Characterizing Long COVID: Deep Phenotype of a Complex Condition.

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. METHODS: The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. FUNDING: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. INTERPRETATION: Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. FUNDING: U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411.

Association of Vitamin D Levels, Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results.

Importance: Deficient (ie, <20 ng/mL) or insufficient (ie, 20 to <30 ng/mL) 25-hydroxyvitamin D (also known as calcifediol) levels are more common in Black individuals than White individuals and are associated with increased coronavirus disease 2019 (COVID-19) risk. Whether COVID-19 risk is associated with differences in vitamin D levels of 30 ng/mL or greater is not known. Objective: To examine whether COVID-19 test results are associated with differences in vitamin D levels of 30 ng/mL or greater, including for White individuals and for Black individuals. Design, Setting, and Participants: This retrospective cohort study was conducted at an academic medical center in Chicago, Illinois. Participants included individuals with data on vitamin D level within 365 days before COVID-19 testing, which was conducted from March 3 to December 30, 2020. Data were analyzed from September 11, 2020, to February 5, 2021. Exposures: The last vitamin D level before COVID-19 testing was categorized as less than 20 ng/mL (ie, deficient), 20 to less than 30 ng/mL (ie, insufficient), 30 to less than 40 ng/mL, or 40 ng/mL or greater. Treatment was defined by vitamin D type and dose 14 days before COVID-19 testing and treatment changes after last vitamin D level. Main Outcomes and Measures: The main outcome was a positive result for COVID-19 in polymerase chain reaction testing. Multivariable analyses tested whether previously measured vitamin D level was associated with having test results positive for COVID-19 in White individuals and in Black individuals, controlling for months and treatment changes since the vitamin D level was measured, as well as demographic characteristics and comorbidity indicators. Results: A total of 4638 individuals (mean [SD] age 52.8 [19.5] years; 3205 [69%] women) had data for a vitamin D level within 1 year before COVID-19 testing, including 2288 (49%) Black individuals, 1999 (43%) White individuals, and 351 individuals (8%) who were another race/ethnicity (eg, Asian, Mideast Indian, >1 race). Stratified by vitamin D level, 1251 individuals (27%) had less than 20 ng/mL, 1267 individuals (27%) had 20 to less than 30 ng/mL, 1023 individuals (22%) had 30 to less than 40 ng/mL, and 1097 individuals (24%) had 40 ng/mL or greater. Lower vitamin D levels were more common in Black individuals (<20 ng/mL: 829 of 2288 Black individuals [36%]) than White individuals (<20 ng/mL: 315 of 1999 White individuals [16%]). A total of 333 individuals (7%) had test results positive for COVID-19, including 102 White individuals (5%) and 211 Black individuals (9%). Multivariate analysis controlling for time since last vitamin D level measurement was used to estimate the outcomes associated with levels 14 days before COVID-19 testing. A positive test result for COVID-19 was not significantly associated with vitamin D levels in White individuals but was associated with vitamin D levels in Black individuals (compared with ≥40 ng/mL: <20 ng/mL incidence rate ratio [IRR], 2.55 [95% CI, 1.26-5.15]; P = .009; 20 to <30 ng/mL IRR, 1.69 [95% CI, 0.75-3.84]; P = .21; 30 to <40 ng/mL IRR, 2.64 [95% CI, 1.24-5.66]; P = .01). Stratified by vitamin D level, estimated COVID-19 positivity rates in Black individuals were 9.72% (95% CI, 6.74%-13.41%) for individuals with a vitamin D level less than 20 ng/mL, 6.47% (95% CI, 3.33%-10.28%) for individuals with a vitamin D level of 20 to less than 30 ng/mL, 10.10% (95% CI, 6.00%-15.47%) for individuals with a vitamin D level of 30 to less than 40 ng/mL, and 3.82% (95% CI, 1.78%-6.68%) for individuals with a vitamin D level of 40 ng/mL or higher. Multivariate analysis in individuals with a vitamin D level of 30 ng/mL or greater found that the IRR of a positive COVID-19 test result was 0.97 (95% CI, 0.94-0.99; P = .008) per 1-ng/mL increase in vitamin D overall and 0.95 (95% CI, 0.91-0.98; P = .003) per 1-ng/mL increase in vitamin D in Black individuals. Conclusions and Relevance: In this single-center retrospective cohort study, COVID-19 risk increased among Black individuals with vitamin D level less than 40 ng/mL compared with those with 40 ng/mL or greater and decreased with increasing levels among individuals with levels greater than 30 ng/mL. No significant associations were noted for White individuals. Randomized clinical trials should examine whether increasing vitamin D level to greater than 40 ng/mL affects COVID-19 risk.

Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results.

Importance: Vitamin D treatment has been found to decrease the incidence of viral respiratory tract infection, especially in patients with vitamin D deficiency. Whether vitamin D is associated with coronavirus disease 2019 (COVID-19) incidence is unknown. Objective: To examine whether the last vitamin D status before COVID-19 testing is associated with COVID-19 test results. Design, Setting, and Participants: This retrospective cohort study at an urban academic medical center included patients with a 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol level measured within 1 year before being tested for COVID-19 from March 3 to April 10, 2020. Exposures: Vitamin D deficiency was defined by the last measurement of 25-hydroxycholecalciferol less than 20 ng/mL or 1,25-dihydroxycholecalciferol less than 18 pg/mL before COVID-19 testing. Treatment changes were defined by changes in vitamin D type and dose between the date of the last vitamin D level measurement and the date of COVID-19 testing. Vitamin D deficiency and treatment changes were combined to categorize the most recent vitamin D status before COVID-19 testing as likely deficient (last level deficient and treatment not increased), likely sufficient (last level not deficient and treatment not decreased), and 2 groups with uncertain deficiency (last level deficient and treatment increased, and last level not deficient and treatment decreased). Main Outcomes and Measures: The outcome was a positive COVID-19 polymerase chain reaction test result. Multivariable analysis tested whether vitamin D status before COVID-19 testing was associated with testing positive for COVID-19, controlling for demographic and comorbidity indicators. Results: A total of 489 patients (mean [SD] age, 49.2 [18.4] years; 366 [75%] women; and 331 [68%] race other than White) had a vitamin D level measured in the year before COVID-19 testing. Vitamin D status before COVID-19 testing was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Overall, 71 participants (15%) tested positive for COVID-19. In multivariate analysis, testing positive for COVID-19 was associated with increasing age up to age 50 years (relative risk, 1.06; 95% CI, 1.01-1.09; P = .02); non-White race (relative risk, 2.54; 95% CI, 1.26-5.12; P = .009), and likely deficient vitamin D status (relative risk, 1.77; 95% CI, 1.12-2.81; P = .02) compared with likely sufficient vitamin D status. Predicted COVID-19 rates in the deficient group were 21.6% (95% CI, 14.0%-29.2%) vs 12.2%(95% CI, 8.9%-15.4%) in the sufficient group. Conclusions and Relevance: In this single-center, retrospective cohort study, likely deficient vitamin D status was associated with increased COVID-19 risk, a finding that suggests that randomized trials may be needed to determine whether vitamin D affects COVID-19 risk.