Table 2 Multisystem phenotypying: serial electrocardiography, biomarkers of inflammation, metabolism, renal function and hemostasis and heart, lung, and kidney imaging at 28–60 days post-discharge

From: A multisystem, cardio-renal investigation of post-COVID-19 illness

    

Myocarditis

 

COVID-19 n = 159

Controls n = 29

P value

Not present n = 17 (11%)

Unlikely n = 56 (35%)

Probable n = 65 (41%)

Very likely n = 21 (13%)

P valuea

ECG n (%), admission (n = 150)

Myopericarditis criteria

31 (20.7)

0 (0)

0.003

3 (17.6)

9 (16.7)

13 (22.4)

6 (28.6)

0.646

Premature ventricular contraction

3 (1.9)

0 (0)

1.000

1 (5.9)

0 (0.0)

0 (0.0)

2 (9.5)

0.013

ECG n (%), enrollment (n = 147)

Myopericarditis criteria

47 (32.0)

0 (0)

<0.001

3 (21.4)

16 (30.2)

20 (32.3)

8 (44.4)

0.586

Premature ventricular contraction

1 (0.6)

0 (0)

1.000

0 (0.0)

1 (1.8)

0 (0.0)

0 (0.0)

0.591

ECG n (%), 28–60 days post-discharge (n = 143)

Myopericarditis criteria

33 (23.1)

0 (0)

0.002

2 (14.3)

10 (20.4)

14 (23.3)

7 (35.0)

0.546

Premature ventricular contraction

2 (1.3)

0 (0)

1.000

1 (5.9)

0 (0.0)

1 (1.5)

0 (0.0)

0.220

CT chest 28–60 days post-discharge

Ground glass opacity and/or consolidation, n (%)

70 (44.6)

1 (4.2)

<0.001

10 (66.7)

26 (46.4)

24 (36.9)

10 (47.6)

0.201

Reticulation and/or architectural distortion, n (%)

47 (29.9)

1 (4.2)

0.006

6 (40.0)

15 (26.8)

18 (27.7)

8 (38.1)

0.600

Pulmonary arterial thrombus, n (%)

5 (3.3)

0 (0.0)

1.000

0 (0.0)

2 (3.6)

2 (3.1)

1 (5.3)

0.905

Visual estimate of % of total lung area abnormal, mean (s.d.)

14.3 (19.0)

0.1 (0.5)

<0.001

19.3 (22.5)

12.7 (17.6)

12.3 (17.5)

21.1 (23.4)

0.286

CT coronary angiogram 28–60 days post-discharge

FFRCT, patient-level (all coronary arteries)

Minimum FFRCT, mean (s.d.)

0.80 (0.10)

0.84 (0.09)

0.006

0.82 (0.08)

0.79 (0.11)

0.81 (0.09)

0.76 (0.13)

0.541

Cardiovascular MRI 28–60 days post-discharge

LV end-diastolic volume index, mean (s.d.), ml/m2

75.9 (17.0)

73.9 (18.7)

0.326

77.2 (17.9)

74.1 (16.6)

77.4 (17.1)

75.2 (17.7)

0.881

LV end-systolic volume index, mean (s.d.), ml/m2

35.3 (12.8)

30.2 (13.7)

0.012

34.6 (11.1)

33.7 (11.7)

36.3 (14.2)

36.6 (12.4)

0.815

LV ejection fraction, mean (s.d.), %

54.1 (9.7)

60.4 (9.3)

<0.001

54.8 (9.8)

55.1 (10.1)

54.0 (8.6)

51.3 (11.5)

0.433

LV ejection fraction reduced, males <48%, n (%)

19 (21.3)

2 (12.5)

0.518

2 (15.4)

6 (17.1)

8 (24.2)

3 (33.3)

0.665

LV ejection fraction reduced, females < 51%, n (%)

12 (17.6)

0 (0.0)

0.346

1 (25.0)

0 (0.0)

6 (18.8)

5 (41.7)

0.012

LV mass index, mean (s.d.), g/m2

91.8 (25.6)

119.4 (26.8)

