Complex patterns of multimorbidity associated with severe COVID-19 and long COVID
Maik Pietzner, Spiros Denaxas, Summaira Yasmeen, Maria A Ulmer, Tomoko Nakanishi, Matthias Arnold, Gabi Kastenmüller, Harry Hemingway, Claudia Langenberg
Communications Medicine, doi:10.1038/s43856-024-00506-x
Background Early evidence that patients with (multiple) pre-existing diseases are at highest risk for severe COVID-19 has been instrumental in the pandemic to allocate critical care resources and later vaccination schemes. However, systematic studies exploring the breadth of medical diagnoses are scarce but may help to understand severe COVID-19 among patients at supposedly low risk. Methods We systematically harmonized >12 million primary care and hospitalisation health records from ~500,000 UK Biobank participants into 1448 collated disease terms to systematically identify diseases predisposing to severe COVID-19 (requiring hospitalisation or death) and its post-acute sequalae, Long COVID. Results Here we identify 679 diseases associated with an increased risk for severe COVID-19 (n = 672) and/or Long COVID (n = 72) that span almost all clinical specialties and are strongly enriched in clusters of cardio-respiratory and endocrine-renal diseases. For 57 diseases, we establish consistent evidence to predispose to severe COVID-19 based on survival and genetic susceptibility analyses. This includes a possible role of symptoms of malaise and fatigue as a so far largely overlooked risk factor for severe COVID-19. We finally observe partially opposing risk estimates at known risk loci for severe COVID-19 for etiologically related diseases, such as post-inflammatory pulmonary fibrosis or rheumatoid arthritis, possibly indicating a segregation of disease mechanisms. Conclusions Our results provide a unique reference that demonstrates how 1) complex cooccurrence of multipleincluding non-fatalconditions predispose to increased COVID-19 severity and 2) how incorporating the whole breadth of medical diagnosis can guide the interpretation of genetic risk loci. From the outset of the COVID-19 pandemic it was evident that underlying conditions were associated with both the risk of infection with SARS-CoV-2, the cause of COVID-19, and the risk of it being severe, based on the risk of hospitalisation, to ventilation and death 1 . Initial focus was on the small number of diseases known to put people at higher risk of other respiratory viral infections, such as influenza. The Center for Disease Control in the US and other national bodies published lists of diseases associated with COVID-19 and in the UK more than 1 million people were identified as
Competing interests The authors declare no competing interests.
Additional information Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s43856-024-00506-x. Correspondence and requests for materials should be addressed to Maik Pietzner, Harry Hemingway or Claudia Langenberg. Peer review information Communications Medicine thanks Marie Pigeyre and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available. Reprints
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