It's an idea we've discussed previously with avian influenza (see Differences In Virulence Between Closely Related H5N1 Strains), seasonal influenza (see EID Journal: Emergence of D225G Variant A/H1N1, 2013–14 Flu Season, Florida), and with COVID-19 (see BMJ: New UK Variant May be Linked to Increased Death Rate, Early Data Indicate).
An idea that may help explain why the case fatality rate for H5N1 in Indonesia was more double that reported by Egypt. Or why human infection with H5N1 in Bangladesh was nearly always mild, and no human infections have been reported in India.That small changes in a virus can cause substantial changes in its impact on its host.
The recent revelation that the UK B.1.1.7 COVID variant may be 30% deadlier than the `wild-type' COVID (see SMC: Expert Reaction To The NERVTAG Report That The UK Variant May Be Linked to Higher Mortality) is another example.
Today we've a new study by researchers at Tulane University - published in the Journal Viruses - that defines 4 distinct clades of COVID-19, and suggests there may be as much as a 5-fold difference in mortality rates between them.While differences in transmissibility between COVID variants have been well established, the data on differences in mortality remains quite limited. For the most part, age and comorbidities have been viewed as the prime determining factors for severity and lethality of COVID infection.
Clade 1, which began in China, is cited as having the lowest mortality rate 2.06% [95%CI 1.28–3.32], followed by Clade 2 with 6.03% [95%CI 4.35–8.31], Clade 3 with 11.61% [95%CI 8.97–14.91], and Clade 4 with 5.84% [95%CI 4.34–7.83].
According to this study, North America appears to have the lowest level of Clade 3 - which has the highest mortality rate - while South America has the most. Asia, meanwhile, has the highest percentage of Clade 1, which has the lowest mortality.
Their conclusions are based on relatively limited information on 2508 patients and genomic sequencing is fairly limited around the globe, and may be less than representative of the global distribution of these clades.
Still, it's a fascinating read that may help explain why some countries have been hit much harder by COVID than others. I've only reproduced the abstract and discussion portions from the study. Follow the link to read it in its entirety.
Genomic Signatures of SARS-CoV-2 Associated with Patient Mortality
by Eric Dumonteil 1,*,Dahlene Fusco 1,2,Arnaud Drouin 2,3 and Claudia Herrera 1
1 Department of Tropical Medicine, Vector-Borne and Infectious Disease Research Center, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA2 Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA
3 Department of Pathology, School of Medicine, Tulane University, New Orleans, LA 70112, USA*Author to whom correspondence should be addressed.
Academic Editors: Luis Martinez-Sobrido and Fernando Almazan Toral
Viruses 2021, 13(2), 227; https://doi.org/10.3390/v13020227 (registering DOI)
Received: 1 December 2020 / Revised: 12 January 2021 / Accepted: 27 January 2021 / Published: 2 February 2021 (This article belongs to the Collection Coronaviruses)
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Abstract
Infections with SARS-CoV-2 can progress toward multiple clinical outcomes, and the identification of factors associated with disease severity would represent a major advance to guide care and improve prognosis. We tested for associations between SARS-CoV-2 genomic variants from an international cohort of 2508 patients and mortality rates. Findings were validated in a second cohort.
Phylogenetic analysis of SARS-CoV-2 genome sequences revealed four well-resolved clades which had significantly different mortality rates, even after adjusting for patient demographic and geographic characteristics. We further identified ten single-nucleotide polymorphisms (SNPs) in the SARS-CoV-2 genome that were associated with patient mortality.
Three SNPs remained associated with mortality in a generalized linear model (GLM) that also included patient age, sex, geographic region, and month of sample collection. Multiple SNPs were confirmed in the validation cohort. These SNPs represent targets to assess the mechanisms underlying COVID-19 disease severity and warrant straightforward validation in functional studies.Keywords: COVID-19; coronavirus; pathogenesis; SNP; genome
(SNIP)
4. Discussion
We identified multiple SARS-CoV-2 genomic signatures in several viral genes that were associated with patient mortality in two independent cohorts. The functional significance of the variants identified here remains to be further investigated. Orf1ab encodes for several nsps, including the RNA-dependent RNA polymerase (RdRp), and it was previously identified as a mutation hot spot, suggestive of potential selection pressure associated with adaptation to human hosts [9]. The frequency of the T/C 14,353 variant (P4714L) has been found correlated with country mortality rates [15], but we found here that it was associated with a lower mortality. This variant falls within the RdRp and may affect viral replication.
However, Orf1ab was also implicated in the pathogenesis of SARS-CoV-1 infections through processes distinct from viral replication that included cell signaling and the modulation of the immune response [18]. The proteins nsp2 and nsp3 have been proposed to play a role in COVID-19 pathogenesis [19], although SNP C/T 2983 associated with mortality and located in the nsp3 sequence did not cause a change in amino acid. Thus, this SNP may have an unknown function in addition to coding for nsp3. Orf8 from SARS-CoV-2 can interfere with type I interferon response in vitro [20], which has been found to be critical for mitigating disease severity [7]. The consequences of the R203K G204R substitutions in the N protein also warrant functional studies to assess its role in pathogenesis, as these are the most frequent variants in this protein [10].
Finally, it is interesting to note that the G614D substitution in the S protein was associated with an increased mortality rate in the bivariate analysis in both cohorts, and in the multivariate model of the validation cohort. Previous works showed that this substitution causes a greater infectivity and higher virus loads, but its effect on disease severity and mortality in patients has been debated [11,12,15]. Our data provide evidence that this substitution can lead to increased mortality.
The changes in the proportion of the different Clades we identified over time indicate that further monitoring is necessary. While changes in the proportion of variants over time can be expected due to founder effect of a virus rapidly spreading into naïve host populations, the associations of several of these variants with patient mortality may help better anticipate the risk for severe disease.
A limitation of our study is that the viral genomes which are sequenced may not be a random sample of the global virus population. Thus, these cohorts could be biased as sequencing effort may vary among health institutions, countries, and over time. Sequencing may also be biased according to patient status, and contact tracing may result in samples being epidemiologically linked. These potential biases may affect the proportion of genome variants and SNPs. The lack of standardized reporting of patient clinical status may also be a limitation and some patients may have died at a later time after sequences were reported. Finally, some comorbidities are known to increase the risk of severe disease, but could not be taken into account as these are not reported in these datasets. Nonetheless, variations in co-morbidities were in part taken into account in the analysis of mortality rates as we adjusted for geographic, age and temporal variations.
In conclusion, we identified here several previously undetected possible determinants of mortality in the SARS-CoV-2 genome. The identified SNPs are potential critical targets to assess the mechanisms underlying COVID-19 disease severity and warrant straightforward experimental validation in functional studies, and further confirmation in additional cohorts.
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