Risk factors for severe disease

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This page collects observations, interpretations, and consequences for action about Risk Factors of SARS-CoV2. Please observe the structure of the page, when you add your content. Please use references where possible. Remember to find the relevant page. For example, if your observation is about Sources, please use that page, instead of posting your content here.

What is already known[edit]

  • Case fatality of COVID19 increases with age. This is a consistent observation world wide.
Age-group (years) % symptomatic cases requiring hospitalisation % hospitalised cases requiring critical care Infection Fatality Ratio
0 to 9 0.1% 5.0% 0.002%
10 to 19 0.3% 5.0% 0.006%
20 to 29 1.2% 5.0% 0.03%
30 to 39 3.2% 5.0% 0.08%
40 to 49 4.9% 6.3% 0.15%
50 to 59 10.2% 12.2% 0.60%
60 to 69 16.6% 27.4% 2.2%
70 to 79 24.3% 43.2% 5.1%
80+ 27.3% 70.9% 9.3%

Table 1: Current estimates of the severity of cases. The IFR estimates from Verity et al. have been adjusted to account for a non-uniform attack rate giving an overall IFR of 0.9% (95% credible interval 0.4%-1.4%). Hospitalisation estimates from Verity et al. were also adjusted in this way and scaled to match expected rates in the oldest age-group (80+ years) in a GB/US context. [1]

Infectious Dose[edit]

What is already known[edit]

  • The evidence suggests an association of viral dose with the severity of the disease. However, the evidence of the relationship is limited by the poor quality of many of the studies, the retrospective nature of the studies, small sample sizes and the potential problem with selection bias. [2]

Observations[edit]

Analysis and interpretation[edit]

Consequences for Action[edit]

Discussions about 'replaced mortality'[edit]

Observations[edit]

  • The University of Cambridge published a comparison of COVID19 case fatality to the regular annual mortality per agegroup. This blog contains an inappropriate graph, where case fatality is plotted in a semilog presentation of overall population mortality by age. [3]

Analysis and interpretation[edit]

  • The Spiegelhalter blog uses the table of Ferguson et al (see Table 1 above), and interprets this (erroneously) as COVID19 mortality.
    • Case fatality is a risk percentage: risk of death due to a disease per 100 patients (no specific time period). Mortality is rate: the risk of death per population (usually 100k or 1M) over a certain period of time (usually 12 months). Comparing both directly is like comparing apples and chewing gum. The only similarity between the two, is that you can put it in your mouth.
    • Better comparison would be to look at the case fatality RATE (that is, the percentage of COVID19 patients dying of COVID19 over a certail period of time. Let's say 1 month.) and compare that with the age-specific mortality rate in the general population over the same time period (so 1 month, not 12).
    • If we do that, we get the following table:
Age-group (years) Overall annual mortality (% per 12 months) Average MONTHLY mortality (%) COVID19 Case Fatality Rate per month (%) Mortality Ratio
0 to 9 0,01% 0,001% 0,002% 2,40
10 to 19 0,03% 0,002% 0,006% 2,88
20 to 29 0,05% 0,004% 0,030% 8,00
30 to 39 0,10% 0,008% 0,080% 10,11
40 to 49 0,23% 0,019% 0,150% 7,83
50 to 59 0,49% 0,041% 0,600% 14,69
60 to 69 1,20% 0,100% 2,200% 22,00
70 to 79 3,38% 0,282% 5,100% 18,11
80+ 10,79% 0,899% 9,300% 10,34


  • Please note that the mortality tables are for UK Population. COVID19 mortality data come from Ferguson et al.
  • This comparison shows that in every age group, COVID19 mortality is significantly higher than one would expect of regular (all-cause) mortality.

Consequences for action[edit]

  • Blogs such as that of Spiegelhalter must be contradicted clear and widely, in order to avoid that the misconception takes hold that COVID19 mortality is simply replacing regular age-specific mortality. The suggestion that 'these old and weak people would have died anyway' is completely against everything we currently know about COVID19, and must be refuted before it settles in the minds of some decision makers.

