Table 2.
Characteristics of the identified subphenotypes (development cohort).
| Variable | Total | Subphenotype I | Subphenotype II | Subphenotype III | Subphenotype IV | P-valuea | P-value (age and sex adjusted)b |
|---|---|---|---|---|---|---|---|
| No. of patients (%) | 8199 (100) | 2707 (33.02) | 3047 (37.16) | 1486 (18.12) | 959 (11.70) | – | – |
| Demographics | |||||||
| Age, y, Median (IQR) | 63.53 (50.57–75.15) | 57.45 (42.70–70.02) | 62.56 (51.63–72.77) | 69.45 (57.05–79.62) | 73.53 (64.10–82.83) | <0.001 | – |
| Sex female, N (%) | 3787 (46.19) | 1601 (59.14) | 1106 (36.30) | 709 (47.71) | 371 (38.69) | <0.001 | – |
| Race, N (%) | |||||||
| White | 2036 (24.83) | 695 (25.67) | 777 (25.50) | 367 (24.70) | 197 (20.54) | <0.001 | – |
| Black | 2155 (26.28) | 697 (25.75) | 611 (20.05) | 503 (33.85) | 344 (35.87) | ||
| Asian | 409 (4.99) | 118 (4.36) | 194 (6.37) | 58 (3.90) | 39 (4.07) | ||
| Other/unknown | 3599 (43.90) | 1197 (44.22) | 1465 (48.08) | 558 (37.55) | 379 (39.52) | ||
| Inflammatory markers | |||||||
| C-reactive protein, mg/L, Median (IQR) | 9.40 (3.70–16.80) | 4.32 (1.16–9.31) | 12.74 (6.60–20.20) | 8.20 (3.50–14.51) | 14.90 (6.70–23.07) | <0.001 | <0.001 |
| ESR, mm/h, Median (IQR) | 69.00 (42.00–97.00) | 53.00 (34.00–81.00) | 76.00 (50.00–100.00) | 75.00 (45.25–102.75) | 77.00 (41.75–106.25) | <0.001 | <0.001 |
| IL-6, pg/mL, Median (IQR) | 19.00 (10.00–42.00) | 13.00 (8.00–21.00) | 21.00 (11.00–45.75) | 17.00 (9.00–47.00) | 27.00 (10.25–52.00) | <0.001 | 0.26 |
| Procalcitonin, ng/mL, Median (IQR) | 0.20 (0.10–0.60) | 0.10 (0.10–0.20) | 0.20 (0.10–0.50) | 0.30 (0.10–0.87) | 0.60 (0.25–2.10) | <0.001 | 0.04 |
| Bands, %, Median (IQR) | 2.00 (0.00–5.00) | 3.00 (0.00–5.75) | 2.00 (0.00–5.00) | 2.00 (0.00–5.00) | 2.00 (0.00–6.00) | 0.37 | 0.14 |
| LDH, U/L, Median (IQR) | 377.00 (280.00–525.00) | 292.00 (229.00–377.00) | 437.00 (343.00–576.00) | 349.00 (268.00–449.00) | 565.50 (409.75–801.50) | <0.001 | <0.001 |
| Lymphocyte count, ×103/uL, Median (IQR) | 1.00 (0.70–1.43) | 1.20 (0.80–1.60) | 1.00 (0.70–1.40) | 0.80 (0.60–1.20) | 0.90 (0.60–1.40) | <0.001 | 0.02 |
| Neutrophil count, ×103/uL, Median (IQR) | 5.30 (3.70–7.90) | 4.00 (2.90–5.40) | 6.70 (4.80–9.50) | 4.70 (3.40–6.60) | 8.20 (5.90–11.00) | <0.001 | <0.001 |
| White blood cell count, ×103/uL, Median (IQR) | 7.20 (5.30–9.90) | 5.90 (4.60–7.60) | 8.50 (6.50–11.50) | 6.30 (4.70–8.30) | 10.30 (7.60–13.57) | <0.001 | <0.001 |
| Inflammation and hepatic markers | |||||||
| Albumin, g/dL, Median (IQR) | 3.70 (3.30–4.10) | 4.00 (3.60–4.30) | 3.70 (3.20–4.00) | 3.50 (3.10–3.90) | 3.40 (2.90–3.80) | <0.001 | <0.001 |
| Ferritin, ng/mL, Median (IQR) | 645.00 (295.90–1347.00) | 323.05 (157.75–594.33) | 868.80 (454.00–1537.50) | 599.00 (217.80–1380.50) | 1174.00 (523.00–2284.00) | <0.001 | <0.001 |
| Hepatic markers | |||||||
