Updates on the COVID-19 pandemic from the Johns Hopkins Center for Health Security.
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EPI UPDATE The WHO COVID-19 Dashboard reports 64.35 million cases and 1.49 million deaths as of 12:00pm ET on December 4. We expect the global cumulative mortality to surpass 1.5 million in the next update.
Over the course of the COVID-19 pandemic, we have focused separately on incidence and mortality, whether in terms of total or per capita values. Today, we will take a closer look at the relationship between these to metrics by discussing the case fatality ratio (CFR). CFR helps us understand how severe a disease is by determining what percentage of patients ultimately die. The CFR for the vast majority of countries remains below 3%. In fact, 86% of countries (163 of 190) and territories tracked by Our World in Data are reporting CFR of 3% or less, 63% (120) are reporting a CFR 2% or less, and 31% (59) are reporting a CFR of 1% or less. Globally, the cumulative CFR is currently 2.3%.
High CFR can be driven by a number of factors. As we observed early in the pandemic, CFR was elevated initially in countries that were severely affected, due in part to a lack of understanding of how to treat COVID-19, an absence of therapeutics against the novel disease, and overwhelmed health systems, which did not allow patients to receive the same level of attention and care they would under normal circumstances. But one of the principal drivers of CFR is testing volume, which factors directly into how CFR is calculated. Early in the pandemic, limited testing capacity meant that only the most severe patients were tested and detected, which meant a higher percentage of identified patients went on to die. As testing volume increased, more mild and moderate cases, as well as asymptomatic infections, were identified, which shifted the CFR down due to detecting more infections relative to deaths. Additionally, improvements in our understanding of how to treat COVID-19 patients, increased availability of effective therapeutic drugs, and waning community transmission that reduced the burden on health systems also reduced COVID-19 mortality.
While most countries are reporting moderate or low CFR, several countries stand out as concerning. Most notably, Yemen is currently reporting a CFR of 28%, meaning more than 1 out of every 4 identified cases ultimately dies. Yemen’s health system has been devastated by years of civil war, including numerous attacks on hospitals and healthcare workers. Without a fully functioning healthcare and public health infrastructure, Yemen’s COVID-19 patients cannot receive the clinical care they need. Yemen does not report testing data, but considering the condition of the public health and healthcare sectors, it is likely that testing volume is extremely low, which would dramatically increase the calculated CFR. Mexico is reporting the second highest CFR globally (9.5%), and 9 other countries are reporting 5% or higher, including several in Africa, South and Central America, and the Eastern Mediterranean region as well as China. Fortunately, 8 of these 11 countries are reporting decreasing trends in CFR. Among this group, only Bolivia, Egypt, and Syria are reporting increasing trends.
Of this group of countries, only Bolivia, Iran, and Mexico have test positivity data available in the Our World in Data database. Bolivia is currently reporting test positivity of 9.2%. This is nearly double the 5% benchmark recommended by the WHO, but it is a significant improvement over its peak of 63.6% in mid-July. Iran’s test positivity has increased steadily since early September, now up to 32.1%. Mexico’s most recent test positivity data is from November 12, when it reported 48.2%. Elevated test positivity indicates that testing volume is not sufficient to capture the full scope of transmission in these countries, which could also potentially account for some portion of the elevated CFR in these countries.
NOTES:
1. We are only discussing case fatality ratio (CFR), as opposed to distinguishing it from infection fatality ratio (IFR). IFR traditionally includes individuals who are determined to be infected but do not exhibit symptoms of the disease as well as symptomatic cases, but the data we have available do not distinguish between cases and infections. The “cases” reported by countries typically include both the individuals with positive tests and those with clinical diagnoses, without differentiating between symptomatic cases and asymptomatic infections. Additionally, many asymptomatic infections are never detected, or even tested, so we cannot include those individuals in this analysis. Considering the expected proportion of infections that are asymptomatic or mildly symptomatic, we expect that the IFR for COVID-19 is considerably lower than both the true CFR and the figures discussed above. Many research efforts are ongoing to better characterize the total number of infections, including those never formally identified, in order to better approximate IFR.
