UK: Updated NERVTAG Report On Increased Severity With COVID Variant B.1.1.7

Mutation of SARS-CoV2 - current variants of concern  - ECDC  

#15,805

On the 21st of January, in UK: NERVTAG paper on COVID-19 variant of concern B.1.1.7, we saw the first analyses (from LSHTM, The University of Exeter, Imperial College London and the PHE) to suggest the UK variant B.1.1.7 might be more severe than the the previously dominant `wild type' variants.  

That announcement was presented in a NERVTAG report, which found there was a realistic possibility that VOC B.1.1.7 is associated with an increased risk of death compared to non-VOC viruses. That increased risk appears at this time to be about 30%.

A `Realistic Possibility' is defined by the scale below as somewhere between a 40% and 50% confidence level. Something less than a slam dunk, but concerning nonetheless. 

While utilizing different methods, these 4 analyses were based on shared, and limited, data. Since then we've seen more detailed information emerge (see LSHTM Preprint: Increased Hazard of Death in Community-tested Cases of SARS-CoV-2 Variant of Concern 202012/01), resulting in greater acceptance of these early findings. 

On Friday, NERVTAG released a new report adding analyses from many more research teams and based on a much larger, and more diverse dataset, which doubles down on the original findings and suggests potentially an even greater increase in severity.

While not all of these studies reached the same conclusion, enough did to reinforce the notion that the B.1.1.7 variant likely carries somewhere between a 30%-70% increased risk of death.  

The full 13-page report can be downloaded from HERE.  I've only reproduced the summary below.  While the new range of increased severity and/or fatal outcomes has increased, in absolute terms the risks of dying from COVID remain low. 

Summary

1. On Thursday, 21st January, NERVTAG presented evidence to SAGE of increased disease severity in people infected with variant of concern (VOC) B.1.1.7 compared to people infected with non-VOC virus variants. In that report it was stated that ‘data will accrue in coming weeks, at which time the analyses will become more definitive’.

2. Here we report updated and additional analyses, which together strengthen the earlier finding of increased disease severity in people infected with VOC B.1.1.7 compared to other virus variants.

3. Independent analyses of the risk of hospitalisation and death for S-gene target failure (SGTF; a proxy for VOC B.1.1.7 in the UK) cases and non-SGTF (non-VOC) cases are (also see data table in annex): 

a. LSHTM: reported that the relative hazard of death within 28 days of test for VOC-infected individuals compared to non-VOC was 1.58 (95%CI 1.40–1.79), or 1.71 (95% CI 1.48- 1.97) if adjustment is made for misclassification of SGTF and missingness of data.

b. Imperial College London: mean ratio of case fatality ratio (CFR) for VOC infected individuals compared to non-VOC was 1.36 (95%CI 1.18-1.56) by a case-control weighting method, 1.29 (95%CI 1.07-1.54) by a standardised CFR method.

c. University of Exeter: an updated analysis estimated the mortality hazard ratio for VOC-infected individuals compared to non-VOC was 1.7 (95% CI 1.3 –2.2) in a matched cohort study.

d. Public Health England: an updated matched cohort analysis has reported a death risk ratio for VOC-infected individuals compared to non-VOC of 1.65 (95%CI 1.21-2.25).

e. Public Health Scotland: the REACT-SCOT study found that the hazard ratio was 1.08 (95% CI 0.78-1.49) for death and 1.40 (95% CI 1.28-1.53) for death or hospital admission in SGTF compared to non-SGTF cases.

f. Public Health Scotland: the EAVE-II study found the risk of being admitted to hospital is higher for cases with SGTF than for those who are S Gene positive - risk Ratio 1.63 (95% CI 1.48, 1.80). The relative risk of death within 28 days of a positive test was 1.37 (95% CI 1.02, 1.84) for SGTF compared to S Gene positive.

g. The Hospital Onset Covid Infection (HOCI) study: found the overall HR for inhospital mortality of B.1.1.7 was 1.09 (95% CI 0.86-1.36, P=0.48). Increased mortality was only observed with the VOC in women over 65 years. The overall HR for ITU admission for B.1.1.7 was 1.15 (95% CI 0.86-1.53, P=0.35).

h. ICNARC and QRESEARCH: found a higher risk of ICU admission for VOC patients (HR: 1.44; 95% CI: 1.25, 1.67) compared to non-VOC patients and no significant difference in the hazard of ICU mortality between the two groups (HR: 0.94; 95% CI: 0.82, 1.09).

i. ONS analysis: found that whilst the hazard ratio suggests that the B.1.1.7 variant is associated with higher risk of all-cause mortality, the number of deaths are too low for reliable inference.

j. CO-CIN (hospitalised patients only): found no statistically significant change in in-hospital CFR comparing proven B.1.1.7 (n=32) with non-VOC (n=184) (OR 0.63, 95%CI 0.20 – 1.69).

k. CO-CIN (hospitalised patients only): a repeat analysis with an updated dataset did not provide evidence to suggest that the variant of concern is linked to a higher risk of in-hospital case fatality (OR 0.67, 95%CI 0.32, 1.40).

l. LSHTM: a population-level analysis at the level of upper-tier local authorities resulted in estimates of a 1.4 (1.3-1.5) times higher number of hospitalisations per case and 1.4 (1.2-1.5) times higher number of fatalities per hospitalisation associated with VOC.

4. There are inevitable limitations to these datasets, including representativeness, power, potential biases in case ascertainment, unmeasured confounders, and secular trends.

5. Whilst studies limited to in-patients did not identify evidence of increased disease severity, this is not incompatible with an overall increase in disease severity.

6. Whilst earlier analyses using linked community testing and mortality data showed comparable increases in case fatality ratios, these were all based on the same datasets, and therefore subject to similar biases reducing the level of certainty in the findings. More recent analyses have added a wider range of data sets and been able to control for additional confounders, increasing confidence in the association of the VOC with increased disease severity.

7. Based on these analyses, it is likely that infection with VOC B.1.1.7 is associated with an increased risk of hospitalisation and death compared to infection with non-VOC viruses.

8. It should be noted that the absolute risk of death per infection remains low

This latest report is subject to a number of limitations, as elucidated below:

  3. Limitations:

a. The majority of these analyses are limited to community testing data, except the HOCI and LSHTM ecological studies.

b. Less than 10% of all deaths are included in some datasets and the number of deaths are too low for reliable inference.

c. There are several confounding factors which may not be adequately adjusted, for example, in these datasets nursing home status may be poorly identified, there may be confounding by setting of infection acquisition, confounded by comorbidities or goals of care (e.g. no transfer to acute care hospitals/advanced measures.)

d. While these analyses are adjusted for age, sex, deprivation, LTLA etc., given increased transmission potential of VOC, this may not be sufficient adjustment if not a) stratified by LTCF and b) adjusted for comorbidities and c) secular trends.

While it is difficult to put an exact number on the increased risk of death or hospitalization posed by this emerging variant,  report concludes:

Conclusion

24. There is evidence from analysis of multiple different datasets that infection with VOC B1.1.7 is associated with an increased risk of hospitalisation and death compared to infection with non-VOC viruses.

25. There are potential limitations in all datasets used but together these analyses indicate that it is likely that VOC B.1.1.7 is associated with an increased risk of hospitalisation and death compared to infection with non-VOC viruses.