity, which could potentially inform safety for return to workplace in some situations, 3) identifying recovered patients who may be candidate donors for providing convalescent plasma, currently being used as an experimental therapy, and 3) reducing the false negative rate of PCR-based COVID-19 testing, which may be over 25% depending on specimen type and timing of collection. We need much more information on performance of this and soon to be released additional antibody assays in a wider range of populations and settings to make definitive recommendations on their optimal use.

4. Are patients with COVID-19 hypercoagulable and would they benefit from intensified anticoagulation interventions?
A hypercoagulable state is well described in patients with pneumonia and sepsis. Elevated D-dimer and elevated IL-6 (mediator of cytokine induced coagulation) are correlated with poor outcomes in COVID-19. Among 21/183 non-survivors hospitalized with COVID-19 pneumonia, 71% met criteria for disseminated intravascular coagulation. In a retrospective study of severe COVID-19 cases with coagulopathy, heparin was not associated with a benefit in reduction of 28-day mortality except in a subset of patients with very high d-dimers levels. Bottom line: More data are needed to inform these clinical decisions. In the meantime, in light of patient isolation and limited mobility, we agree with The American Society of Hematology (ASH) recommendationthat “all hospitalized patients with COVID-19 should receive pharmacologic thromboprophylaxis with low molecular weight heparin (LMWH ) or fondaparinux (suggested over unfractionated heparin to reduce contact) unless the patient is judged to be at increased bleeding risk.”

Further questions, feel free to reach out.

UCSF Hospital Epidemiology and Infection Prevention COVID-19 webpage: https://infectioncontrol.ucsfmedicalcenter.org/ucsf-health-covid-19-resources

San Francisco DPH link: https://www.sfcdcp.org/infectious-diseases-a-to-z/coronavirus-2019-novel-coronavirus/

 

----------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: April 3, 2020
EPIDEMIOLOGY

Local

As of today, there are over 11,277 confirmed COVID-19 cases and 250 deaths in California. In San Francisco, there are 497 confirmed COVID-19 cases and 7 deaths. Across the UCSF/ZSFG/VA system, 42 patients with COVID-19 are hospitalized (18 in ICU). Testing capability is now available at all three hospitals’ microbiology labs with shorter turn-around times and expanded testing. (SF numbers are tracked by SFDPH.)

National

Cases in the US continue to climb and now exceed 270,000, with testing capability still not being adequate countrywide. In the last 24 hours, there were over 77,756 new cases reported. New York State and NYC continue, unfortunately, as the epicenter of the epidemic in the United States: New York State has 92,381 cases and >1,500 deaths, with 57,159 of those cases in New York City. Nearly a quarter of the cases in the U.S. are now in New York City. We spotlight the situation in Michigan today: They are reporting 12,744 cases and 479 deaths, with Detroit reporting over 2,500 cases and ~100 deaths. Detroit became the largest city in the country’s history to file for bankruptcy in 2013, but was well on its way to recovery before COVID-19 hit. Now, Ford Motors and General Motors, who had employed thousands of people in Detroit since 2013, have shut down production and laid off thousands of workers.

Global

Globally, we passed a million cases yesterday afternoon with current reporting showing 1,093,103 cases and 58,729 deaths due to COVID-19. The US (the third most populous country in the world) leads the world in number of cases, followed by Italy, Spain and then Germany. Germany is reporting 91,159 cases and 1,275 deaths.

PUBLIC HEALTH ACTION

Major public health actions continue worldwide. The debate has turned to universal masking for the public (see FAQ below). Governor Gavin Newsom has been discussing this for California, but is concerned about preserving personal protective equipment supplies for healthcare workers. Yesterday, Mayor Eric Garcetti of Los Angeles told everyone in the nation’s second-largest city to start wearing masks to combat the pandemic. In other public health actions, the 21-day lockdown in India continues with NO2 emissions falling dramatically as a result in one of the world’s most polluted countries. However, millions of Indians, including migrant workers, who depend on each day’s wages for their daily meal were thrown out of work. As transport options were shut down, many families in New Delhi and other major cities began to walk home to their distant villages with little access to food. Bangladesh, Sri Lanka and Pakistan—who will face similar economic crises with national lockdowns—have locked down only certain districts in their countries.


DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES

UCSF researchers develop a map of viral-human protein interactions to identify potential therapeutic agents, including existing drugs.

Most antiviral drug discovery is directed towards developing drugs that directly inhibit or interfere with specific viral proteins. However, viral proteins often interact with specific host proteins, and blocking those interactions or even the host protein function is an innovative avenue for anti-viral drug discovery. The Krogan and Shokat labs at UCSF led a multi-institutional scientific collaboration tour-de-force, to apply their newly developed technologies to identify host proteins targeted by the virus causing COVID-19 (SARS-CoV-2). They reported successful expression of 26/29 predicted SARS-CoV-2 proteins individually in human cells, purified the viral protein in such a way that the interacting human proteins would still be binding to it, and then used mass spectroscopy to identify the interacting human proteins. This analysis predicted SARS-CoV-2 interactions with ~300 human proteins. They further identified 67 druggable human proteins or factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or pre-clinical compounds. Their work may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 helping to treat COVID-19.

Hydroxychloroquine for treatment—where are we now?

Hydroxychloroquine (HCQ) has in vitro lab activity against the COVID-19 virus (SARS-CoV-2) and may act as both an anti-viral and anti-inflammatory, but data to treat disease are limited. Two small trials in China (30and 62 patients each) randomized patients with generally mild COVID-19 disease to receive 5 days of HCQ vs. no HCQ; all received standard therapy which included a variety of antiviral treatments. There was no difference in viral suppression at day 7 (only available in one study) and no substantial differences in clinical outcome or safety. There was a trend toward chest CT improvement with HCQ, and four patients progressed to severe disease in the control arm while none did in HCQ arm, but the small size of the studies limits our ability to draw any conclusion about HCQ efficacy. Two French studies reported on the use of HCQ given with azithromycin. Eighty patients with generally mild COVID-19 all received HCQ + azithromycin and most improved clinically. SARS-CoV-2 viral load and detectable live virus declined during treatment. However, these clinical and virologic outcomes may not be different from what is seen in those with mild disease without treatment. In contrast to an earlier article suggesting that HCQ with or without azithromycin led to more rapid viral clearance, a single arm study of eleven French patients receiving HCQ + azithromycin reported no evidence of rapid viral clearance or clinical benefit. The bottom line: We need larger randomized controlled data to definitively inform us if HCQ impacts viral clearance or clinical course and if any observed benefits outweigh risks. Outside the context of clinical trials, providers considering hydroxychloroquine as part of COVID-19 treatment should weigh the risks and benefits for the individual, evaluate for comorbidities and drug interactions that may affect safety of HCQ administration, and monitor during treatment.


FAQ

1. Should masks be used by the general public in crowded spaces?

We support face masks or face covering in addition to present guidance on social distancing and hand hygiene for 3 reasons—the highly contagious nature of the virus, asymptomatic transmission and empiric evidence from Asia where masks are routinely used. Supplies of hospital grade masks for health care works must be prioritized, but excess surgical masks or homemade masks of multilayered cotton likely provide more protection compared to nothing during the epidemic. An increasing number of cities in the US are embracing this recommendation as an adjunct measure: Stay in place, keep your space and cover your face.

2. What are the common comorbidities associated with severe COVID-19 in US?

To date, most studies have examined conditions associated with severe COVID-19 outside the US. Findings in the US are similar to other countries. Among 7,162 cases reported to the CDC with data on comorbidities and other risk factors, 37.6% had at least one comorbidity or risk factor for severe disease. The most common included diabetes (10.9%), chronic lung disease (9.2%), and cardiovascular disease (9%). A higher proportion of persons admitted to the ICU had at least one comorbidity or risk factor (78%) versus persons hospitalized but not admitted to the ICU (71%) or not hospitalized (27%). Of 184 fatal cases, 94% were among persons with one or more major comorbidity. These findings are not surprising in light of what is observed with other respiratory viral infections such as influenza, but we have much to learn regarding COVID-19’s impact on other patient populations such as persons living with HIV.