| Alanine aminotransferase, U/L, Median (IQR) | 29.00 (19.00–48.00) | 24.00 (17.00–36.00) | 41.00 (26.00–68.00) | 20.00 (13.00–29.00) | 37.00 (22.00–65.00) | <0.001 | <0.001 |
| Aspartate aminotransferase, U/L, Median (IQR) | 39.00 (26.00–63.00) | 31.00 (23.00–42.00) | 52.00 (35.00–80.00) | 31.00 (22.00–46.00) | 65.00 (36.00–118.00) | <0.001 | <0.001 |
| Bilirubin, mg/dL, Median (IQR) | 0.30 (0.20–0.60) | 0.20 (0.20–0.40) | 0.40 (0.20–0.70) | 0.30 (0.20–0.50) | 0.40 (0.20–0.70) | <0.001 | <0.001 |
| Cardiovascular markers | <0.001 | <0.001 | |||||
| Creatine kinase, U/L, Median (IQR) | 154.00 (78.00–359.00) | 122.00 (72.00–227.00) | 165.00 (83.00–387.50) | 126.00 (63.00–288.00) | 352.00 (137.00–1039.50) | <0.001 | <0.001 |
| Lactate, mmol/L, Median (IQR) | 1.90 (1.40–2.60) | 1.50 (1.20–2.10) | 2.00 (1.50–2.70) | 1.60 (1.20–2.10) | 3.10 (2.20–4.80) | <0.001 | <0.001 |
| Troponin I, ng/mL, Median (IQR) | 0.10 (0.06–0.30) | 0.10 (0.00–0.10) | 0.10 (0.06–0.30) | 0.10 (0.10–0.21) | 0.20 (0.10–0.50) | <0.001 | 0.16 |
| Troponin T, ng/mL, Median (IQR) | 0.01 (0.01–0.03) | 0.01 (0.01–0.01) | 0.01 (0.01–0.01) | 0.03 (0.01–0.09) | 0.05 (0.01–0.14) | <0.001 | <0.001 |
| Renal markers | |||||||
| Bicarbonate, mmol/L, Median (IQR) | 23.00 (21.00–26.00) | 24.00 (22.00–27.00) | 23.00 (21.00–25.00) | 23.00 (20.00–25.00) | 20.00 (17.00–23.00) | <0.001 | <0.001 |
| BUN, mg/dL, Median (IQR) | 17.00 (11.00–31.00) | 12.00 (9.00–17.00) | 16.00 (12.00–24.00) | 31.00 (18.00–53.00) | 52.00 (32.00–84.00) | <0.001 | <0.001 |
| Creatinine, mg/dL, Median (IQR) | 1.00 (0.80–1.50) | 0.86 (0.70–1.04) | 1.00 (0.80–1.29) | 1.70 (1.00–4.40) | 2.10 (1.38–3.60) | <0.001 | <0.001 |
| Chloride, mmol/L, Median (IQR) | 100.00 (97.00–104.00) | 101.00 (98.00–104.00) | 99.00 (95.00–102.00) | 101.00 (97.00–105.00) | 104.00 (98.00–113.00) | <0.001 | <0.001 |
| Sodium, mmol/L, Median (IQR) | 137.00 (134.00–140.00) | 138.00 (136.00–140.00) | 136.00 (132.00–138.00) | 138.00 (134.00–141.00) | 141.00 (136.00–152.00) | <0.001 | <0.001 |
| Hematologic markers | |||||||
| D-dimer, ng/mL, Median (IQR) | 1360.00 (620.00–3370.00) | 660.00 (370.00–1310.00) | 1390.00 (690.00–3210.00) | 1740.00 (836.50–3520.00) | 4000.00 (2000.00–13582.50) | <0.001 | <0.001 |
| Hemoglobin, g/dL, Median (IQR) | 13.10 (11.50–14.60) | 13.40 (12.30–14.60) | 13.80 (12.50–15.10) | 10.80 (9.00–12.30) | 12.75 (10.70–15.00) | <0.001 | <0.001 |
| Platelet count, ×103/uL, Median (IQR) | 211.00 (162.00–277.00) | 204.00 (163.00–253.00) | 225.00 (172.00–303.00) | 194.00 (145.00–270.00) | 217.00 (156.00–296.00) | <0.001 | <0.001 |
| Prothrombin time, s, Median (IQR) | 13.30 (12.20–14.60) | 12.70 (11.90–13.60) | 13.50 (12.50–14.70) | 13.20 (12.00–14.60) | 14.80 (13.15–20.55) | <0.001 | <0.001 |
| Red blood cell distribution width, %, Median (IQR) | 13.80 (12.90–15.00) | 13.40 (12.80–14.40) | 13.40 (12.70–14.20) | 15.50 (14.00–17.50) | 15.10 (13.80–16.70) | <0.001 | <0.001 |
