Our "Discussions" section of Medical Legible is used to transmit information on relevant topics for readers that are both important, and sometimes, unwieldy. Medical research evolves quickly. Constantly. Keeping track of it, synthesizing it, and even putting it to good use can be overwhelming. "Discussions" will attempt to make that a little easier, using up-to-date, peer-reviewed work meant to represent information of the highest quality. For the sake of clarity, "SARS-CoV-2" will be used to refer to the virus itself, and "COVID-19" will be used to refer to the syndrome, or set of symptoms, associated with SARS-CoV-2 infection. In-text citations and bibliography in Vancouver style.
Today's topic: updates on COVID-19
The discourse surrounding vaccines has always been fraught with misinformation, hyperbole, and hidden agendas. In fact, both supporters of vaccines and those against them will claim the "other side" is guilty of such tactics. Let me be clear on one thing: this website fully supports vaccination and its place in medical practice. One should still consult their doctor(s) about receiving them, but there is no doubt they are safe and efficacious. This includes all vaccines for SARS-CoV-2, the virus that causes COVID-19. The public discussion surrounding the COVID-19 vaccine specifically has typically been polluted by big words from small people for the last year. The last six weeks, however, has seen a decided change in that tenor; it is now dominated by a more science-based hysteria.
The Astrazeneca Vaccine
In March, reports began to surface in the EU of rare blood clots in those taking the AstraZeneca vaccine for SARS-CoV-2 (the virus that causes COVID19). This triggered temporary halts on its distribution in multiple countries across the globe. Cornering exact data on the incidence of these events is difficult as some of it comes in the form of government reports (1), while other data is derived from databases that are analyzed in peer-reviewed journals (2). This data is then reported in innumerable articles widely accessible to the public, and because this reporting is based on data that is constantly being updated, it is never the same from week to week.
The culprit clot being widely reported is known as Cerebral Venous Sinus Thrombosis (CVST). The cerebral venous sinuses make up a reservoir network of cranial veins that help drain deoxygenated blood from the brain back to the heart (see below) (3). These cerebral thromboses obstruct blood flow in these vessels, and because the skull has a fixed volume, build up of blood due to a clot can cause stroke, seizure, headache, and even leaks of the cerebrospinal fluid.
By The Numbers
Current research suggests the incidence of CVST in the general population is 0.22-1.57 cases per 100,000 (4-6). Risk factors include oral contraceptives, pregnancy, cancer, infection, head injury, and disease states that increase clotting (7). At least a few of these explain the 3:1 increased incidence in females over males as well as the median age of 37 (8). This contextual data is often missing from discussions surrounding the AstraZeneca vaccine. In fact, the first questions when adverse drug reactions (ADRs) occur should be "how often do these events happen without the vaccine, when, and to whom?" Just because a clot occurs after a vaccine does not it mean it was caused by the vaccine.
Corralling data on the incidence of CVST after vaccines is more difficult; multiple bodies are collecting data and do so with varying degrees of rigour. The highest incidence was found in a German database showing 13 cases out of 1,600,000 doses given (2); the EMA, which included this data in its ongoing surveillance, has reported 18 cases in 18,000,000 people vaccinated in Europe (9); the MHRA, a UK regulatory agency, reports 22 cases within 18,100,000 doses (1).
It is difficult to assess the incidence here because when only the number of doses is counted, it is impossible to tell whether those counts include any second doses. At the time of this data's publication, it's safe to say most were probably first doses as it was only healthcare workers that were getting second doses. The EMA's data mentioned above amounts to 0.1 cases per 100,000 people vaccinated.
If we wanted to extrapolate the German database, this amounts to 0.81 cases per 100,000 doses; the MHRA data amounts to 0.12 cases per 100,000. Given these are rates per dose, it's safe to assume they are slightly underestimating the risk per person as some of these doses were given to the same person in the form of their second dose.
So where does that leave us? 0.1 per 100,000 (the EMA) is far below the baseline rate of 0.22-1.57 per 100,000. 0.81 and 0.12 cases per 100,000 (German and MHRA databases respectively) are either at the baseline rate or below it, even if we consider them to be slight underestimates.
Should you be worried?
The answer to this question right now is, "no one." It does not appear that there is any signal in the preliminary data to suggest the incidence of CVST is any higher in vaccinated people than in the general population. You could even twist yourself into a pretzel and interpret the above data as suggesting the vaccine has a protective effect against CVST, though I would not.
Let me be clear about one thing: we can not conclude from this data that there is no risk of CVST associated with the vaccine. However, right now, we have no solid data to suggest that it is. This is a crucial distinction, both within the scientific literature, and in the real world of public health.
When countries pause vaccinations for a period of time, it is a safe assumption that this will lead to an increase in COVID-19 spread (though the extent is unknown). Since the mortality of COVID-19 is not zero, increased spread means more people die when fewer people get the vaccine.
Whether a country should, or shouldn't, have paused their AZ vaccine program is not for me to say. Science depends on a never-ending iterative process of review which yield incremental improvements over time. The purpose for this discourse is to assuage worries of people experiencing vaccine hesitancy. The bottom line: if you have the opportunity to get the AZ vaccine, you should take it.
Is this important?
In the midst of a global pandemic, a decision to receive or reject a vaccine can have sometimes-unknown consequences, including medical morbidity, and death. Multiplied over the millions of people in a city, or the billions of people worldwide, and it quickly becomes clear that under-vaccinating can be catastrophic. It is challenging, however, to contextualize risk. There are innumerable articles published, some better than others, that offer comparisons of various risks you may or may not know you are subject to every single day, in an effort to convince those hesitant towards vaccines, that vaccine risk itself is small compared to risks one is exposed to every single day. Let's dive into some of those risks.