2. You may be more familiar with the terms “case/infection fatality rate” (also commonly referred to by the acronym CFR/IFR); however, “rate” implies a temporal nature to the data (ie, cases/death over a specified period of time). We are evaluating the total data from the beginning of the pandemic so we will refer to it as “case fatality ratio.”
UNITED STATES
The US CDC reported 13.82 million total cases and 272,525 total deaths. Yesterday, the CDC reported 196,227 new cases. While this certainly includes delayed reports from last week, it does set a new record high for single-day incidence. Typically, we expect that the updates published on Fridays and Saturdays—corresponding to data through Thursday and Friday, respectively—will be the highest incidence reports of the week, so it is certainly possible that the US could continue to set new records in the coming days.
Additionally, the CDC reported 2,461 and 2,762 deaths, respectively, over the past 2 days. Again, these updates contain some delayed reports from the Thanksgiving holiday weekend, but they do represent the eighth and fourth highest single-day mortality, respectively, since the onset of the US epidemic. Yesterday’s mortality is the highest single-day total reported since April 21. Even with the depressed reports over Thanksgiving, the average daily mortality has nearly returned to its pre-holiday level, with 1,607 deaths per day (compared to 1,658 on November 25). At this rate, the US is averaging 1.1 COVID-19 death per minute.
As a reminder, these elevated reports do not necessarily represent a surge in transmission or mortality due to Thanksgiving travel and gatherings; that will take several weeks to become apparent. The elevated figures include cases and deaths from last week as state and local health departments and health systems catch up from delayed reports over Thanksgiving. It will take several weeks before we will be able to observe the effects of Thanksgiving on the US epidemic.
The US could surpass 14 million cumulative cases and 275,000 deaths in this afternoon’s update.
Data published by The COVID Tracking Project indicate that the US surpassed 100,000 current hospitalized COVID-19 patients, 40% more than at the peak of either of the 2 previous surges.
US VACCINE ALLOCATION No vaccine has yet received Emergency Use Authorization (EUA) from the US FDA, but the FDA’s Vaccines and Related Biological Products Advisory Committee is scheduled to meet on December 10 and December 17 to discuss the Pfizer and Moderna vaccine candidates, respectively. In anticipation of an EUA for one or both vaccines, the US Advisory Committee on Immunization Practices (ACIP) convened an emergency meeting on December 1 to vote on proposed recommendations for the Phase 1a allocation of the initial SARS-CoV-2 vaccine supply.
ACIP voted 13-1 in favor of the including frontline healthcare workers and long-term care facility (LTCF) residents in Phase 1a, with the one objecting vote stemming from the lack of safety and efficacy data available for LTCF resident populations. The recommendation will prioritize about 21 million healthcare workers and about 3 million adults currently residing in LTCFs. ACIP did not vote on allocation for the rest of Phase 1, but other Phase 1 tiers are expected to include non-medical essential workers and others at risk for severe disease and death, including adults aged 65 years and older and those with underlying medical conditions.
VACCINE CLINICAL TRIAL CONTROL GROUPS At least 2 Phase 3 clinical trials for SARS-CoV-2 candidate vaccines have collected enough data to evaluate efficacy; however, longer-term evaluation for both safety and efficacy is required to better characterize the vaccine’s effects, including the duration of conferred immunity. One major outstanding question is how to handle trial participants who received the placebo once a vaccine is authorized for public use. Clinical trial participants are not informed whether they received the vaccine or not, but some may suspect they received the placebo, particularly if they did not experience common side effects, such as fever or fatigue. As these vaccines move closer to emergency authorization—or receive emergency authorization, as is the case in the UK—trial participants and patient advocates argue that they should be able to receive the real vaccine.