3. In the setting of a shortage of nasopharyngeal flocked swabs, what other swabs can we used for detection of COVID-19 by PCR?
Swab shortages can limit testing capacity and therefore being able to use alternative swab types is important to maintain our ability to test patients. Recommended approaches when standard small tip size nasopharyngeal (NP) flocked swabs are not available include using a single large tip size flocked swab to first collect from the oropharynx and then from the mid nasal turbinate; or using a single synthetic (non-flocked) swab to collect first from the oropharynx and then from the mid nasal turbinate. Flocked refers to a type of swab that has multi-length fibers at the tip designed to enhance absorption of specimen. Flocked swabs come in both small (designed for NP sampling) and large (designed for oropharyngeal sampling) tip sizes.

4. Where can patients with recovered COVID-19 donate blood for convalescent sera treatment trials?

We discussed in the last digest that researchers reported clinical improvement in patients receiving convalescent sera. Whether this approach is truly efficacious requires rigorous study. Recovered patients interested in donating can contact Vitalant and the Red Cross.

Further questions, please feel free to reach out.

-------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 31, 2020
EPIDEMIOLOGY

Local

As of today, there are over 7,500 confirmed COVID-19 cases and 150 deaths in California. In San Francisco, there are 397 confirmed COVID-19 cases and 6 deaths. Across the UCSF/ZSFG/VA system, 33 patients with COVID-19 are hospitalized (16 in ICU). Testing capability is now available at all three hospitals’ Microbiology labs with shorter turn-around times and expanded testing. (SF numbers are tracked by SFDPH.)

National

Cases in the US continue to climb, now exceeding 185,000, although we know these numbers are underestimates because diagnostic testing capability has not yet been ramped up to meet the needs. In the last 24 hours, there were over 21,482new cases reported. New York State and NYC continue to face a difficult burden: New York State reported >7,000 new cases of COVID-19 yesterday, bringing the total to over 67,000 with half of these cases in New York City. Governor Cuomo of New York reported that “case doubling” time in New York is starting to slow (from every 2 days to every 6 days now) and a Navy Ship hospital is starting to offload local hospitals. We spotlight the situation in Louisiana today: They are reporting 5,237 cases (1,834 cases in New Orleans) and 239 deaths. Compare these numbers to those in California, where we have over 7,500 cases reported but our population is nearly 10 times the size. New Orleans has repurposed their Convention Center, where many of us have attended medical/scientific meetings, to a 1000-bed hospital.

Global

Globally, over 857,000 cases and 42,000 deaths due to COVID-19 have been reported. The US leads the world in number of cases. Spain and Germany join the US, Italy and China in reporting >70,000 cases. Spain reported over 9,000 new cases and 900 deaths in a single day and are now reporting 95,923 cases and 8,464 deaths. (Global numbers via Johns Hopkins.)

PUBLIC HEALTH ACTION

Major public health actions continue worldwide. President Trump declared that social distancing orders for the entire country will be extended until April 30. Here in San Francisco, as of this morning, many hospital systems are requiring their health care workers to wear isolation masks for clinical care in both outpatient and inpatient settings. Extending these recommendations to universal masking for the public is an active debate in many jurisdictions. Courageous and makeshift medical responses around the country and world are springing up. To list a few: Central Park erecting a tent field hospital in New York City for coronavirus; the Detroit Auto Show being canceled amid plans to repurpose its venue as temporary coronavirus field hospital; sports stadiums being used as testing centers in Florida and elsewhere; and hotels in Spain being converted to medical bunkhouses. Diagnosed cases in Africa are still low, but there are concerning signals, with South Africa now reporting 1,353 cases. Countries in Africa have implemented anticipatory public health actions, with a 21-day lockdown order declared in South Africa on Monday March 27. Uganda (now reporting 44 cases) instituted a 14-day lockdown and Monday and further restricted movement yesterday, banning all private cars on the road after voluntary measures to restrict vehicles were not followed. Many metrics are demonstrating how social distancing is happening, including incredible reductions in air pollution and NO2 emissions in large cities with less use of cars, transport vehicles, and manufacturing. In the US, jigsaw puzzle sales are at an all-time high for home entertainment.


DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES

Passive antibody treatment for COVID-19: An old approach to a new disease may be promising
A case series of 5 mechanically ventilated patients in Wuhan with persistently positive COVID-19 PCR were treated with large volume infusions of convalescent sera (passive antibody therapy) reported clinical improvement. The donor plasma had IgG and IgM antibodies to the COVID-19 spike protein and neutralized the virus in the cell culture infection model. The treated patients demonstrated significant clinical improvement after 1 week, which included an increase in neutralizing antibody titers, and PCR became negative 1-12 days after transfusion. Possible benefit of convalescent plasma was confounded by concurrent use of antivirals and steroids. An additional study reports treatment of 19 patients with COVID-19 with convalescent serum and subsequent clinical improvement. Optimal dosage, timing of administration and whether hyperimmune or convalescent sera may be more effective remains to be determined. Based on this preliminary data and past use of convalescent sera for other viral epidemics, the FDA approved emergent use of this therapy on 3/25/20. The National COVID-19 Convalescent Plasma Project is planning trials across the country.

More data about the challenges of COVID-19 in long-term care facilities

There are at least 400 long-term care facilities in the US dealing with COVID-19 outbreaks, including in our own city at Laguna Honda. Clients residing in these facilities are among the most vulnerable in society to succumb to COVID-19. A recent study described an outbreak of COVID-19 in a SNF of 82 residents in King County, Washington. The investigation was initiated after a symptomatic healthcare worker was diagnosed with COVID-19. Universal PCR testing via nasopharyngeal swab was performed on 76 (93%) residents. They identified that 23 (30%) of residents were positive for COVID-19. Amongst those who tested positive, 13 (57%) were asymptomatic at the time of initial testing. Ten (77%) of the asymptomatic patients developed symptoms of COVID-19 in the following week, while 3 remained asymptomatic. Quantitative assessment of viral burden by PCR was similar among those who were symptomatic, pre-symptomatic, or asymptomatic infection. This study tells us that “symptom-based screening” (which can be difficult in this population) may miss over half of patients in this setting. It also confirms that those with and without symptoms are contributing to spread.


FAQ

1. Was SARS-CoV-2 introduced to Northern California through a single event?
No, data suggest that there were several different introductions of the virus causing COVID-19 into California. An elegant and extremely interesting study done by UCSF investigators mapped the viral genomes from 29 patients diagnosed with COVID-19 infection from February 3rd through Mar 15th 2020 in Northern California. Through phylogenetic analyses they found 8 different SARS-CoV-2 lineages. These included viruses linked to the first known case in Seattle (WA-1), virus spread across counties, virus with interstate spread (New York), and international spread (Europe and China). The results suggest that multiple independent introductions of the virus into California occurred. Where transmission chains were originally introduced via both international and interstate travel, rather than widespread community transmission of a single predominant lineage.

2. Are GI symptoms common in patients with COVID-19 and can these patients present with GI symptoms alone?
GI symptoms in COVID-19 do occur, although not in the majority of patients. We know the virus causing COVID-19 can infect the gut, so it is not surprising that this would occur. A large case series reported 1-10% of patients with COVID-19 with diarrhea or nausea/vomiting on presentation. Other studies reported diarrhea in 14-27% of patients at the time of diagnosis. Emerging reports are now describing patients presenting with GI symptoms (i.e., diarrhea, nausea, or vomiting) without respiratory symptoms in 3-10% of cases. We continue to learn about the clinical presentation of this disease and expect that we will learn more about GI presentations and disease over the coming months.

3. Should SARS-CoV2 PCR testing be done in asymptomatic patients before going to a skilled nursing facility?
Yes, this makes sense. Patients in a skilled nursing facility are often older and have multiple co-morbidities, therefore they are at high-risk for severe COVID-19. While symptomatic patients will likely be identified, preventing the introduction of infected patients who are asymptomatic or pre-symptomatic to these settings is also important to prevent spread of disease, which can become rampant (as noted in the Washington State experience described above). This approach is not failsafe; false negatives can occur. Therefore isolating patients for a period of time upon transfer to chronic care facilities is considered as an alternative or adjunctive strategy.

