CFR, IFR, and You: What is the true COVID-19 death rate?

Approximately 6 months off from the official start of the COVID-19 outbreak in China (although the actual start of the outbreak is debated) and over 3 months from the initial nationwide shutdown in the United States, there is much uncertainty as to the true mortality rate of the disease. It is first important to define terms, as there are different types of “mortality” or “fatality” rates.

Defining Case Fatality Rate vs. Infection Fatality Rate

As shown in Figure 1, the reported number of COVID-19 cases does not necessarily represent the true number of infected individuals. The confirmed number of cases (positive tests for active infection) is smaller than the number of probable infected (sick patients believed to be infected based on symptoms and likely exposure but who never received a diagnostic test), which is smaller than the actual number of total infected individuals.

Figure 1. Relationships between measured number of COVID-19 cases via different metrics and number of deaths (not necessarily to scale)

A case fatality rate(CFR) is the proportion of deaths from a disease compared to the number of people diagnosed.

An infection fatality rate (IFR) is the proportion of deaths among all infected individuals, in other words the true fatality rate. While related to the CFR, an IFR attempts to estimate the mortality rate including non-diagnosed cases (e.g. not tested, asymptomatic). An IFR should be lower than the CFR, since the denominator would be expected to be larger.

 

Visually, these can be represented as shown in Figure 2 below, based on the relative differences in confirmed vs. total cases as shown in Figure 1. Note that deaths can be scored as either confirmed deaths or probable deaths. As testing becomes more widespread, the difference between “confirmed” and “total” infected shrinks, as does the difference between CFR and IFR.

Figure 2. Visual representation of Case Infection Rate (CFR) and Infection Fatality Rate (IFR)

Going Vape Shit Over E-cigarettes

Vaping History and Use

According to VapingDaily.com, vaping is “the act of inhaling vapor produced by a vaporizer or electronic cigarette. The vapor is produced from a material such as an e-liquid, concentrate, or dry herb.” An important distinction from traditional “smoking” is that vaping refers to breathing in heated water vapor, NOT the incineration products of a burning reaction. The earliest form of vaping traces all the way back to 440 BC, with stories of people inhaling the resulting vapor from marijuana placed onto hot stones. The hookah, invented in 1542, is also analogous to vaping. The first true vaporizer was invented by a Korean war veteran in 1962, although the idea for an e-cigarette comes from 1927. The modern e-cigarette was created by a Chinese pharmacist in 2003.

E-cigarettes (or “vapes”) work by using a battery to heat up vaping material until it becomes an inhalable vapor. While waxy concentrates and dry herb can be vaporized as well, vapes typically utilize an easily vaporizable liquid such as propylene glycol or vegetable glycerin. Flavoring and drugs, typically nicotine, can be dissolved within this liquid for easy inhalable delivery to the user upon heating. Often, the dissolved drug is nicotine. The presence of nicotine in these cigarettes is both functionally useful and problematic, depending on the user. Vapes come in many sizes, styles, and options (Figure 1). These options include various accessories and cartridges that may contain flavoring or recreational drugs.

Figure 1: Examples of vape designs. Source: https://www.cdc.gov/tobacco/basic_information/e-cigarettes/pdfs/Electronic-Cigarettes-Infographic-508.pdf

Nicotine in E-cigarettes

E-cigarettes can serve as an effective smoking cessation method. Use of nicotine e-cigarettes resulted in 7% of regular smokers remaining abstinent from smoking after 6 months, slightly higher than the rate from nicotine patches (5.8%) and higher still compared to e-cigarettes without nicotine (4.1%). Additionally, while the toxicity of vapes can vary depending on what they contain and the mechanics of heating, the UK government declared in 2015 that use of e-cigarettes is approximately 95% less harmful than traditional cigarettes. Heating of vape liquid can result in exposure to various carcinogenic metals and other toxic compounds, however vaporization is likely to produce much less harmful volatile organic compounds than traditional cigarettes. This is likely due to both the absence of tobacco and reduced release of chemical degradation products that would be produced from burning.

