Clonal hematopoiesis is associated with risk of severe Covid-19

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.


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Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable: -Accession codes, unique identifiers, or web links for publicly available datasets -A list of figures that have associated raw data -A description of any restrictions on data availability Kelly Bolton, Ahmet Zehir 2/10/2021 No software was used for the data collection R version 4.0.1 was used to analyze the data in this study; R code used is available on GitHub. The following packages were used in our analyses. Sequencing data for the IMPACT study was analyzed using BWA (version 0.7.5a), ABRA (version 0.92), Genome Analysis Toolkit The following data availability statement has been added "The minimal clinical and mutational data necessary to replicate the findings in the article are publicly available on Github: https://github.com/kbolton-lab/papers/tree/main/CH_COVID_NatureComm2021" nature research | reporting summary

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The sample size for MSK and KoCH was determined based on the number of individuals with Covid-19 and blood sequencing data available as of the time of the data freeze following the end of the first wave of Covid-19. Due to the unique circumstances of the pandemic, we chose to move forward with the analysis with our available sample size.
For the IMPACT cohort, subjects were excluded who had an active hematologic malignancy at the time of blood draw. Seven subjects with Covid-19 had minimal documentation of clinical course following Covid-19 infection and were excluded. In three individuals with metastatic cancer there was clear progression of disease at the time of Covid-19 and it was unclear whether documented hypoxia could be attributed to Covid-19 or disease progression. These subjects were also excluded. For the KoCH cohort, Subjects who had an active malignancy at the time of blood draw were excluded.
Our main hypothesis and analysis was the association between clonal hematopoiesis (CH) and Covid-19 severity. We show through a combined analysis in two cohorts (MSK and KoCH) that CH is associated with Covid-19 severity. In secondary (exploratory) analyses we study the relationship between CH mutation types and Covid-19 severity and the relationship between CH and infection risk (in the MSK cohort). We present this manuscript alongside that of Zekavat et al. which also shows, using a different CH detection methodology and in a different population, that CH is associated with risk of severe Covid-19 and certain classes of infection. While not a exact replication due to differences in CH detection methodology and the definition of Covid-19 severity and infection classification, we view the findings of these two manuscripts as supporting our main conclusions that CH is associated with Covid-19 severity and infection risk.
As this was not a randomized study, this was not relevant.
Data collection took place independently of mutational analysis. Mutational analysis occurred prior to the Covid-19 outbreak and so data analysts were in effect blinded to Covid-19 outcomes. Clinical and mutational data frames were processed and analyzed separately before combining.