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Over 530 million people worldwide are estimated to have had covid-19 by June 2022, resulting in more than 6.3 million deaths.1 Although most people have few symptoms or mild to moderate illness, a substantial minority are at higher risk of more severe disease (requiring hospital admission) and adverse outcomes, including death and long covid. Results strongly support the inclusion of SCT as an adverse prognostic factor for COVID-19. 2019;95:103208103281. Conceptually, this analysis is similar to examination of comorbidity indices in epidemiology studies to determine if specific comorbid conditions, represented by frequently used laboratory measures or disease codes, are enriched among cases. Such information will also support policy decisions, allowing consideration of the differential economic, social, and health effects of protective interventions, including societal restriction. Design, Setting, and Participants The same association was not observed in COVID-19negative patients (OR, 1.13; 95% CI, 0.90-1.42; P=.31). ER, Cellmer Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans., Little The hemoglobin beta S (HbS) allele (rs334-T). 2022 American Medical Association. Associations between SCT and COVID-19 outcomes were examined using firth regression. Underlying medical conditions associated with higher risk for severe COVID-19: information for healthcare providers. Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. Centers for Disease Control and Prevention. The presence of SCT was associated with increased risk of mortality and acute kidney failure following COVID-19. PA has received research grants from Zhejiang Yongning Pharmaceuticals unrelated to this topic. National Center for Immunization and Respiratory Diseases (NCIRD) DoVD. Hb C allele Association Results With COVID-19 Outcome Severity, eTable 9. Bias reduction of maximum likelihood estimates., Kosmidis et al; VA Million Veteran Program COVID-19 Science Initiative. Phecodes that showed association with sickle cell trait (SCT) were tested for their association with COVID-19related death in individuals of African ancestry (left lower); SCT-related conditions postCOVID-19 were tested for their mediation of SCT-related death in COVID-19 (right lower). J, eTable 4. Privacy Policy| Additional Contributions: We are grateful to our veterans for their contribution to MVP. 2021;397(10270):220232. Drs Iyengar and Luoh jointly supervised this work. H, Hippisley-Cox Flowchart With the Number of Individuals Selected for the Association Study, Figure 2. Mr Thompson reports grants from Vanderbilt University Medical Center Vanderbilt Medical Scholar during the conduct of the study. CDW, Beach Risk factors for hospitalization, mechanical ventilation, or death among 10131 US veterans with SARS-CoV-2 infection., WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. RP. D, Seoane P, eTable 3. MT, Novelli Accepted for Publication: April 23, 2022. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review., Kalpatthi Thromboinflammatory mechanisms in sickle cell diseasechallenging the hemostatic balance., Kaspar Accessed February 11, 2022. Would you like email updates of new search results? Bethesda, MD 20894, Web Policies Disclaimer, National Library of Medicine Epub 2021 Nov 3. 2009;42(2):377381. OV, Jones 8600 Rockville Pike Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. -, Carf A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID19. Laboratory-Wide Association Studies of the Hb C allele (rs33930165-T) in MVP Participants From AFR Ancestry, eAppendix. Sickle cell disorders and severe COVID-19 outcomes: a cohort study., Gandhi The US Centers for Disease Control and Prevention regularly reviews all such studies to update the list of conditions associated with greater risk of severe covid-19 and death.3 While risks generally increase with age and are higher among men, strong evidence now shows increased risks for people with various health conditions, including chronic kidney disease, diabetes, lung and liver diseases, cardiovascular disease, obesity, immunodeficiency, certain disabilities, and mental health conditions. Science brief: evidence used to update the list of underlying medical conditions associated with higher risk for severe covid-19. Symptom occurrence and severity were measured through questionnaires. Fang 2022. We addressed this issue in the Million Veteran Program (MVP) within the Department of Veterans Affairs (VA). -, Huang C, Huang L, Wang Y, et al. Hospitalization and mortality among Black patients and White patients with COVID-19.. The most significant association observed was sickle cell anemia/trait-related condition (phecode: 282.5; odds ratio [OR], 93.17; 95% CI, 78.60-110.44; P=110300). We