Any questions, please feel free to reach out.

----------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 27, 2020
EPIDEMIOLOGY

Local

As of today, there are 4,205 confirmed COVID-19 cases and 85 deaths in California. In San Francisco, there are 279 confirmed COVID-19 cases and 3 deaths. Across the UCSF/ZSFG/VA system, 26 patients with COVID-19 are hospitalized (12 in ICU). Testing capability has ramped up at all three hospitals, with local capacity in the three associated clinical labs.

National

The US, which is the third most populous nation on the planet, now has the highest number of cases of COVID-19 in the world, exceeding those in China and Italy as of Thursday, March 26. Latest US estimates are over 100,000 cases and 1,500 deaths. The surge in cases in the US has been most dramatic in New York State, which accounts for just under half of the nation’s infections. New York State as of today had44,635 confirmed cases, 5,327 hospitalizations, and 519 deaths. The majority of the cases and deaths were in New York City, with 25,573 cases and 365 deaths. Over 100 deaths were reported in NY on March 26 and hospital systems were overwhelmed, including emergency rooms, inpatient wards, and intensive care units. Governor Andrew Cuomo of New York had ordered a lock-down of the state with all non-essential services to be closed and people sheltering in place on March 20. New York is not the only city or region facing case surges. Cook County (Chicago), Wayne County (Detroit), and Atlanta are others, to name a few.

Global

There are over 590,000 cases of COVID-19 and 26,943 deaths globally.* Europe was the epicenter of the pandemic until the US surpassed Italy in number of cases yesterday. Italy’s number of new cases of coronavirus has been slowing with lower numbers of new cases occurring daily for the 6th consecutive day as of today. However, the case fatality rate in Italy still remains the highest in the world with 8,215 deaths and 80,059 cases (10.1%)—see below for recent publication on Italy’s high mortality rate. (Global numbers via Johns Hopkins.)

Public Health Action:

Major public health actions continue worldwide, with Prime Minister Narendra Modi of India announcing a national lockdown on the country on Tuesday, March 24 for 21 days, impacting 1.3 billion people. Countries across Africa and many in Latin America are on lockdown although Brazil and Mexico were initial “hold outs” for such public health measures. The government of Mexico mandated stay at home orders on Tuesday March 24 and many cities across Brazil (despite President Jair Bolsonaro’s reluctance) has imposed shelter in place mandates. The global number of people under some form of lockdown is now around 2.6 billion – one-third of the human population, more humans than were even alive during World War II.


DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


UP TO THE MINUTE DISPATCHES

Can pregnant women transmit COVID-19 to their infants?

We previously reported there was no evidence to date for congenital COVID-19. In multiple small case series (n<20 in each), newborns to women with COVID-19 were either asymptomatic or had mild disease consistent with post-natal acquisition. However, two articles published in JAMA on March 27, 2020 suggest vertical transmission might occur [Dong et al, Zeng et al]. A total of three infants born to women with mild COVID-19 disease were found to have elevated SARS-CoV-2 IgM levels at birth. Because IgM molecules are generally too large to cross the placenta (in contrast to IgG and cytokines), these results provide serologic evidence of in utero transmission. These infants remained asymptomatic and had negative RT-PCR virologic testing. Limitations of these reports include their small number and the potential false positivity of IgM. So, as of today, we can say the answer to this question is “Maybe.” UCSF has launched a nationwide registry for pregnant women with suspected or confirmed COVID-19 and their infants called PRIORITY.

Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy
SARS-CoV-2 case fatality rate in Italy is 10.1%, substantially higher than that observed in China (2.3%) and South Korea (1.0%). Authors attributes this discrepancy to three possibilities: 1) Population age. The case fatality rate (CFR) within age strata from 0-69 years is similar between Italy and China. However, older people in Italy make up a greater proportion of those diagnosed. The overall older age distribution in Italy might in part explain the higher overall CFR. However, even when the sample is stratified by age, the mortality rate of older Italians is substantially higher (20.2% vs 14.8% for those over 80). 2) Case definition. Clear criteria for the definition of COVID-19-related deaths are not available. In Italy, death was attributed to COVID-19 in any patient with positive SARS-CoV-2 PCR, regardless of pre-existing diseases or indication for admission. 99% of COVID-19 deaths in Italy involved at least one medical comorbidity; 3) Testing strategies. The Italian government prioritized testing for patients with more severe clinical symptoms--nearly 20% of all tests were positive. This is in contrast to other countries like South Korea, which instituted widespread testing (larger denominator) and thus far has calculated a case fatality rate of around 1.0%. These are reasonable points, but we still have much to learn to explain these wide ranging mortality rates.


FAQ

1. What proportion of cases of COVID-19 in the US are among health care workers?
We do not yet know the answer for the US. We do have some data from other countries. Among 72, 314 cases in mainland China (through 2/11/20), 3.8% were in health care personnel [Guan et al]. 75% of these cases were diagnosed in Hubei Province. In a separate study of a selected group of 1099 patients from mainland China with laboratory-confirmed COVID-19 the percentage of healthcare workers among the cases was 3.5% [ICN]. In Italy, which continues to experience widespread community transmission, 9% of COVID-19 cases are in healthcare workers. Currently the California Department of Health is reporting 42/3006 (1.3%) in their latest stats that include HCW. It is likely that depending on local outbreaks this number will vary. We can say HCW transmission is lower than seed with SARS. In the SARS outbreak in Canada in 2002-2003, 43% of the cases were in healthcare workers.

2. Can SARS-CoV-2 cause cardiac injury?
Perhaps. This is an evolving story. We know patients with underlying cardiovascular disease are at higher risk for severe COVID-19. However, COVID-19 itself may be associated with cardiac injury. Studies of patients hospitalized with COVID-19 in China reported cardiac injury in 17-20% of cases. One study found that patients with cardiac injury were older, had more comorbidities, and a higher risk of death when compared to those without cardiac injury. Another study reported that 7% of 68 COVID-19 related deaths were due to myocardial damage/heart failure. Whether COVID-19 associated cardiac injury is due to direct viral injury or other mechanisms requires further research. Awareness of this potential complication, particularly when considering medications with potential cardiac toxicities is to be noted while researchers study potential mechanisms.

3. Should patients without symptoms undergoing transplantation or intensified immunosuppression be tested for COVID-19 in settings with widespread community circulation?
Yes, if the logistics allow for it. Physicians may decide to alter management for a patients with a positive PCR for COVID-19 undergoing these procedures. We have described in prior digests that patients can have high viral loads detected on PCR prior to symptoms. It is important to note that the current tests are is only 70% -80% sensitive—so using current assays, one is reducing but not eliminating the possibility the patient has COVID-19 underlying disease. In other words, a positive test confirms disease, but a negative test does not completely rule it out.

4. Are loss of smell and loss of taste symptoms of COVID-19 infection?
Yes, this is likely true. Physicians in several countries have reported anosmia/hyposmia (loss of/decreased smell) and ageusia/dysgeusia (loss of/dysfunction of taste) as symptoms associated with COVID-19 infection. A cross-sectional survey of 59 hospitalized COVID-19 patients in Italy demonstrated that 34% had at least 1 taste or olfactory disorder symptom; 19% had both. Onset of symptoms occurred prior to hospitalization in 20% (including 91% of taste disorders); the remaining 14% occurred during the hospital stay. Symptoms were more common in women (53%) vs. men (25%) and in younger individuals (affected median age 56 vs. non-affected median age 66). Anecdotal reports have described anosmia in 30% of a COVID-19 cohort in South Korea and in >66% of 100 non-hospitalized COVID-19 patients in Germany. The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) proposed that anosmia and dysgeusia is included in clinical screening algorithms for when alternative explanations are absent (i.e. allergic rhinitis, rhinosinusitis).

Any questions, please feel free to reach out.
 