| Glucose, mg/dL, Median (IQR) | 121.00 (101.00–165.00) | 108.00 (95.00–127.00) | 133.00 (110.00–201.00) | 117.00 (98.00–153.00) | 164.00 (119.00–271.75) | <0.001 | <0.001 |
| Other markers | |||||||
| Oxygen saturation, %, Median (IQR) | 69.00 (50.00–85.00) | 65.00 (47.00–85.00) | 69.00 (51.50–85.00) | 69.00 (48.00–80.00) | 76.50 (57.75–91.20) | 0.05 | 0.06 |
| BMI, kg/m2, Median (IQR) | 28.00 (25.00–33.00) | 29.00 (25.00–34.00) | 28.95 (25.00–33.00) | 27.00 (23.00–32.00) | 26.00 (23.00–31.00) | <0.001 | 0.73 |
| Comorbidity, (missing = 590), N (%) | |||||||
| Hypertension | 4744 (62.35) | 1238 (49.68) | 1696 (60.16) | 1095 (78.44) | 715 (79.27) | <0.001 | – |
| Diabetes | 3104 (40.79) | 666 (26.73) | 1198 (42.50) | 730 (52.29) | 510 (56.54) | <0.001 | – |
| Coronary artery disease | 1753 (23.04) | 360 (14.45) | 530 (18.80) | 523 (37.46) | 340 (37.69) | <0.001 | – |
| Heart failure | 1132 (14.88) | 176 (7.06) | 286 (10.15) | 430 (30.80) | 240 (26.61) | <0.001 | – |
| COPD | 972 (12.77) | 264 (10.59) | 259 (9.19) | 290 (20.77) | 159 (17.63) | <0.001 | – |
| Asthma | 1091 (14.34) | 392 (15.73) | 372 (13.20) | 232 (16.62) | 95 (10.53) | <0.001 | – |
| Cancer | 1438 (18.90) | 363 (14.57) | 444 (15.75) | 423 (30.30) | 208 (23.06) | <0.001 | – |
| Hyperlipidemia | 3262 (42.87) | 825 (33.11) | 1169 (41.47) | 779 (55.80) | 489 (54.21) | <0.001 | – |
| Obesity | 3039 (37.07) | 1105 (40.82) | 1179 (38.69) | 495 (33.31) | 260 (27.11) | <0.001 | – |
| Outcomes (60 days), N (%) | |||||||
| Mortality | 1529 (18.65) | 188 (6.94) | 528 (17.33) | 337 (22.68) | 476 (49.64) | <0.001 | – |
| Mechanical ventilation (intubation | 1154 (14.07) | 190 (7.02) | 527 (17.30) | 195 (13.12) | 242 (25.23) | <0.001 | – |
| ICU admission | 1494 (18.22) | 242 (8.94) | 675 (22.15) | 242 (16.29) | 335 (34.93) | <0.001 | – |
| Medications, N (%) | |||||||
| Antibiotics | 2952 (36.00) | 731 (27.00) | 1219 (40.01) | 559 (37.62) | 443 (46.19) | <0.001 | – |
| Corticosteroids | 1666 (20.32) | 331 (12.23) | 725 (23.79) | 319 (21.47) | 291 (30.34) | <0.001 | – |
| Enoxaparin | 3312 (40.40) | 1016 (37.53) | 1582 (51.92) | 418 (28.13) | 296 (30.87) | <0.001 | – |
| Heparin | 1310 (15.98) | 255 (9.42) | 585 (19.20) | 304 (20.46) | 166 (17.31) | <0.001 | – |
| Vasopressor | 608 (7.42) | 120 (4.43) | 308 (10.11) | 96 (6.46) | 84 (8.76) | <0.001 | – |
Categories of variables were bold.
BUN blood urea nitrogen, COPD chronic obstructive pulmonary disease, ESR erythrocyte sedimentation rate, ICU intensive care unit, IL-6 interleukin 6, IQR interquartile range, LDH lactate dehydrogenase.
aComparisons across all 4 subphenotypes were performed using the Kruskal–Wallis test (with Dunn’s test for post-hoc pairwise comparisons) or χ2 test.
bP-values, adjusting for age and sex, were calculated by analysis of covariance (ANCOVA) was performed based on General Linear Model.