now have a better understanding of the conditions that increase risk of severe covid-19, but unanswered questions remain about their role in longer term outcomes. Association of Sickle Cell Trait With Kidney and Hematologic Laboratory Measurements Through Laboratory-Wide Association Study Analysis in African Ancestry Individuals, Table 2. The MVP participants were predominantly male but represented one of the largest African ancestry cohorts available. JM, Concato The full summary statistics for association with laboratory measurement are presented in eTable 5 in Supplement 2. All rs334-Tpositive individuals had only 1 copy of the sickle allele and 1 copy of the nonsickle allele and therefore carried the SCT. COVID-19 in patients with hematologic-oncologic risk factors: complications in three patients., Singh Provenance and peer review: Commissioned; not externally peer reviewed. Dr Natarajan reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, Novartis, and TenSixteen Bio; holding equity in TenSixteen Bio and Genexwell; and spousal employment at Vertex; all outside the submitted work. Although pre-existing conditions and hospital admission were associated with higher risk overall, some outcomes, such as mental health diagnoses, were increased irrespective of age and comorbidities.16 A large UK based cohort study of people admitted to hospital with covid-19 reported similar findings.17, Risk of SARS-CoV-2 infection, severe disease, and death have reduced in populations with high vaccine uptake.18 Nevertheless, breakthrough infection still occurs, and there is some evidence that older people (>65 years) and those with underlying conditions remain at greatest risk, possibly because vaccine effectiveness wanes more quickly in these groups.1920 Vaccines also reduce the risk and duration of long covid symptoms, but the effect is smaller than the reduction in mortality and severe disease.21. The polymerization of hemoglobin beta sickle protein in SCD contributes to vaso-occlusion.32 In individuals with SCT, sickling due to low oxygenation tension in the kidneys may cause kidney dysfunction,33,34 which can be exacerbated by COVID-19, in addition to other potential mechanisms.35 Of note, gout has a known association with SCD,36 but its linkage to SCT identified through association studies has not been previously reported. et al. Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. Accessed February 11, 2022. Renal oxygenation in the pathophysiology of chronic kidney disease., Conran If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. However, the association of SCT with COVID-19 is unclear. Data from a US administrative claims database showed that 14% of adults who had had covid-19 developed new clinical conditions within six months; a 1.65% higher incidence than that seen after other viral infections.16 Clinical sequelae included interstitial lung disease, respiratory failure, congestive heart failure, arrythmia, and type 2 diabetes.16 The cluster of symptoms and clinical outcomes differed by age, between men and women, and between those who were and were not admitted to hospital. The current state of sickle cell trait: implications for reproductive and genetic counseling., Folsom The ICD-10 Codes Used in the Definition of the Post-Index Conditions of AMI, AKF, CKD, CKF and Nephrosis, eTable 2. J, Clayton Journal of Medical Virology published by Wiley Periodicals LLC. Archives of Neurology & Psychiatry (1919-1959), Subscribe to the JAMA Internal Medicine journal, https://www.cdc.gov/ncbddd/sicklecell/features/keyfinding-trait.html, https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html, https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.374.1508&rep=rep1&type=pdf, 10.1146/annurev-pathmechdis-012418-012838, JAMA OtolaryngologyHead & Neck Surgery, CONSERVE 2021 Guidelines for Reporting Trials Modified for the COVID-19 Pandemic, FDA Approval and Regulation of Pharmaceuticals, 1983-2018, Global Burden of Skin Diseases, 1990-2017, Managing Asthma in Adolescents and Adults: 2020 NAEPP Asthma Guideline Update, Practices to Foster Physician Presence and Connection With Patients in the Clinical Encounter, US Burden of Neurological Disease, 1990-2017, USPSTF Recommendation on Screening for Colorectal Cancer, USPSTF Recommendation on Screening for Hypertension, USPSTF Recommendation on Screening for Lung Cancer, USPSTF Recommendation on Screening for Prediabetes and Type 2 Diabetes, Statement on Potentially Offensive Content, Register for email alerts with links to free full-text articles. RP, The study design with the number of individuals selected for different analyses is presented in Figure 1. J Biomed Inform. Data for the study were collected between March 2020 and February 2021. Left, phenome-wide association study (PheWAS) and laboratory-wide association study (LabWAS) analysis; middle, outcome severity; right, association study with clinical outcomes that occurred within 60 days of COVID-19 testing/diagnosis. Measuring success: utility of biomarkers in sickle cell disease clinical trials and care., Henry A better quantification of the relation between comorbidities and different outcomes and the populations at risk is essential for future health system planning. Pecker This is particularly true for people with comorbidities. EB, COVID-19 in individuals with sickle cell disease/trait compared with other Black individuals., Price-Haywood R, Novelli In this genetic association study, SCT was associated with increased COVID-19 mortality and a number of preexisting chronic medical conditions in African ancestry individuals. Statistical analysis: Verma, Gao, Minnier, Rajeevan, Zekavat, Pathak, Zhou, Polimanti, Iyengar, Luoh. Dr ODonnell is an employee of Novartis Institute for Biomedical Research. LH, Naik -. Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E, Berry S, Canas LS, Graham MS, Klaser K, Modat M, Murray B, Kerfoot E, Chen L, Deng J, sterdahl MF, Cheetham NJ, Drew DA, Nguyen LH, Pujol JC, Hu C, Selvachandran S, Polidori L, May A, Wolf J, Chan AT, Hammers A, Duncan EL, Spector TD, Ourselin S, Steves CJ. E, Green Our main focus was the African ancestry individuals from the MVP where SCT has more prevalence. JC, Naik et al; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Hematology & Hemostasis, Diabetes, and Structural Variation TOPMed Working Groups. Our work can be strengthened by replication studies. In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. et al. Although the exact mechanisms by which pre-existing conditions influence disease susceptibility and severity are not known, inflammatory and hormonal pathways are postulated,5 as well as social factors such as living in crowded or institutionalised settings.6. Risks are highest for people with complicated diabetes, obesity, and anxiety related disorders (relative risk about 1.3 compared with people without these conditions), and less for those with cardiovascular disease (relative risk roughly 1.1).4 Evidence is more limited for other conditions such as overweight, sickle cell disease, and substance use disorders and inconsistent for asthma, hypertension, and viral hepatitis. Objective Please see the eMethods in Supplement 1 for specific details on the mediator model. Associations of Pre-COVID-19 Comorbidities and COVID-19 Related Death in the African Ancestry Participants, eTable 7. The direction of each triangle represents the direction of effect of the associations, with the upward triangle representing increased risk and the downward represents reduced risk. I, Newlin Is the presence of sickle cell trait (SCT) associated with worse outcomes of COVID-19? To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. In addition, SCT was significantly associated with a diagnosis of AKF within 60 days of COVID-19. et al; VA Million Veteran Program. AK, Saatci Keywords: These kidney sequelae were extracted by using 1 of the following: natural language processing, International Classification of Diseases codes, Current Procedural Terminology codes, or laboratory data. These results are presented in eTable 7 in Supplement 2. JAMA Intern Med. Critical revision of the manuscript for important intellectual content: Verma, Huffman, Gao, Minnier, Wu, Cho, Ho, Goman, Pyarajan, Rajeevan, Joseph, McGeary, Suzuki, Reaven, Wan, J. Lynch, Petersen, Meigs, Freiberg, Gatsby, K. Lynch, Zekavat, Natarajan, Dalal, Jhala, Thompson, Pathak, Donskey, Wells, Gelernter, Huang, Polimanti, Chang, Liao, Tsao, Sun, Wilson, Hung, ODonnell, Gaziano, Hauger, Iyengar, Luoh. How we built our covid-19 risk estimator. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, 3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n=3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P=.01). brglm2: Bias reduction in generalized linear models. W. AC, Peacock Next, we examined the association of the 31 preexisting conditions identified from the aforementioned comorbidity association studies with COVID-19 outcomes among MVP participants of African ancestry (March 2020 to February 2021). JAMA. In summary, there was an increased risk of death from COVID-19 among SCT carriers. eTable 5. J Biomed Inform. Dr Lynch reports grants from Janssen Pharmaceuticals Inc outside the submitted work. Sickle cell trait affects more than 3 million people in the US and 300 million people globally, but because it is not routinely assessed, there is a paucity of data on the association between SCT and COVID-19 outcomes. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease.

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