--------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 24, 2020

The COVID-19 global epidemic spread is continuing to accelerate. The United States is joining Europe as an epidemic epicenter. New York is at the center of the increases. Last week, the US was #8 globally in number of confirmed cases. This week the US is #3. It is important to note that interpretation of increases in confirmed COVID-19 cases is highly dependent on testing access; however deaths (less subject to bias in detection) are rapidly increasing – 140 deaths in the US on Monday alone. Although hundreds of clinical trials for COVID-19 are ongoing, there is no proven treatment for this disease to date.

EPIDEMIOLOGY

Local

As of today, there are 152 confirmed COVID-19 cases and 0 deaths in San Francisco.* In many medical centers, the hospital census of persons under investigation (PUI) is far higher than hospitalized cases, in part because of slow testing turnaround in some settings. Disposition of non-critically ill PUI with unstable housing/supportive services also continues to be a challenge, leading to hospitalizations for this group. At present, intensive care needs are being met; and plans across the city are underway to meet possible increased demand as we carefully monitor our local epidemic curve under shelter-in-place conditions. (SF numbers are tracked by SFDPH.)

National

There are 46,805 confirmed cases in the US; on Monday over 10,000 new cases were reported. New York State (25,000 cases, of these ~15,000 in New York city) is experiencing a rapid surge in confirmed cases and hospitalized patients and now accounts for 5% of all global cases. New York City’s health care system is experiencing challenges in every level of the response including staffing, hospital and ICU beds, and PPE. City leaders are breaking new ground in innovative approaches to increase capacity for care provision including repurposing operating rooms and underutilized buildings. (National numbers via CDC.)

Global

There are over 407,000 cases of COVID-19 and 18,200 deaths globally. The death toll in Italy (~ 6,800 to date) continues to exceed what has been seen in many other regions in terms of case fatality rates, and the health systems are overwhelmed by critically ill patients. For 2 days, new cases and deaths in Italy decreased, but deaths rose to 743 today (Tuesday) - the epidemic is still raging.

Public Health Action:

We are seeing an escalation in public health interventions in most settings and de-escalation in a few Asian countries where the cases have declined. In the US, where cases are rapidly escalating, many states have joined California in shelter-in-place policies. The US has put strict restrictions on border crossing from Canada and Mexico. Increasingly, countries in South America and Africa are ramping up public health strategies, including shelter-in-place, with a goal to mitigate spread in their regions by acting early since COVID-19 came later to these regions. It is estimated that 1.2 billion persons are being asked globally to stay in their homes.

Several Asian countries/regions had rapid responses to COVID-19 including Hong Kong, Singapore and Taiwan. It will be instructive to watch as these regions scale back their public health interventions. Each of these countries has plans or is already implementing loosening restrictions. Hong Kong had previously reported only 150 cases, and on March 2, allowed persons to return to work. They subsequently noted a new spike of 30 cases associated with return of citizens to the island. Maintaining epidemic control is going to require robust contact testing and tracing systems to succeed when movement restrictions are loosened. The last 2 weeks has seen massive global movement of persons returning to their native countries (including to the US) which can be the source of new epidemic outbreaks.


DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


COVID TESTING CAPACITY

Testing capacity for inpatient facilities continues to improve. The turnaround for UCSF Health is ~ 12 hours, for ZSFG is 12-24 hours and for the VA is 24-48 hours.


UP TO THE MINUTE DISPATCHES

What are the data behind the new interest in using hydroxycholroquine and azithromycin for COVID-19 treatment?

A very small, non-randomized French study (available as a pre-print) evaluated hydroxychloroquine (HCQ) 200 mg TID for 10 days for treatment of hospitalized COVID patients. The control arm was COVID patients who declined treatment or who were at another medical center. At day 6, the SARS-CoV-2 was undetectable in 70% of those taking HCQ vs 12.5% of those not on HCQ. There was a suggestion that the addition of azithromycin, given at provider’s discretion, might increase potency, as HCQ plus azithromycin was associated with 100% viral load undetectable vs 57% with HCQ alone at day 6. However, there are several significant limitations: (1) patients in control group had higher baseline viral loads than those in the HCQ group vs. those in the HCQ/Azithro group, (2) six patients were lost to follow-up in the HCQ arm, including 3 who were transferred to the ICU and one who died and (3) clinical outcomes were not reported. Based on this study, it is not clear if hydroxychloroquine or hydroxychloroquine plus azithromycin reduces viral loads in patients or results in improved clinical outcomes. Randomized controlled data with clinical outcomes are needed. We need to be cautious about the potential side of effects of hydroxychloroquine, including QTc prolongation.

In case you missed it, intense tracking of hospital contacts of early case of COVID-19 in the US—the patient’s husband but not hospital contacts were infected.
Overview of the 1st known person-person transmission in the USA from The Lancet

The index patient was 60 year-old traveler who visited a sick relative and other family members in Wuhan, developed symptoms in retrospect as early as 1 day after return, was hospitalized with pneumonia and tested positive for COVID-19 seven days after returning to Illinois. Her only close contact (husband with COPD, did not travel), developed symptoms as early as 4 days after her return, became COVID-19 positive 11 days after her return, and was hospitalized 14 days after her return. Extensive contact tracing that included use of video surveillance cameras in the hospital revealed 372 contacts of both patients; 347 underwent active symptom monitoring for 14 days (152 community contacts and 195 HCW contacts; 66% low risk, 34% medium risk or higher). 43 PUI’s (fever, cough, and/or SOB within 14 d of exposure; 41% low risk, 59% medium risk or higher) and 32 asymptomatic, exposed HCWs tested negative. COVID-19 transmission occurred only in husband (1/347 monitored contacts), who had prolonged, unprotected exposure. There was no transmission to other contacts. This is a single case, and severity of illness, extent of viral shedding, and timing of exposures may have contributed to the apparent limited transmission. We will continue to share information on risk for HCW as the epidemic unfolds.


FAQ

1. Do infected persons gain immunity to SARS-CoV-2?
It is not known if infection with SARS-CoV-2 results in long-lasting immunity. However, a recent study in rhesus monkeys suggests that at least short-term immunity is likely. Researchers infected rhesus monkeys with SARS-CoV-2 and documented clinical disease and viral shedding. Twenty-eight days after primary infection, monkeys were re-exposed to the virus. None of the re-exposed monkeys demonstrated clinical disease nor were found to have viral shedding. However, studies of common coronaviruses that cause upper respiratory tract infection in humans have been shown to result in only partial, short-term immunity. Whether natural infection with SARS-CoV-2 will result in short term or durable immunity in humans remains unknown and an area for further research.

2. Does temperature (climate) effect COVID-19 spread?
SARS-CoV-2 transmissions have occurred predominantly within a temperature range of 3-17 C and a humidity of 4-9 g/m3, suggesting SARS-CoV-2 transmission may be less efficient in warmer humid climate (Bukhari). Similarly, in temperate climates, infections by other coronaviruses has been shown to occur primarily in winter (Gaunt). While it may be reasonable to expect a decline in contagiousness of SARS-CoV-2 in warmer weather, the degree to which weather will impact transmission is not known and will need further monitoring.

3. Why are people talking about ACE/ARB blockers in relation to COVID?
SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptor for viral cell entry, the expression of which is increased when taking renin-angiotensin-aldosterone system (RAAS) inhibitors (ACE/ARB blockers that block the ACE1 receptor). The clinical significance of ACE2 modulation in human SARS-CoV-2 infection is unknown. RAAS inhibition has been argued to pose a theoretical increased risk of a higher susceptibility to infection due to increased ACE2 expression (Kuster). On the other hand, animal models suggest increased ACE2 expression is protective from severe acute lung injury induced by aspiration, sepsis, and SARS-CoV infection (Imai, Kuba). Currently, there is no data proving a causal relationship between ACE2 activity and human SARS-CoV-2 associated mortality. We do not recommend stopping or starting a RAAS inhibitor because of SARS-CoV-2 infection. There are intervention and observational studies planned to address this association.