Vaping has been on the rise for the past several years, especially among young people. According to Pew Research (Figure 2), the percentage of 12^th graders who report having vaped at least once in the past month doubled from less than 14% to 27% between 2016 and 2018. A similar trend was presented in a study by the New England Journal of Medicine, which reported prevalence increases from 11.0% to 25.4% among 12^th graders between 2017 and 2019 (Figure 3). While the inclusion of nicotine in e-cigarettes can be beneficial for current smokers aiming to quit, it is obviously problematic for young non-smokers. In addition to promoting nicotine addiction in general, there is evidence that e-cigarette use is associated with a much greater likelihood to begin smoking traditional cigarettes as well (however this association cannot establish a causal relationship).

EVALI outbreak and causes

Beyond only these concerns, 2019 brought a very concerning spike in e-cigarette or vaping product use-associated lung injury, formally coined as EVALI. As of December 27, 2019, EVALI has resulted in 2,561 hospitalizations and 55 deaths. While cases have been gradually increasing since 2017, there was a sudden outbreak beginning in June 2019 prior to a decline in new cases as of September 2019. As described above, modern e-cigarettes have been in use since 2003. Based on this timeline, what could have been the cause? Could it simply be due to the rapid increase in prevalence of use (Figures 2-3), or did something change about either the e-cigarettes themselves or their content?

Figure 2: The percentage of 8^th grade, 10^th grade, 12^th grade, and college students who self-reported vaping during the last month. The highest rate exists among 12^th graders, however all grades increased at a similar rate between 2016 and 2018. Source: https://www.pewresearch.org/fact-tank/2019/09/26/vaping-survey-data-roundup/

Figure 3: Prevalence of nicotine vaping among adolescents over different time intervals. Results are presented for 2017, 2018, and 2019. Source: https://www.nejm.org/doi/full/10.1056/NEJMc1910739

An important consideration in discovering the cause of the outbreak was the fact that the outbreak was restricted to the United States, despite being used throughout the world. This suggested that the source of EVALI was not inherent to e-cigarettes overall, but must be something that is specifically being used in the United States. A CDC investigation found that the vast majority of EVALI cases were associated with products containing THC, the active ingredient in marijuana that makes you high. The presence of the chemical vitamin E acetate was a common component in the e-liquid of these THC-containing vapes. Researchers also identified vitamin E acetate in the lung fluid of 94% of examined patients, compared to 0% of controls. Vitamin E is naturally found in foods and also can be useful as a supplement (despite some risks), however the acetate form appears to be the cause of lung toxicity from vaping when inhaled.

Targeting to Youth

As would be expected, the majority of THC vapes are purchased off the black market and therefore are likely not subject to much quality control or oversight. Black market products are most likely to be used by youths who do not have legal access to legal products. Therefore, EVALI is even more concerning in that it is likely to affect children. Even certain legal products are more likely to be used by younger customers, including those who may have not otherwised smoked. Even though many of the major e-cigarette companies now claim that their products are only for adults, the use of social media advertising and fun flavors suggests that targeting youths was at least once an active strategy.

As discussed above, e-cigarettes may have actual health benefits for adult smokers and remain a potentially safer recreational option for all adults. However, in response to the EVALI outbreak and the rapid increase in youth usage, the FDA and local health departments have been under strong pressure to more regulate vaping access overall. San Francisco completely banned the sale of e-cigarettes to anyone beginning in 2020 and other localities are likely to follow. Most recently, President Trump announced on the last day of 2019 that he was planning to ban all e-cigarette flavoring except tobacco and menthol. Allowing these two flavors to remain, especially menthol, was a compromise in favor of both vape shops as well as adult customers who claim they are trying to get away from the tobacco smell and flavor. Time will tell whether this partial ban will adequately minimize youth vaping, however any regulation cannot prevent access to black market products.

For an interesting discussion with some more details on the issue from a nuanced perspective, I highly recommend the Freakonomics podcast episode about vaping regulation. The podcast additionally dives into some of the nuances of previous and existing FDA regulation of e-cigarettes, and how that actually restricts the ability of vape companies to advertise only as a smoking cessation aid.