Rumours about interaction with medicines[edit]

What is already known about this[edit]

  • Long-term use of NSAIDs has been shown to be associated with an increased risk of a heart attack. Individual data from four studies of 446,763 individuals including 61,460 with acute myocardial infarction showed that taking any dose of NSAIDs for one week or more was associated with a 50% increased risk of a heart attack. Odds ratios for increased: Ibuprofen, 1.48 (1.00 to 2.26); Diclofenac, 1.50 (1.06 to 2.04) and Naproxen 1.53 (1.07 to 2.33).
  • A retrospective analysis of 9,793 patients with incident acute myocardial infarction in Taiwan between 2007 and 2011 found that the use of NSAIDs during acute respiratory infection was associated with [4]:
    • Increased risk of a heart attack; adjusted odds ratio * 3.41; 95% CI 2.80–4.16); [4]
    • Without NSAIDs led to a 2.7-fold increased risk (aOR = 2.65; 95% CI = 2.29 to 3.06): [4]
    • Parenteral NSAIDs (any non-oral means of administration) was associated with much higher risk (OR = 7.22; 95% CI = 4.07 to 12.81). [4]
  • Verdict: there is a need for caution when using NSAIDs in the context of acute respiratory infections (ARI). Pre-existing medications and conditions need to be taken account of when deciding to prescribe NSAIDs for symptomatic ARI. The lowest effective dose should be prescribed for the shortest period of time. Parenteral use of NSAIDs during an ARI should be avoided.[4]

NSAIDs do not significantly reduce total symptoms or duration of respiratory infections.

Observations[edit]

  • Recent studies suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. This observation makes some researchers hypothesize that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. [5]
  • "Ibuprofen should not be used for managing symptoms", say some doctors. [6]
  • In the Netherlands, rumours circulate (and are even discussed at National Television) that Ibuprofen and NSAID in general increase the risk of severe COVID19 disease outcome.
  • In Greece, the same rumours have led to a shortage of paracetamol in the pharmacies. The representative of the Ministry of Health said that there is not enough evidence thus it would be good when people have symptoms to prefer paracetamol.

Analysis and interpretation[edit]

  • The study of Fang et al. is relevant and credible. However, the study alone does not (yet) constitute convincing evidence that ACE2-inhibitors are risk factors for COVID19 and severe outcome. The association is plausible, yet requires more study to generate supporting evidence.
  • Notwithstanding the above, it is important to take note of the study of Fang et al. The observation deserves consideration, especially by clinicians treating patients who are in known risk groups for severe COVID19
  • The news item in the BMJ by Michael Day on Ibuprofen, seems to support the rumours that are observed in some countries. This is still at the level of case reports and observations, without explanatory study results.
  • After the news item in BMJ by Michael Day, the WHO places an announcement that they have no indication to recommend against ibuprofen.

Consequences for action[edit]

  • Additional studies to find supporting evidence (or refuting) are needed for both topics (ACE-inhibitors and Ibuprofen)
  • Clinicians should take note of the study of Fang et al., and make decisions on a case by case basis

Does Smoking increase the risk of COVID19?[edit]

What is already known about this[edit]

  • Verdict Yes: Smoking is a risk factor for all respiratory infections. It increases the risk of becoming infected with acute respiratory infections, as well as the risk of those infections becoming severe. As well as affecting the respiratory system, smoking can also cause or exacerbate co-morbid conditions such as cardiovascular disease and diabetes. Evidence from China shows that comorbidities such as cardiovascular disease, respiratory conditions, and diabetes all increase risk of serious complications and death from COVID-19.[7]
  • As well as increasing risks of acute respiratory infections in people who smoke, second-hand smoke also increases risks of acute respiratory infections in young people.[7]

References[edit]

  1. Ferguson, Neil M., et al. "Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand."
  2. SARS-CoV-2 viral load and the severity of COVID-19. The Centre for Evidence-Based Medicine (CEBM) Oxford. March 26, 2020.
  3. How much ‘normal’ risk does Covid represent? By David Spiegelhalter. University of Cambridge. 21 March 2020 https://medium.com/wintoncentre/how-much-normal-risk-does-covid-represent-4539118e1196
  4. 4.0 4.1 4.2 4.3 4.4 NSAIDs in Acute Respiratory Infection. The Centre for Evidence-Based Medicine. COVID19 Evidence. March 16, 2020
  5. Fang, Lei, George Karakiulakis, and Michael Roth. "Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?." The Lancet Respiratory Medicine (2020).
  6. Michael Day. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists BMJ 2020;368:m1086 doi:10.1136/bmj.m1086 (Published 17 March 2020)
  7. 7.0 7.1 Smoking in acute respiratory infections. The Centre for Evidence-Based Medicine. March 20, 2020

Images[edit]

WHO announcement Ibuprofen (18 March 2020)
News item BMJ 17 March on Ibuprofen and Covid19