4. What is the survival rate after intubation (mechanical ventilation)?
In published studies to date, the survival rate after intubation is quite low (0-14%). Yang et al reported on 52 critically ill patients in Wuhan and found that of 22 intubated patients, only 3 (14%) survived. Zhou et al reported on the clinical course of 191 patients in Wuhan and found that among 32 intubated patients, only 1 (3%) survived. Similarly, Wu et al reported on risk factors for ARDS and death in 201 patients from Wuhan; only 6 patients were intubated and none survived. Lastly, a report on 21 critically ill patients from Evergreen hospital in Washington was published last week (Arentz et al, JAMA March 19). They reported that 15 patients required intubation (71%) and of the 21 patients, 67% have died, 24% remain critically ill, and 10% have discharged from the ICU; they do not specify in the report a specific mortality rate for the intubated group.

Any questions, please feel free to reach out.

----------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 20, 2020
EPIDEMIOLOGY

Local

As of today, there are 1039 confirmed COVID-19 cases and 19 deaths in California. In San Francisco, there are 76 confirmed COVID-19 cases and 0 deaths. Hospitals are seeing more patients seeking evaluation for COVID. The UCSF/ZSFG/VA campuses have all been activated and things are running smoothly in terms of rule-out procedures and treatment algorithms. It is important to note that we are still in influenza “season” in San Francisco. (SF numbers are tracked by SFDPH.)

National

Latest US estimates are 14,250 cases and 205 deaths. Testing is expanding to include drive-through options in many cities, but overall, capacity remains inadequate. On March 18, the CDC released data in the MMWR on outcomes among the 4,226 cases reported in the US since March 16. The report found that 31% of cases, 45% of hospitalizations, 53% of ICU admissions, and 80% of deaths occurred among adults aged ≥65 years with the highest percentage of severe outcomes among persons aged ≥85 years (similar to what was seen in China). As of this morning, New York City had 5,151 cases with ~1,250 hospitalized. Health systems are preparing for a surge in cases and have been limiting hospital visits, non-essential surgeries and clinic visits. There is a massive transition to telemedicine in many health systems in an effort to maintain the healthcare workforce. (National numbers via CDC.)

Global

There are over 247,400 cases of COVID-19 and 10,067 deaths globally. Europe is now the epicenter of the epidemic—with the greatest number of cases in Italy at 41,035 cases (3,405 deaths). The United Kingdom, slow to implement aggressive public health measures, has experienced a rapid increase in cases and reports with 3,297 cases to date. (Global numbers via Johns Hopkins.)

Public Health Action:

Over the last week, there has been more, important public health actions taken by US states and countries around the world (e.g. shelters in place, border closings, city “lock downs”). San Francisco and surrounding counties extended their early measures (limitations on gathering size and school closure) to shelter in place” on March 16, which was ahead of the nation. Yesterday on March 19, Governor Gavin Newsom gave a shelter in place order for the entire state of California (nearly 40 million people). Mayor Bill de Blasio put a strong stay at home order in place in NYC yesterday, but not as restrictive as in SF, and there has been an alarming rise in cases in New York State (now at 7,845 cases) over this past week. The UK, after an initially slow response, is now putting restrictive social distancing orders into place after an increase in cases. In Africa, 33 African countries had reported more than 600 cases and 17 deaths due to COVID-19, but testing has been limited. Many African countries (Kenya, Senegal, Rwanda, South Africa, Ethiopia, Zambia, Tanzania, among others) are putting restrictive orders in place for social distancing in anticipation. Countries in Latin America and the Caribbean have been affected later than other regions from the pandemic and therefore have a chance to flatten the curve of contagion; Columbia, Peru, Chile, Costa Rica and Panama, for instance, have all put aggressive public health measures in effect.


DAILY UPDATES

https://www.who.int/emergencies/diseases/novel-coronavirus-2019


COVID TESTING CAPACITY

COVID-19 PCR testing at UCSF Medical Center is currently at 80 tests/day and is expected to increase to 200-500 tests/day within a week. Currently, NP/OP swab kits are a limiting reagent. At Zuckerberg San Francisco General Hospital, capacity for inpatient samples is being met; outpatient testing remains limited. The turnaround for test results is 6-12 hours at UCSF and 24hours (from DPH) at ZSFGH and 3-5 days when sent to private labs who are experiencing extreme backlogs.


RESEARCH DISPATCHES

Lopinavir–Ritonavir not effective in Randomized study in Adults Hospitalized with Severe Covid-19 (NEJM 03.18.20)

Lopinavir-ritonavir, a viral 3CL protease inhibitor that had been commonly used to treat patients with HIV infection, has been shown in vivo to have activity against coronaviruses. A randomized, controlled, open-label trial comparing lopinavir-ritonavir in adults hospitalized with severe COVID-19 was just published. The study was conducted in China and randomized patients with confirmed (PCR+) COVID-19 and hypoxia (O2 saturation < 95% on room air OR PaO2/FiO2 < 300 mm Hg) to receive lopinavir-ritonavir (400mg/100mg) twice daily for 14 days versus placebo. Primary end-point was improvement on a seven-category ordinal scale or discharge from hospital. 199 patients were enrolled. Patients had a mean of 13 days of illness prior to randomization. Treatment with lopinavir-ritonavir was not associated with clinical improvement. Mortality was not statistically different in the treatment and control groups. There was also no difference in detectable viral RNA during the course of disease in either group. Gastrointestinal side effects were more common in the treatment group and 13.8% of patients in the treatment arm had stopped treatment stopped. There were several limitations in the trial; most notably, it was an open-label study. Although in vivo studies have demonstrated activity of lopinavir-ritonavir against SARS-CoV-2, it does not offer clinical benefit. It is terrific to have this information, and given the results of this study, we are not recommending regular use in the care of our patients with COVID-19. Its role in patients at earlier stage of disease is unknown.

SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients

COVID-19 early high viral load (NEJM 03.19.20)
Researchers recently published a study where they monitored SARS-CoV-2 viral loads in upper respiratory specimens from 18 patients in Guangdong, China within two family clusters. They analyzed the viral load in relation to the day of onset of any symptoms. Higher viral loads were detected soon after symptom onset, with higher viral loads detected in the nose than in the throat. The pattern of nucleic acid shedding with SARS-CoV-2 appeared very different from that previously reported in patients infected with SARS-CoV, where viral shedding for SARS-CoV peaked much later in the course of illness. The researchers also report a possible case of asymptomatic transmission of SARS-CoV-2. It is hypothesized that this early, high-level viral shedding may be a key factor in the transmission dynamics of SARS-CoV-2 and may help explain the difference in extent of spread of SARS-CoV-2 when compared to SARS-CoV.


FAQ

1. Can SARS-CoV2 be spread via blood products?
To date, there have not been any reported cases of SARS-CoV-2 spread via blood products. In a recent study that examined PCR samples from many body compartments, only 1% of 307 blood samples were positive. Viremia is most likely to occur in patients with symptomatic infection. Patients are not recommended to donate blood when they have signs and symptoms of COVID-19. Testing of blood products for SARS-CoV-2 is not presently used in the United States. Additional information from the American Association of Blood Banks can be found here.

2. What are best practices to reduce transmission of SARS-CoV2 who require surgical procedures?
(1) Avoid surgical procedures on patients with COVID-19 unless medically urgent; (2) minimize the number of people in the operating room during aerosol generating procedures (e.g., intubation and extubation); (3) all individuals in the OR during the surgical procedure require PAPR or N95 with face shield/goggles plus gowns and gloves; (4) bring patients directly to the OR and recover the patients in the OR—avoid pre-op holding and PACU

3. If my patient has COVID-19, how many days into their illness might they develop hypoxia and respiratory failure? In a study of 191 patients in China with COVID-19, dyspnea developed at about day 7 of illness and respiratory failure requiring ICU admission on day 12 of illness.

4. Is chloroquine useful for prophylaxis against COVID-19?
Data for use of hydroxychloroquine and chloroquine are limited to in vitro studies thus far, with a number of RCTs currently underway. These trials are examining the role of chloroquine or hydroxychloroquine for active COVID-19 treatment as well as post exposure prophylaxis. Given the lack of data available, providing these medications widely off-label to patients for prevention outside of a study is not advisable.

Any questions, please feel free to reach out.