CVST is a particularly nasty version of a group of clots known as venous thromboembolisms (VTE). What's important to know about VTEs is they are clots (thrombo-) confined to veins (venous) that have the potential to travel to a location different from where they were formed (embolism). VTEs come in many different flavours; deep vein thromboses (DVTs), named for the type of vein in which they form, often develop in the leg, but can also be found in the arm. On their own, they can cause swelling, cramping, and pain, but their real danger is in their ability to embolize, or travel, to the lung, causing a different kind of VTE known as a pulmonary embolism (PE). Not all PEs are the result of leg DVTs, and not all DVTs result in PEs, but the association between them is strong. A lot is made of PEs because of their potential to cause pulmonary infarctions, reduced blood oxygenation, and strain on the cardiovascular system (10). Ultimately, large and/or untreated PEs can be fatal.
The overall incidence of VTE is 70-113 cases/100,000 people/year (11). There is no major difference in incidence between males and females, but age is a major risk factor: 25-35 year olds are ten to fifteen times less likely to suffer any VTE as compared to those 70-79 years old. In some epidemiological studies, up to half of VTEs are PEs if autopsy is included. Aside from age, the two most significant risk factors for VTE are cancer and recent surgery. However, among modifiable risk factors with strong associations to VTE are smoking and taking the oral contraceptive pill (OCP).
A meta-analysis in 2014 showed that smoking increases your risk of all VTEs by 24%, and that even former smokers have a 5% higher risk of VTE years after quitting (12). It has also been shown that there is a dose relationship, where your risk of VTE increases by 10% for every ten additional cigarettes smoked per day (13), though this is confounded by both body weight, and the length of time one has smoked this amount.
The risks of VTE in contraceptive use are more stark. While the evidence is equivocal as to whether progestin-only contraceptives (POCs, including pill, injectable, and implantable modalities) lead to increased rates of VTE (14), all other combined oral contraceptives show 50-100% increased rates of VTE as compared to POCs (15).
What does it all mean?
We have digested many statistics to this point, admittedly without very much meaning. Why is it that the CDC, probably along with your doctor, are staunchly advocating for vaccination if there's a chance it could be associated with a specific, dangerous type of clot? The answer is simple: even if it was associated with a minor increase in the risk of all clots, including CVST, the risk is almost equal to baseline numbers, and far lower than all modifiable risk factors for VTE. This includes, smoking, contraceptives, and as we'll now discuss, catching COVID-19 itself.
Severe COVID pneumonia has been associated with a 25% increase in risk of VTE, overall (16). It bears repeating; 25 out of every 100 people with severe COVID pneumonia will suffer some form of VTE. In another study of hospitalized patients, this time not discriminating by severity, this incidence was 46% (17). There is even evidence that those treated prophylactically for VTE (18,19) and those on full anticoagulation for previous VTE (20) are at higher risks for subsequent VTE.
Aside from increased rates of VTE, suppression of the immune system, loss of platelets (crucial for clotting), and disseminated intravascular coagulation, have been found with increasing prevalence in COVID-19 (21). Cardiac injury has been documented both as a result of COVID-19, as well as a risk factor for severe COVID pneumonia (22). A not-uncommon sequel to COVID-19 infection is the necessity for ongoing oxygen support, even in the very young who are discharged from hospital. Pulmonary fibrosis, a well-known result of acute respiratory distress syndrome (ARDS), may be the culprit (23). COVID-19 has also been associated with testicular damage (24), acute pancreatitis (25), and exacerbations of inflammatory bowel disease (26). Strikingly, when compared to stroke patients without COVID-19, those who suffer stroke after contracting COVID-19 are younger, have strokes in larger blood vessels, suffer greater deficits, and die at higher rates (27). Loss of smell and taste, once thought but a peculiarity of the disease, is now a well-documented adverse effect of COVID-19, which in certain cases has been shown to be lost indefinitely (28).
At the best of times, sensationalizing the risk of CVST is the result of ignorance on the part of reporters. At the worst of times, it is driven by an anti-vaccination agenda meant to sow fear and distrust among the general population. Regardless of the cause, these risks are both exaggerated and poorly understood. The risk of CVST after the AstraZeneca vaccine is vanishingly small, and it pales in comparison to the benefits it confers by protecting against COVID-19 and the adverse events linked to infection. Unfortunately, discussion around the adverse reactions to vaccines ignores both the baseline incidence of these conditions in the population, as well as the dangers of not getting vaccinated. As it stands, there is no reason to refuse a vaccine if offered one; the benefits to you and those around you far outweigh the risks. You might even be saving the life of someone you haven't even met yet.
Bibliography
25. de-Madaria E, Capurso G. COVID-19 and acute pancreatitis: examining the causality. Nat Rev Gastroenterol Hepatol. 2021 Jan;18(1):3–4.
26. Sanz Segura P, Arguedas Lázaro Y, Mostacero Tapia S, Cabrera Chaves T, Sebastián Domingo JJ. Involvement of the digestive system in covid-19. A review. Gastroenterol Hepatol. 2020 Jun 19;
27. Nannoni S, de Groot R, Bell S, Markus HS. Stroke in COVID-19: A systematic review and meta-analysis. Int J Stroke Off J Int Stroke Soc. 2021 Feb;16(2):137–49.
28. Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol - Head Neck Surg. 2020 Aug;277(8):2251–61.