From an ethics perspective, many agree that trial participants should be prioritized for vaccination, in recognition of their willingness to risk their health to serve in the trials; however, control groups (ie, those who received the placebo) are critical to assessing the vaccines’ safety and efficacy, including over the longer term. Phase 3 trials are ongoing and need to continue in order to understand the true impacts of the vaccine and, ultimately, apply for full regulatory approval. Additionally, administering the vaccine to the control group now could also definitively indicate that these participants received the placebo initially, which would eliminate the “blinding” that is important to conducting clinical trials. While some experts, including NIH Director Dr. Francis Collins, have previously supported immunization for control group participants, other experts, including some at the US FDA, have argued against doing so. Some companies, including Pfizer, have committed to informing control group participants about the availability of the vaccine as well as their potential eligibility to receive it.
US VACCINE DISTRIBUTION In addition to decisions about who to give the vaccine to, there is the immense challenge of actually distributing and administering the vaccine. Rapid mass vaccination across the US was immensely challenging, even before the COVID-19 pandemic, and the urgency and scale of the upcoming mass vaccination effort for SARS-CoV-2, logistical challenges for shipping and storing the vaccine, long-standing health disparities and distrust in health systems, concerns that vaccine development and evaluation were rushed, and a myriad of other issues will undoubtedly compound these challenges. Additionally, state and local public health departments that play a central role in coordinating mass vaccination have been long underfunded and under-resourced.
The military has had a large role in planning the logistics for distribution, as part of Operation Warp Speed. Once an EUA is issued, Pfizer and the US government expect that first vaccine shipments will be sent to healthcare facilities within 24-48 hours; however, it will likely take weeks to vaccinate some of the earliest batches of priority populations. Depending on supply, it will probably take 6 months or longer to vaccinate the majority of the country. Officials from Operation Warp Speed have indicated that state and local jurisdictions will be evaluated and graded on their ability to meet aggressive vaccination timelines set by the federal government. Public health experts have expressed concern that forcing health departments and health systems to proceed too quickly could ultimately have negative effects on the vaccination effort. The Association of Immunization Managers and the Association of State and Territorial Health Officers (ASTHO) continue to urge the Congress to provide sufficient funding and support to state and local health departments to support planning and operations for the mass vaccination campaign. They argue that funding on the order of US$8 billion is needed; however, only US$340 million has been distributed thus far.
According to multiple reports, the US CDC plans to issue COVID-19 vaccination cards so that individuals can verify their vaccination status, much like cards used for other vaccinations, such as the ICVP “yellow card” for yellow fever. Additionally, the CDC is reportedly designing templates for buttons and stickers that health departments and providers can provide to vaccinated individuals, similar to the “I Voted” stickers handed out to many voters on election day. These templates will be included in the CDC’s SARS-CoV-2 vaccination toolkit to “educate and promote vaccination.”
UK VACCINATION On December 2, the UK announced that its Medicines and Healthcare products Regulatory Agency (MHRA) issued an emergency authorization for Pfizer’s SARS-CoV-2 vaccine—for adults aged 16 years and older. Vaccinations are expected to begin as early as next week. Like with the US FDA’s Emergency Use Authorization (EUA), the vaccine is not fully licensed in the UK, but it is permitted to be used in response to the COVID-19 pandemic. Additionally, the UK’s Joint Committee on Vaccination and Immunisation (JCVI) issued guidance on prioritization for the initial doses of vaccine available in the UK. Not surprisingly, individuals in long-term care facilities (LCTFs) and frontline healthcare workers are in the top 2 tiers of Phase 1, followed by other high-risk individuals such as those with underlying health conditions and adults aged 50 and older. Notably, LTCF residents are the #1 priority in the UK, with healthcare workers listed as #2, whereas these 2 groups are lumped together in the US CDC’s ACIP guidance.
Reports indicate that hospitals can expect to begin receiving the first vaccine shipments as early as December 7. While LTCF residents are listed as the highest priority, a report by The Guardian (UK) suggests that vaccination efforts could start with healthcare workers due to logistical considerations, including the availability of ultra-cold freezers. Once supply increases sufficiently, access will be expanded to local and regional vaccination sites, largely operated by local primary care practitioners. The UK’s National Health Service (NHS) and the local practitioners will proactively notify eligible individuals in order to schedule a vaccination appointment, and a second appointment will be required 21 days later to receive the second dose. The UK’s Statement by Secretary of State for Health and Social Care Matt Hancock indicated that the UK has already purchased enough of the Pfizer vaccine to cover 20 million people, and the initial shipment will include enough doses for 400,000 people. In total, the UK has purchased more than 350 million doses across 7 different vaccines.