---------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 17, 2020
EPIDEMIOLOGY

Local

As of today, there are 43 confirmed COVID-19 cases and 0 deaths* in San Francisco. Hospitals are seeing more patients seeking evaluation for COVID. It is important to note that we are still in influenza “season” in San Francisco. As of last week, 10-20% of samples sent to labs are positive for influenza. *from SF DPH

National

Latest US estimates are 4,226 cases and 75 deaths. * Testing is expanding to include drive through options in many cities, but overall, capacity still remains inadequate. Health systems are preparing for a surge in cases and have been limiting hospital visits, non-essential surgeries and clinic visits. There is a massive transition to telemedicine in many health systems in an effort to maintain the healthcare workforce. *from CDC

Global

There are over 196,00 cases of COVID-19 and 7,800 deaths globally. Europe is now the epicenter of the epidemic; with the greatest number of cases in Italy. The United Kingdom, slow to implement aggressive public health measures has experienced a rapid increase in cases and reports around 1,950 cases to date. *from Johns Hopkins CSSE

Public Health Action:

Over the last 72 hours, there has been unprecedented actions taken by countries around the world (e.g. border closings, mandatory 14 day quarantines of all persons entering a country, regional quarantines). After a period of inaction, the US Federal government has put in place multiple aggressive measures (e.g, closing border to Europeans) to contain the spread of COVID-19. San Francisco and surrounding counties extended their early measures (limitations on gathering size and school closure) to “shelter in place”—a new term for most persons. The three week “shelter in place” public order requires citizens to stay at home unless they are providing (e.g. health care) or executing (e.g. food purchase) essential services.

Some optimistic news from Italy: A region (Lodi) that implemented strict adherence to measures consistent with “shelter in place” in mid -February has contained cases vs a region (Bergamo) that did not. See Figure 1.


DAILY UPDATES
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


COVID TESTING CAPACITY

COVID-19 PCR testing at UCSF Medical Center is currently at 80 tests/day and is expected to increase to 200-500 tests/day within a week. Currently, NP/OP swab kits are a limiting reagent. At Zuckerberg San Francisco General Hospital, capacity for inpatient samples is being met; outpatient testing remains limited. The turnaround for test results is 6-12 hours at UCSF and 24hours (from DPH) at ZSFGH and 3-5 days when sent to private labs who are experiencing extreme backlogs.


PATIENT EVALUATION

UCSF Health updated its adult inpatient/ED algorithm, developed workflow for the ambulatory setting, and is working to provide clarification of points around PPE use.

  • Updates in testing: In an effort to maximize sensitivity of testing while conserving testing materials, they now recommend either a single nasopharyngeal (NP) swab when using a single flocked swab kit or when using a dual flocked swab kit, place the NP swab and oropharyngeal swab into a single vial. Also, all respiratory viral testing (COVID-19, RVP, rapid flu/RSV) should be done on the same swab. Order should be either for RVP or rapid flu/RSV but not both.
  • Workflow for patients with respiratory symptoms in the ambulatory setting: Depending on patients symptoms and risk factors, they may be triaged to either home self-monitoring, a UCSF Health respiratory screening clinic, or the emergency department. Details can be found on UCSF Health link below
  • PPE for patients being evaluated for COVID-19 or diagnosed with COVID-19:
    • Routine care for patients who are not receiving aerosol-generating interventions: Don surgical mask/eye protection plus gloves/gown
    • Obtaining an NP+/-OP swab: Don (N95 mask/eye protection or PAPR) plus gloves/gown
    • Patient receiving nebulized medication or other discrete aerosol-generating procedures: Don (N95 mask/eye protection or PAPR) plus gloves/gown (1-hour after procedure is complete can return to routine care recommendations)
    • Patient intubated, high-flow nasal canula, non-invasive ventilation, or tracheostomy in place: Don (N95 mask/eye protection or PAPR) plus gloves/gown (in negative pressure isolation)
  • Cohorting has begun of inpatients with COVID-19 to a single floor when possible

FAQ

1. What is the sensitivity of the PCR test to diagnose COVID-19?

The sensitivity of a single nasopharyngeal (NP) swab PCR is ~75-80%. Sampling by pooled NP + oropharynx (OP swab likely increases sensitivity by another ~ 10%. The addition of a lower respiratory sample (BAL, endotracheal aspirate) may further increase sensitivity.

2. Should steroids be used in the treatment of severe disease?
Presently, there are insufficient data to recommend steroids during ARDS in the setting of COVID-19. One recent small retrospective study (N=201 hospitalized patients in China ) published by Wu, et al in JAMA Internal Medicine reported 84 (42%) with ARDS, and a 54% mortality among the 84 patients. Some of the risk factors associated in ARDS/mortality included older age, higher neutrophil count and organ dysfunction. Higher fever (>39) was associated with higher risk (1.77) of ARDS and lower mortality rate (0.41) . Among, the 84 patients with ARDS, steroids were used in 31%.The hazard ratio death was lower (0.38, 95% CI 0.20-0.72) in steroid recipients. Despite this association, it is not possible to assess the effect of steroids in absence of a randomized comparison; other studies have also shown prolonged viral shedding in the presence of steroids.

3. What treatment trials are up and going at ZSFG and UCSF hospitals?
We have 2 active trials here; there are many trials ongoing around the world. Both ZSFG and UCSF are participating in an NIH sponsored double blinded, placebo controlled RCT of IV remdesivir (nucleoside analogue that inhibits viral RNA polymerase) given for up to 10 days to hospitalized individuals with COVID-19 (NCT04280705, UCSF PI Luetkemeyer). Patients are eligible if they are have radiographic findings or evidence of hypoxia and are required to have PCR confirmation of COVID-19. More severely ill patients with ARDS may qualify for a study of mesenchymal stromal cells, which may reduce lung injury by targeting several ARDS-triggered pathways to reduce injury and accelerate repair (NCT02097641, UCSF PI Matthay). Please contact the COVID ID service (remdesivir) and Pulmonary/Critical Care (mesenchymal stromal cells) at each site to discuss potential participants or you can reach out to [email protected] or [email protected]

4. Are there any prevention trials for COVID ongoing?
Yes, post-exposure prevention trials are being planned, and some are underway. Chloroquine and hydroxychloroquine (Plaquenil) show robust in vitro activity against the virus causing COVID-19. This mechanism of action is thought to be interference with viral entry. We will be participating in a study using hydroxychloroquine for household contacts of known COVID-19 cases. Expected start date is late April 2020. Lopinavir/ritonavir (Kaletra) has been used for post-exposure prophylaxis during MERS in a small series, and is being actively investigating for both prophylaxis and treatment in COVID-19. There are many trials ongoing around the world investigating other agents with potential COVID-19 activity for post-exposure prophylaxis.

Any questions, please feel free to reach out.

 

 

------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 13, 2020
EPIDEMIOLOGY

Local

As of today, there are 23 confirmed COVID-19 cases and 0 deaths in San Francisco. San Francisco school officials announced yesterday that they are closing Pre-K through Grade 12 schools for 3 weeks. Most, if not all other Bay Area Catholic schools and independent schools have also closed. The Mayor announced temporary housing for homeless persons awaiting COVID testing results or with confirmed cases.

National

Latest US estimates report 1,629 cases and 41 deaths. The president extended travel restrictions to non-US citizens from a majority of European countries (excluding the United Kingdom and Ireland) entering the United States. First in-depth report of US community transmission published in Lancet – household but not HCW transmission in this case. Disembarkation from the Grand Princess Cruise ship docked in Oakland on Monday is still ongoing.

Global

There are nearly 138,000 cases of COVID-19 and ~5,000 deaths globally. The situation in Italy continues to be dire, with an increase in cases, deaths and severe strain on the health system and providers. Cases in Iran are rising rapidly, and several high-level government officials have been infected. Cases are continuing to decline in China. *Data from CSSE at Johns Hopkins


DAILY UPDATES

https://www.who.int/emergencies/diseases/novel-coronavirus-2019


PATIENT EVALUATION

COVID-19 PCR testing is ramping up on our campuses. The Chan-Zuckerberg Biohub donated two high-throughput PCR machines. Once the testing on this machine meets CLIA standards (which will take 1-2 weeks), the in-house test capacity is expected to increase to over 200 tests/day. LabCorp, Quest, and ARUP are now live with their COVID-19 PCR tests. As testing becomes more easily available, each of our campuses are updating their screening algorithms, which can be found on the clinical links at the end of this digest.