<0.001

100.9 (18.9)

93.2 (21.5)

89.7 (27.8)

87.6 (31.6)

0.170

RV end-diastolic volume index, mean (s.d.), ml/m2

73.3 (17.7)

79.7 (14.1)

0.019

77.8 (18.7)

72.7 (19.7)

72.6 (17.0)

73.3 (13.9)

0.760

RV end-systolic volume index, mean (s.d.), ml/m2

35.9 (11.3)

34.4 (10.0)

0.948

34.6 (12.4)

36.6 (11.9)

35.0 (11.5)

38.1 (8.3)

0.487

RV ejection fraction, mean (s.d.), %

50.9 (10.5)

58.5 (9.3)

<0.001

54.6 (15.9)

49.9 (9.5)

51.9 (9.0)

47.5 (11.4)

0.210

Myocardial tissue characterization

Increased global T1 (>1,233 ms), n (%)

55 (34.8)

5 (19.2)

0.174

2 (12.5)

14 (25.0)

31 (46.2)

9 (42.9)

0.016

Increased global T2 (>44 ms), n (%)

10 (6.3)

0 (0.0)

0.312

0 (0.0)

0 (0.0)

6 (9.2)

4 (19.0)

0.007

T2 ratio (myocardium/serratus anterior muscle)

1.7 (0.2)

1.6 (0.1)

0.180

1.6 (0.2)

1.6 (0.2)

1.8 (0.2)

1.8 (0.3)

<0.001

Increased global extracellular volume (>27.4%), n (%)

71 (49.7)

5 (20.8)

0.014

1 (7.7)

22 (41.5)

35 (60.3)

13 (68.4)

<0.001

Late gadolinium enhancement

Myocardial late gadolinium enhancement, n (%)

30 (19.0)

2 (7.7)

0.262

4 (25.0)

7 (12.5)

13 (20.0)

6 (28.6)

0.329

Ischemic distribution, n (%)

8 (5.5)

0 (0.0)

0.658

0 (0.0)

2 (3.9)

5 (8.1)

1 (5.6)

0.769

Non-ischemic distribution, n (%)

24 (16.3)

2 (8.0)

0.606

4 (28.6)

5 (9.8)

8 (12.9)

7 (35.0)

0.033

Pericardial thickening, n (%)

33 (21.2)

0 (0.0)

0.176

1 (5.9)

10 (18.5)

15 (23.4)

7 (33.3)

0.197

Myocardial inflammation (Lake Louise criteria), n (%)

Probable (1/2)

74 (46.8)

1 (3.4)

<0.001

4 (25.0)

49 (87.5)

21 (32.3)

0 (0.0)

<0.001

Definite (2/2)

67 (42.4)

1 (3.4)

<0.001

0 (0)

2 (3.6)

44 (67.7)

21 (100.0)

<0.001

Renal MRI, mean (s.d.)

Average cortex T1 of right and left kidneys, ms

1,544 (62)

1,519 (70)

0.118

1,548 (66)

1,535 (58)

1,541 (63)

1,585 (60)

0.110

Average medulla T1 of right and left kidneys, ms

1,934 (69)

1,953 (59)

0.161

1,935 (66)

1,924 (65)

1,925 (66)

2,008 (57)

0.003

Average T1 corticomedullary differentiation of kidneys

0.80 (0.03)

0.78 (0.03)

<0.001

0.80 (0.03)

0.79 (0.03)

0.80 (0.03)

0.79 (0.02)

0.535

Biomarkers at enrollment, central laboratory

eGFR, median (IQR), ml/min/1.73 m2

96 (85, 106)

89 (70, 98)

0.025

95 (88, 103)

94 (84, 107)

97 (83, 105)

98 (94, 104)

0.931

C-reactive protein, median (IQR), mg/L

5.5 (1.6, 22.3)

1.5 (0.8, 3.5)

<0.001

6.0 (1.6, 18.2)

5.5 (1.4, 22.8)

4.9 (1.8, 21.6)

14.0 (0.9, 21.5)

