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.

Prospective evaluation of the relationship between C-reactive protein, D-dimer and progression of peripheral arterial disease.

OBJECTIVE: Elevated levels of C-reactive protein (CRP) and D-dimer (DD) have been associated with the presence and progression of various forms of atherosclerotic disease, particularly coronary heart disease. We hypothesize that there is a relationship between elevated levels of baseline CRP and DD and progression of peripheral arterial disease (PAD) in patients with symptomatic PAD. The current study is a prospective evaluation of this hypothesis. METHODS: Between 1996 and 2003, 384 subjects were enrolled in a National Institutes of Health-sponsored blinded, prospective trial evaluating the effects of multiple atherosclerotic risk factors on progression of symptomatic PAD. Baseline levels of CRP and D-dimer were obtained in 332 subjects. Subjects were followed every 6 months with clinical history and exam, ankle-brachial pressure index (ABI), and carotid artery duplex scanning (CDS). The primary study end point was a composite of ABI progression, CDS progression, stroke, myocardial infarction, amputation, and death from cardiovascular disease. Secondary end points included each of the components of the primary end point. The relationship between time to the various endpoints and baseline CRP and DD levels was examined by life-table analysis and Cox proportional hazards analysis. RESULTS: Adequate baseline samples for CRP and DD were available in 332 subjects (mean age, 67 years; 57.8% men) with mean follow-up of 38.4 months (range, 1 to 99 months). Mean baseline levels (+/- SD) for CRP were 0.8 +/- 1.14 (range, 0.03 to 13.0), and mean DD levels were 227.4 +/- 303.3 (range, 1.9 to 2744.8). Progression, as defined by the primary end point, occurred in 48.5% of subjects. Subjects with elevated CRP (highest tertile) were no more likely to have any of the progression end points than those with the lowest values (lowest tertile) (P = NS, log-rank test, for all comparisons). By univariate analysis, subjects with elevated DD (highest tertile) were significantly more likely to die from any cause compared with subjects with the lowest DD values (lowest tertile) (P = .03, log-rank test). They were, however, no more likely to reach any of the other progression end points, including the primary end point (P = NS, log-rank test for all other comparisons). Multivariate analysis showed that DD level was a significant independent variable associated with occurrence of myocardial infarction (hazard ratio, 2.3; P = .02). CONCLUSIONS: In subjects with symptomatic PAD, elevated baseline DD, a marker of thrombotic activity, was significantly associated with the occurrence of myocardial infarction. This study did not confirm a relationship between progression of PAD and baseline DD or CRP during the first 3 years. Baseline DD and CRP do not provide useful risk stratification in patients at high risk for progression of symptomatic PAD. Future studies should evaluate serial levels of these markers to assess their utility in predicting progression of symptomatic PAD.

Relationship between site of initial symptoms and subsequent progression of disease in a prospective study of atherosclerosis progression in patients receiving long-term treatment for symptomatic peripheral arterial disease.

PURPOSE: There have been few studies of the natural history of peripheral arterial disease (PAD), and none have used serial noninvasive laboratory examinations for the objective quantification of disease progression. The relationship between the site of initial symptoms of PAD (lower-extremity disease [LED] vs cerebrovascular disease [CVD]) and the site of subsequent symptomatic progression (LED vs CVD vs coronary heart disease [CHD]) has not been examined. METHODS: This is a long-term, blinded prospective clinical research study of the relationship of PAD progression to multiple clinical, laboratory, and noninvasive vascular laboratory parameters. Patients with symptomatic LED, CVD, or both underwent comprehensive risk-factor assessment and were seen every 6 months for follow-up examinations. In addition to history and physical examination, all subjects underwent serial noninvasive lower-extremity and carotid artery testing. The relationship between the initial symptomatic site(s) and subsequent progression was examined by means of multivariate proportional hazards analysis, which was adjusted for age, diabetes mellitus, hypertension, smoking, cholesterol, homocysteine level, lowest initial ankle/brachial index (ABI), worst carotid stenosis, ABI progression, and carotid stenosis progression, because each of these factors was significantly associated with one or more aspects of progression. RESULTS: There were 397 study subjects (mean age, 66 years; 38% women) with a mean follow-up period of 48.5 months. LED was initially present in 88% of subjects and CVD in 37% of subjects (both were present in 25% of subjects). There were 78 deaths, 47 (60%) of which were caused by cardiovascular disease (18% mortality rate after 5 years by means of life table). Progression of disease as documented by means of vascular laboratory findings occurred in 90% of subjects by means of life table after 5 years (ABI progression, 31%; carotid stenosis progression, 40%). Symptomatic clinical progression of disease occurred in 52% of subjects by means of life table after 5 years (LED progression, 22%; CVD progression, 23%; CHD progression, 31%). By means of multivariate analysis, no significant relationship was found between the site of initial symptoms of PAD and the site(s) of subsequent symptomatic clinical progression (LED vs CVD vs CHD; P = not significant for all hazard ratios). CONCLUSION: Patients with symptomatic PAD experience symptoms of ongoing LED, CVD, and CHD with a frequency that is not influenced by the site(s) of their original symptoms. The hypothesis that lesions and resulting symptoms of systemic atherosclerosis occur at various anatomic sites as a matter of random chance should be tested with other studies.