UCSF health just updated its adult inpatient/ED algorithm. The important changes are:

· Increased test availability: Tests should be ordered per algorithm as “COVID-19 RNA, qualitative.” Approval for testing is no longer required.

· Test collection: Pooled oropharyngeal and nasopharyngeal swabs will be collected in one test. Instructions for collection can be found here.

· Updated PPE guidance: The algorithm now specifies patients requiring “Novel Respiratory Isolation” and those requiring "Respiratory Illness Evaluation without Negative Pressure."

· Discontinuation of isolation: The algorithm now specifies necessary steps.

 

UP-TO-THE-MINUTE DISPATCHES

Patient with Flu and COVID-19: There is a report of a patient in China who presented with LRI symptoms 1 day after returning from a 5-week visit in Wuhan. He tested positive for influenza A but negative for SARS-CoV-2 on a NP swab x 2. He was sent home on oral oseltamivir. One week later, he returned for worsening symptoms. A repeat NP swab and sputum sample was negative for SARS-CoV-2. He required mechanical ventilation. 11 days after his initial presentation, metagenomic sequencing and RT-PCR of BALF and RT-PCR of sputum tested positive for SARS-CoV-2. This case illustrates that (i) SARS-CoV-2 testing may not be initially positive (although we cannot rule out nosocomial transmission) and (ii) although reportedly unusual, patients can be co-infected with both Influenza A and SARS-CoV-2.

Children were infected early during the COVID-19 outbreak in China: A retrospective review of 366 children hospitalized near central Wuhan from January 7-15, 2020 and that were all tested for respiratory pathogens revealed that 23 (6.3%) tested positive for Influenza A, 20 (5.5%) tested positive for Influenza B, and 6 (1.65%) tested positive for SARS-COV2. Age range was 1-7 years old. The most common symptoms in the 6 patients were high fever (6/6), cough (6/6), N/V (4/6). 6/6 had lymphopenia; 4/6 had abnormal chest CT. 1/6 required ICU admission; all were discharged. This study suggests that children were infected early during the epidemic in China.


RESEARCH
COVID-19 RESEARCH UPDATE WITH AN EMPHASIS ON SOME BASIC AND APPLIED VIROLOGY TO HELP UNDERSTAND THIS COVID-19 PANDEMIC

The S (for Surface or Spike, because the protein looks like a spike protruding from the virus) protein of coronaviruses is crucial for the virus to bind to a specific receptor on the host cell, enter into the host cell (which it does by fusing with the host cell membrane. The host cell receptor also defines what cells, tissues, and species can be infected and therefore is considered the best target for vaccine development. Several groups have demonstrated that human angiotensin converting enzyme protein (hACE2) is the receptor for SARS-CoV-2. This protein is expressed in much more in cells of the lower respiratory tract than in the upper respiratory tract, explaining why COVID-19 causes lower respiratory (rather than upper respiratory) tract infections. Mutations that naturally arose in the SARS-CoV-2 S protein during the SARS outbreak that affect the binding affinity of SARS-CoV-2 to hACE2 correlated with the replication, transmissibility, and disease severity of SARS-CoV. Two groups have now published structural studies with SARS-CoV-2 and finds that its S protein binds to hACE2 up to 10 times better than SARS-CoV, possibly explaining the enhanced human-human transmission of SARS-CoV-2. Like the SARS-CoV S protein, the SARS-CoV-2 spike protein is highly glycosylated (ie, it has lots of sugars attached to the protein). These sugar residues are important for the protein to fold correctly, get processed by host proteases, and to be recognized by neutralizing antibodies. The authors were able to visualize the 3D structure of the SARS-CoV-2 S protein and provided evidence that some but not all neutralizing antibodies to SARS-CoV will likely block binding to SARS-CoV-2. This study will hopefully help in the development of an effective vaccine against SARS-CoV-2.

NIH has issued their policy and information on COVID-19-related potential delays for grant applications, progress reports, meeting etc
1. FAQs regarding proposal submission and award management
2. Policy regarding late applications due to COVID-19

-------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 10, 2020
EPIDEMIOLOGY

Local

As of today, there are 13 confirmed COVID-19 cases and 0 deaths in San Francisco; the Department of Public Health (DPH) is providing daily updates. Santa Clara County has reported 43 cases, and the first death in a woman in her 60s. To reduce the pace of spread of COVID-19, the SFDPH recommends rescheduling or cancelling non-essential events and that vulnerable populations refrain for attending events of 50 or more persons. Starting Wednesday, Santa Clara County is banning events of over 1,000 persons until the end of the month.

National

Latest US estimates are 647 cases and 25 deaths. Yesterday, New York State reported an increase in cases—173 total to date with eight hospitalizations. The National Guard is sending troops to assist in testing and setting a “containment area” in New Rochelle, NY until March 25, where a cluster of cases has been detected. The Grand Princess Cruise ship docked in Oakland yesterday, and disembarkation will occur over the next few days under Federal guidance.

Global

There are nearly 120,000 cases of COVID-19 and 4,200 deaths globally. The epidemic in Italy is not abating-- 9,173 cases and 463 deaths to date. Yesterday, Italy announced all forms of public gathering for the entire country would be put on hold, and non-essential travel was being restricted until April 3. A overview presented virtually at CROI 2020 details the global arc of the virus.


DAILY UPDATES

https://www.who.int/emergencies/diseases/novel-coronavirus-2019


PATIENT EVALUATION
COVID-19 PCR testing went live at UCSF Medical Center yesterday. They are able to run 20-40 tests per day and are hoping to quickly escalate to over 100 samples per day within the next week. As testing become more widespread, each of our campuses are updating their screening algorithms. LabCorp, Quest, and ARUP are now live with their COVID-19 PCR tests.


EDUCATION
The Cross-campus ID Task Force can provide updates by ID faculty on COVID-19 to your department, division or team in varying formats: a 15-minute talk, a Grand Rounds, a Q&A session or another format that might suit your group. For more information or to schedule a session, please contact us.


RESEARCH
A study of 181 confirmed cases of SARS-CoV-2 infection found that the median incubation period was 5.1 days and that 97.5% of patients will develop symptoms within 11.5 days of infection. A clearer understanding of incubation period helps providers make best decisions on quarantine to prevent spread. Although it is believed that respiratory droplets are the primary mode of transmission of infection, patients have been noted to have stool with positive PCR testing for SARS-CoV-2. Researchers identified an asymptomatic child with stool positive for SARS-CoV-2 PCR 17 days after last exposure. Transmission is primarily via virus-laden droplets and implications of asymptomatic stool carriage as a vector for transmission is unclear.


FREQUENTLY ASKED QUESTIONS

1.What is the difference between SARS-COV2 and COVID-19?
SARS-COV2 (the virus) stands for Severe Acute Respiratory Syndrome – Coronavirus. COVID-19 (the disease) stands for Coronavirus Disease first reported in 2019.

2. Which patients are at highest risk for death from COVID-19?
Based on data from a large study in China of 72,314 infected patients, case fatality was 2.3% in all patients. However, risk of death increased with increasing age in years 0-39 (0.2%), 40-49 (0.4%), 50-59 (1.3%), 60-69 (3.6%), 70-79 (8%), and >79 (14.8%) and for patients with cardiopulmonary disease, diabetes, hypertension, and cancer.

3. What are the most common laboratory abnormalities you should expect to see in patients with COVID-19 pneumonia?
In two recent studies describing clinical characteristics of patients from China with COVID-19 pneumonia (Guan W et al and Chen N et al), leukocytosis was uncommon and leukopenia (30-45%) and lymphopenia (33-85%) were frequently seen. C-reactive protein was elevated in most (60.7%) patients while procalcitonin was unlikely elevated (5.5%).