0.971

High-sensitivity troponin I, median (IQR), ng/L

3 (2, 6)

4 (4, 6)

0.059

4 (3, 5)

3 (2, 7)

3 (2, 5)

4 (3, 7)

0.609

NT-proBNP, median (IQR), pg/ml

114 (57, 262)

58 (38, 99)

0.004

108 (57, 246)

116 (65, 258)

93 (49, 278)

139 (65, 274)

0.546

Ferritin, median (IQR), µg/L

366 (202, 675)

186 (96, 254)

<0.001

428 (143, 576)

398 (281, 658)

313 (172, 683)

379 (187, 637)

0.529

Haptoglobin, median (IQR), g/L

2.1 (1.3, 3.1)

1.5 (1.2, 1.8)

0.001

2.2 (1.8, 3.2)

2.0 (1.5, 2.8)

1.9 (1.2, 3.1)

2.6 (1.6, 3.2)

0.738

Prothrombin time, mean (s.d.), s

12.1 (3.7)

11.2 (0.8)

0.106

12.1 (2.0)

12.7 (5.5)

11.7 (2.4)

12.0 (1.5)

0.042

D-dimer, mean (s.d.), ng/ml

259 (221)

152 (149)

<0.001

290 (195)

263 (178)

246 (168)

260 (192)

0.374

Fibrinogen, mean (s.d.), g/L

4.1 (1.7)

3.2 (1.1)

0.006

3.9 (1.5)

4.1 (1.7)

4.0 (1.6)

4.5 (1.9)

0.659

Factor VIII, mean (s.d.), IU/dL

184 (94)

99 (39)

<0.001

208 (88)

183 (97)

181 (99)

173 (73)

0.527

VWF:GP1bR, mean (s.d.), IU/dL

236 (127)

137 (70)

<0.001

257 (176)

241 (118)

224 (123)

246 (122)

0.755

VWF:Ag, mean (s.d.), IU/dL

243 (145)

204 (251)

0.002

310 (235)

233 (118)

228(135)

261 (140)

0.380

Biomarkers at 28–60 days post-discharge, central laboratory

eGFR, median (IQR), ml/min/1.73 m2

95 (83, 106)

88 (70, 98)

0.047

91 (79, 103)

95 (82, 106)

95 (87, 105)

98 (79, 105)

0.954

C-reactive protein, median (IQR), mg/L

1.9 (0.9, 3.5)

1.5 (0.8, 3.5)

0.572

1.7 (1.1, 3.5)

2.0 (1.2, 3.4)

1.8 (0.8, 4.4)

1.9 (0.9, 3.1)

0.996

High-sensitivity troponin I, median (IQR), ng/L

2 (1, 4)

4 (4, 6)

<0.001

2 (2, 4)

2 (1, 5)

2 (1, 4)

2 (1, 4)

0.941

NT-proBNP, median (IQR), pg/ml

83 (54, 198)

58 (38, 99)

0.022

60 (30, 172)

112 (65, 207)

87 (56, 148)

75 (52, 213)

0.290

Ferritin, median (IQR), ug/L

144 (72, 282)

186 (96, 254)

0.529

145 (86, 299)

158 (94, 296)

129 (57, 206)

157 (99, 319)

0.360

Haptoglobin, median (IQR), g/L

1.3 (0.9, 1.6)

1.5 (1.2, 1.8)

0.031

1.4 (1.1, 1.6)

1.2 (0.8, 1.6)

1.3 (0.8, 1.6)

1.3 (0.9, 1.8)

0.709

D-dimer, mean (s.d.), ng/ml

205 (252)

152 (149)

0.146

171 (111)

207 (200)

194 (193)

266 (517)

0.965

Fibrinogen, mean (s.d.), g/L

3.4(1.4)

3.2 (1.1)

0.439

3.6 (2.4)

3.2 (0.9)

3.5 (1.3)

3.8 (1.7)

0.468

Factor VIII, mean (s.d.), IU/dL

149 (65)

108 (58)

<0.001

151 (96)

141 (54)

151 (70)

160 (50)

0.606

VWF:GP1bR, mean (s.d.), IU/dL

143 (80)

137 (70)

0.912

138 (104)

136 (76)

144 (79)

165 (77)

0.345

VWF:Ag, mean (s.d.), IU/dL

164 (97)

204 (251)

0.479

151 (79)

155 (85)

157 (88)

224 (144)

0.091

Urine biomarkers

Albumin:creatinine ratio at 28–60 days post-discharge, mean (s.d.)