QUARANTINE DURATION The US CDC published updated guidance regarding quarantine after known exposure to SARS-CoV-2. The CDC’s quarantine guidance continues to direct individuals to quarantine for 14 days* after the last known exposure to a COVID-19 patient, but the updated guidance provides options to shorten the quarantine period. Under the new guidance, individuals who do not exhibit any COVID-19 symptoms can end their quarantine as early as Day 10* without testing and Day 7* if they have a negative diagnostic test result (RT-PCR or antigen test). Importantly, for individuals who get tested, the test specimen should be collected within 48 hours of ending the quarantine period, which means that individuals should be tested at Day 5 or later. Even if a test conducted on Day 5 or 6 is returned before Day 7, in no case should quarantine be terminated prior to Day 7.
The CDC estimates that testing at Day 5 or later (and terminating the quarantine at Day 7 or later) would reduce transmission risk to 5-12%. For individuals who do not get tested, the CDC estimates that ending the quarantine period at 10 days can reduce transmission risk to 1-10%. The transmission risk is defined as the probability that an infected individual would transmit the infection after leaving quarantine, if quarantine were ended on a given day. For context, the model estimates the transmission risk at Day 1 to be approximately 60%, with or without a negative test.
*The day of the last known exposure is designated as Day 0.
The CDC still recommends that individuals continue to monitor for symptoms and maintain strict adherence to mask use, appropriate physical and social distancing, enhanced hygiene, and other non-pharmaceutical interventions (NPIs)/risk mitigation measures for the full 14 days, even if they end the quarantine period prior to that point. Notably, the 14-day quarantine period remains the CDC’s primary recommendation, but the new options can allow individuals to return to work or other activities prior to that point while still substantially reducing transmission risk. In addition to reducing economic and other burden on affected individuals, the shortened quarantine period also reduces the stress on public health officials who monitor quarantined individuals, particularly in areas with high transmission and COVID-19 prevalence.
Some experts have criticized the new guidance, because it aims to promote compliance by easing the rules rather than increasing support for affected individuals that would enable them to complete the full, 14-day period. They argue that the government should increase the resources available to quarantined individuals—including financial and social support—in order to better enable them to complete the full 14-day period rather than allowing them to complete a shorter quarantine, which increases transmission risk. They also argue that some individuals who have the means to quarantine for 14 days will end it early, simply because that option is available to them.
FALSE NEGATIVE TESTS Researchers from Harvard University and Massachusetts General Hospital (Boston, US) published findings from a study on false negative test results for SARS-CoV-2 diagnostic tests. The study, published in Open Forum Infectious Diseases, retrospectively analyzed the results of tests administered to more than 15,000 individuals in Massachusetts in March-May in order to identify the prevalence of false negative results. They specifically evaluated nucleic acid amplification tests, such as PCR-based tests, and they defined false negative tests as at least one negative test followed by a positive test within 14 days and during the “same episode of illness.”
In total, 2,699 individuals who tested negative initially were subsequently tested again, and 60 (2.2%) of these individuals were determined to have false negative results in their initial test. Of all the 3,734 total individuals with positive test results, 1.6% had false negative results in their initial test. The researchers found that “most subjects with [false negative test results] had symptoms (52/60; 87%) and chest radiography (19/32; 59%) consistent with COVID-19.” They also determined that the proportion of false negative results peaked the same week as the overall test positivity. The study led the researchers to recommend repeat testing for suspected COVID-19 patients, particularly those with symptoms and other clinical factors consistent with COVID-19 and during periods of high COVID-19 incidence.