4. Has lung transplantation been used as a treatment for patients with COVID-19 pneumonia?
Yes, in China there have been two lung transplants performed for patients with COVID-19 disease. Both these patients had been on ECMO and had failed to improve.

5. How does SARS-COV2 cause respiratory failure?
The pathogenesis of SARS-COV2 is poorly understood. It is thought that the virus is able to infect respiratory epithelial cells via binding to the angiotensin converting enzyme (ACE) 2 receptor. Once it infects the cells, immune-mediated attack of virally infected cells may be a driver of clinical disease. In fact, researchers in China are studying the IL-6 receptor blocker, tocilizumab, as a possible therapy. Tocilizumab has been used for the treatment of “cytokine storm” in patients being treated with CAR T-cells.

 

-------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 6, 2020
EPIDEMIOLOGY

Local

The situation is evolving rapidly with 2 confirmed community-transmitted hospitalized cases in San Francisco announced yesterday, and many suspected cases under evaluation. Public health officials are working around the clock discussing and expanding community mitigation strategies. City and health officials are also working diligently and collaboratively to insure health care worker safety as our response is intensified.

National

More cases COVID-19 are now being recognized around the United States. As of today, there are 233 cases and 14 deaths. There have been notable increases in the Los Angeles area, as well as New York. Many of the deaths have been in elderly persons, and in particular, elderly residential group facilities. There have been no deaths among children in the US to date.

Global

We’ve reached over 100,000 cases of COVID-19 globally. Cases from India are now being increasingly reported. It is somewhat encouraging that new cases from China are starting to decrease, but the burden there remains high. Health care workforce shortage remains a great challenge there-- more than 3000 physicians in China have been infected and at least 22 have died—underscoring the importance of us putting the resources needed to insure health care work safety from the start.

DAILY GLOBAL UPDATES:
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


PATIENT EVALUATION

Increased access to COVID-19 laboratory testing is actively happening in San Francisco with a revision of the recommended isolation and testing algorithms. Each of our campuses are updating their screening algorithms, which can be found on the clinical links at the end of this digest. LabCorp has launched a COVID-19 PCR test as of today and Quest will have a test available by Monday.


EDUCATION

The UCSF ID COVID-19 Task Force can provide updates by ID faculty on COVID-19 to your department, division or team in varying formats: a 15-minute talk, a Grand Rounds, a Q&A session or another format that might suit your group. For more information or to schedule a session, please contact Chesa Cox at [email protected].


RESEARCH

Scientists are busy sequencing the virus and sharing on a common platform – https://nextstrain.org/ncov

There was recognition of 2 separate strains reported yesterday (“L” and “S”) and a suggestion that there was correlation with clinical outcomes—but much more information on this possible association and what it means is needed. UCSF is in the process of validating a SARS-CoV2 PCR assay and this should be completed in the coming week with an estimated turnaround of 20 samples per day. Steve Miller, Director of the UCSF Microbiology Lab, is leading this effort. There is also ongoing work at Moffitt to bring online a higher throughput commercial PCR instrument and a CRISPR/Cas12a-based diagnostic test in the upcoming weeks.


FREQUENTLY ASKED QUESTIONS

1. What is the risk of COVID-19 in pregnancy?
Based on the limited available data it does not appear that pregnant women are more susceptible to COVID-19 and clinical presentation in pregnancy has been similar to that of non-pregnant patients. Reported complications rates to date are much lower than seen previously with SARS, but there have been reports of fetal distress and preterm delivery in some cases. There has not been convincing evidence of intrauterine maternal to child transmission, however infants born to a mother with known infection are clearly at risk and appropriate infection control measures to prevent transmission post-partum are warranted.

See Lancet and ACOG articles for more information

2.Can asymptomatic people test positive for COVID-19 and if so, are they infectious?

Several asymptomatic persons tested positive for COVID-19 and were the presumed sources of transmission to close contacts. In one case, the chest CT was normal; the person never developed symptoms and cleared COVID on subsequent testing. The second case appears to have transmitted COVID during the incubation period prior to developing symptoms. These cases raise important questions about how much transmission is driven by those without symptoms, what the relationship is between viral load and infectiousness, and what the implications of this will be for control of this epidemic

3.How many negative tests are enough to demonstrate that a person is no longer infected and infectious?
The current guidance is for two sequential negative PCR tests and clinical improvement for discharge from hospital or quarantine. Post-clinical viral shedding may occur and is under study.

 

If you have further questions, please feel free to reach out and we can direct your query appropriately. UCSF is maintaining a microsite with updates as well.

-----------------------------------------------

COVID-19 DIGEST

From the Infectious Diseases Divisions at UCSF, ZSFGH, and VAMC

Update: March 3, 2020

EPIDEMIOLOGY

Local

There is clear evidence for community transmission in the Bay Area—cases where there is no known direct link to travel or to infected persons. Five new diagnosed patients including two East Bay Health workers were announced over the weekend. This was expected and not surprising, given what is currently known about COVID-19 transmission and circulation. San Francisco’s outstanding Public Health Department is monitoring and responding to our local situation.

National

Cases of COVID-19 are now being recognized around the United States. There have been 105 cases in 15 states. California is reporting the largest number of new cases (20). Washington State has sadly reported 9 fatalities as of today. Many of these deaths were associated with transmission in a nursing home setting.

Global

Over 90,000 cases of COVID-19 have been reported in > 70 nations. In Europe, cases are now being detected in many countries beyond Italy, and various measures are being taken in these countries to mitigate spread. Some countries have already called for cancelling events where more than 1,000 persons gather; museums, such as the Louvre in Paris, are temporarily closed. Many large meetings—including those in medicine, science and tech—are being cancelled and are choosing to share conference information digitally. An overview of the global situation is updated daily here:

Daily Updates:
https://www.who.int/emergencies/diseases/novel-coronavirus-2019


PATIENT EVALUATION

SF Public Health Department lab is actively testing specimens for COVID-19. Each of our campuses are updating their screening algorithms and testing capacity. 


EDUCATION

The UCSF Task Force can provide updates by ID faculty on COVID-19 to your department, division or team in varying formats: a 15-minute talk, a Grand Rounds, a Q&A session or another format that might suit your group. Please contact us if interested.


RESEARCH

Treatments and vaccines are areas of active and intense investigation. There is no proven antiviral treatment for COVID-19. Several antimicrobial agents may have activity against COVID, including both experimental and FDA approved drugs. One promising agent is remdesivir, an investigational nucleotide analogue under active investigation for COVID-19 in two phase 3 randomized open label studies enrolling in Asian countries and a Phase 2 double blinded, placebo controlled NIH-funded study actively enrolling in the U.S. at Univ. of Nebraska Medical Center. This trial has potential to expand to other sites. Remdesivir is also available through compassionate use from Gilead Sciences for qualifying patients on a case-by-case basis.

An electron microscope image showing particles of the new coronavirus being released from an infected cell. Image credit: The University of Hong Kong


FREQUENTLY ASKED QUESTIONS

1. What is the increased risk for disease acquisition or mortality for persons on immune suppression?

Although there are limited data on this, medical comorbidities including malignancy have been associated with higher risks for severe outcomes (data from China). In other coronaviruses, immunocompromised patients may show fewer symptoms at onset but later have more severe disease; it is not known if this is the case with COVID-19. There are no data to determine if people living with HIV specifically are at greater risk of COVID-19 acquisition or more severe disease.

2. What do we know about COVID-19 spread to children?

In Germany, a schoolteacher fell ill with COVID-19 pneumonia. Of the 114 children exposed to this teacher, 100 were tested. Four children in this classroom have subsequently developed COVID-19 with mild symptoms. There are school closings in Europe where teachers have fallen ill with the disease, but no reported deaths among children.

3. Can COVID-19 relapse?

There have been reports from China, Japan, and the US of persons who tested positive weeks after recovering from COVID-19 disease. There is insufficient information at the present time to interpret these reports, which could represent assay error, prolonged waxing/waning viral shedding, true reinfection or true relapse. This is an area of active investigation.

 

If you have further questions, please feel free to reach out and we can direct your query appropriately. UCSF is maintaining a microsite with updates as well.