3.8 (10.9)

6.2 (26.9)

0.257

5.1 (13.4)

5.1 (15.2)

3.4 (5.4)

3.8 (6.4)

0.900

  1. An expanded version is provided in Supplementary Table 2.
  2. Missing data in the COVID-19 (admission, enrollment, 28–60 days) and control groups: myopericarditis criteria: n = 9, n = 12, n = 16, n = 0. Missing data in patients after COVID-19 at 28–60 days and controls: CT chest atelectasis, reticulation, ground glass: n = 2, n = 5; pulmonary arterial thrombus: n = 8, n = 6; CT coronary angiogram 28–60 days and controls: Agatston score: n = 7, n = 4; CAD-RADS score: n = 5, n = 4; FFRCT: n = 27, n = 4; cardiovascular MRI 28–60 days post-discharge: left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left ventricular ejection fraction, left ventricular strain: n = 2, n = 3; left ventricular mass: n = 2, n = 3; right ventricular end-diastolic volume index, right ventricular systolic volume index: n = 4, n = 3; right ventricular ejection fraction: n = 3, n = 3; global T1: n = 1, n = 3; global T2: n = 1, n = 3; global extracellular volume: n = 16, n = 5; late gadolinium enhancement: n = 1, n = 3; ischemic distribution: n = 14, n = 4; non-ischemic distribution: n = 12, n = 4; mixed distribution: n = 14, n = 4; pericardial thickening: n = 3, n = 3; pericardial effusion: n = 2, n = 3; right and left atrial area: n = 1, n = 3; myocardial inflammation: n = 1, n = 0. Missing data for blood biomarkers in the COVID-19 (enrollment and 28–60 days) and control groups: eGFR: n = 9, n = 10, n = 8; C-reactive protein: n = 4, n = 6, n = 2; high-sensitivity troponin I: n = 6, n = 8, n = 2; ΝΤ-proBNP: n = 6, n = 10, n = 2; total cholesterol, triglycerides, HDL cholesterol: n = 4, n = 6, n = 2; fibrinogen: n = 5, n = 10, n = 2; D-dimer: n = 5, n = 9, n = 2; Factor VIII: n = 5, n = 9, n = 2; antithrombin: n = 5, n = 10, n = 3; protein C: n = 5, n = 10, n = 3; protein S: n = 3, n = 11, n = 3; VWF:GP1bR: n = 6, n = 9, n = 2; VWF:Ag: n = 5, n = 9, n = 2. aPTT, activated partial thromboplastin time; CAD-RADS, Coronary Artery Disease-Reporting and Data System; ECV, extracellular volume; eGFR (CKD-EPI), estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology equation39; EF, ejection fraction; EDV, end-diastolic volume; ESV, end-systolic volume; FFRCT, fractional flow reserve computed tomography; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LV, left ventricle; MESA, Multi-Ethnic Study of Atherosclerosis; NT-proBNP, N-terminal pro B-type natriuretic peptide; PT, prothrombin time; RV, right ventricle; T1, longitudinal relaxation time; T2, transverse relaxation time; TCT, thrombin clotting time; vWF:Ag, von Willebrand factor antigen.
  3. aCategorical data are summarized as frequency and percentage and compared between groups using Fisher’s exact tests. Continuous data are summarized as mean and standard deviation or median and IQR (defined as the upper and lower quartiles) and compared between groups using Kruskal–Wallis tests. All P values are two-sided. No adjustments were made for multiple comparisons. The Kendall’s tau rank correlation between Lake Louise criteria and the final adjudication (four levels) was 0.75 or, with two levels, was 0.72, representing moderately strong correlations.
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