US SEROPREVALENCE IN DONATED BLOOD A study led by researchers at the US CDC and American Red Cross analyzed specimens collected from donated blood to determine if the SARS-CoV-2 virus was circulating in the US prior to first COVID-19 cases identified on January 19, 2020. The study, published in Clinical Infectious Diseases, included samples from nearly 7,500 routine blood donations collected across 9 US states from December 13, 2019 to January 17, 2020. The researchers performed ELISA-based tests, pseudoneutralization assays, and true viral neutralization assays to analyze for the presence of SARS-CoV-2 antibodies in the donations.
In total, 106 donations tested positive for SARS-CoV-2 antibodies. Among 90 samples that were available for subsequent testing, 84 had “neutralizing activity” against the SARS-CoV-2 virus, including 1 sample effective against the S1 subunit of the spike protein and 1 effective at blocking the ACE2 protein/receptor binding domain. The researchers identified neutralizing activity in donations from across all 9 states. The earliest specimens included in the study were collected December 13-16 in California, Oregon, and Washington, and 2% of these specimens had detectable antibodies. The overall seropositivity was approximately 1.4%, which is within the expected range of the test’s false positivity rate, but the ability of antibodies from those samples to demonstrate neutralizing activity against SARS-CoV-2 lends further support to the findings.
Some experts have questioned whether the positive results could be a result of cross-reactivity with SARS-CoV-1 or other coronaviruses; however, the study analyzed antibodies against the S1 spike protein that is more specific to SARS-CoV-2. Additionally, considering that the earliest specimens collected were found to be seropositive, it is unclear what the background rate of seropositivity might be in this population. Without a period of 100% seronegative specimens, it is possible that SARS-CoV-2 reactive antibodies existed at some low level prior to the emergence of SARS-CoV-2. The presence of SARS-CoV-2 antibodies, including neutralizing activity, does suggest that the SARS-CoV-2 virus may have been circulating in the US at a low level well before the first cases of COVID-19 were detected anywhere, let alone the US. The study does not provide definitive proof that the virus was circulating in the US in mid-December, but it certainly provides additional data in support of this argument.
EVICTION MORATORIUMS Researchers from several US universities published findings from a study (preprint) on the impact of US housing evictions on COVID-19 incidence and mortality. The research focused on the 44 states that instituted eviction moratoriums in March. Over the course of the study, 27 of the 44 states lifted their eviction moratoriums, and the researchers found that COVID-19 incidence and mortality were significantly higher in states that lifted their eviction moratoriums than in states that kept them in place. Specifically, the COVID-19 incidence in states that lifted their moratoriums was 1.6 times higher 10 weeks later and more than double at 16 weeks. Similarly, COVID-19 mortality was 1.6 times higher after 7 weeks and 5.4 times higher after 16 weeks. In total, the researchers estimated that lifting the eviction moratoriums contributed more than 430,000 excess COVID-19 cases and 10,700 excess COVID-19 deaths over the study period. COVID-19 incidence and mortality are driven by a number of complex and interdependent factors, but the researchers accounted for major variables, including testing volume and other public health interventions (eg, “stay at home” orders) in their analysis.
The study ended in September, which was around the time when the US CDC issued a national moratorium on evictions and just prior to the start of the current COVID-19 surge in the US. The report is published as we approach the end of the CDC’s national moratorium, which is scheduled to terminate on December 31. The study underscores the need for social support, in particular to keep individuals and their families in their homes.
MAFIA LOCKDOWN PROTESTS Anti-lockdown protests have emerged in Italy as business owners fear the new restrictions may hurt their businesses. Organized crime has long profited from failing businesses, particularly during emergencies, by investing in or taking over operations from owners who do not have funding available to remain in business on their own. But COVID-19 restrictions, including increased law enforcement presence, are reportedly hindering the mafia’s ability to conduct their illicit operations. In response, the mafia has orchestrated violence at anti-lockdown protests in Naples last week. Several known mafia members thought to be directing violence were identified at the protests, where police and several journalists were assaulted. Regional Governor Vincenzo de Luca described the acts as “guerilla warfare.” The operating restrictions on bars and restaurants, including nightclubs and other nightlife, are estimated to have decreased the Camorra mafia’s drug revenue by as much as 60 percent. These incidents further illustrate the complex downstream effects of COVID-19 and associated risk mitigation measures.
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