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Open Access

ALLY in fighting COVID-19: magnitude of albumin decline and lymphopenia (ALLY) predict progression to critical disease

Johanna S van Zyl, Amit Alam, Joost Felius, Ronnie M Youssef, Dipesh Bhakta, Christina Jack, Aayla K Jamil, Shelley A Hall, Göran B Klintmalm, Cedric W Spak, Robert L Gottlieb
DOI: 10.1136/jim-2020-001525 Published 4 March 2021
Johanna S van Zyl
1 Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
2 Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas, USA
3 Baylor Annette C and Harold C Simmons Transplant Institute, Baylor Scott and White Health, Dallas, Texas, USA
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Amit Alam
1 Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
2 Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas, USA
3 Baylor Annette C and Harold C Simmons Transplant Institute, Baylor Scott and White Health, Dallas, Texas, USA
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Joost Felius
1 Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
2 Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas, USA
3 Baylor Annette C and Harold C Simmons Transplant Institute, Baylor Scott and White Health, Dallas, Texas, USA
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Ronnie M Youssef
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Dipesh Bhakta
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Christina Jack
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Aayla K Jamil
1 Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
2 Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas, USA
3 Baylor Annette C and Harold C Simmons Transplant Institute, Baylor Scott and White Health, Dallas, Texas, USA
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Shelley A Hall
1 Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
2 Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas, USA
3 Baylor Annette C and Harold C Simmons Transplant Institute, Baylor Scott and White Health, Dallas, Texas, USA
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Göran B Klintmalm
1 Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
3 Baylor Annette C and Harold C Simmons Transplant Institute, Baylor Scott and White Health, Dallas, Texas, USA
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
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Cedric W Spak
1 Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
3 Baylor Annette C and Harold C Simmons Transplant Institute, Baylor Scott and White Health, Dallas, Texas, USA
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
5 Division of Infectious Disease, Baylor University Medical Center, Dallas, Texas, USA
6 Texas Centers for Infectious Disease Associates, Dallas, Texas, USA
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Robert L Gottlieb
1 Baylor Scott & White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
2 Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas, USA
3 Baylor Annette C and Harold C Simmons Transplant Institute, Baylor Scott and White Health, Dallas, Texas, USA
4 College of Medicine, Texas A&M Health Science Center, Texas A&M University, Dallas, Texas, USA
7 Division of Precision Medicine, Baylor University Medical Center, Dallas, Texas, USA
8 Department of Internal Medicine, TCU and UNTHSC School of Medicine, Fort Worth, Texas, USA
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    Figure 1

    Subject flow diagram for the derivation and test sets.

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    Figure 2

    Risk prediction of progression to critical disease status by 10 days post admission. (A) Receiver operating curve for best multivariable logistic regression and subcomponent models. The best multivariate model consists of lymphocyte (%) at baseline and the change in albumin from baseline to nadir. The triangle indicates the sensitivity (0.78) and specificity (0.71) at a probability cut-off at the event rate of 0.18. (B) Predicted risk based on the best multivariable logistic model with baseline lymphocyte (%) and delta albumin (change from baseline to lowest level within 5 days, g/dL). Predicted risk above 0.18 (dashed line) indicates high risk for progression to critical disease (ie, a patient with a −1 g/dL drop in albumin from baseline and baseline lymphocyte of 20% has a high risk probability of 0.34 (>0.18) of progression to critical disease). AUC, area under the receiver-operator characteristic curve.

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    Figure 3

    Association of the decrease in mean albumin from baseline within 7 days postadmission. (A,B) Observed subject-specific profiles by patients who progressed to (A) critical disease and (B) those who did not with an overall mean between subsequent albumin change from baseline measures. (C) Predicted decrease from baseline and rate of change in albumin by time from admission and progression to critical disease subgroups. The change in albumin from baseline decreases by 0.06 g/dL (0.02, 0.10; p=0.003) per day faster in the critical progression group compared with those who do not progress. In fact, the mean change from baseline in albumin does not decrease significantly from the initial change following admission in the non-progression group (slope: −0.02 (–0.03, 0.01); p=0.01) compared with a rate of change of –0.08 (−0.11 to –0.04) g/dL in the progression group. (D) Association of change from baseline to nadir albumin within 5 days with progression to critical disease status. The median fall in albumin is significantly larger in patients who progress to critical disease (–0.8 (–1.1, –0.5) vs –0.5 (–0.7, –0.3) g/dL; p<0.001).

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  • Table 1

    Baseline results

    VariableDisease severity on admissionP value
    ModerateSeriousCritical
    (n=59)(n=34)(n=10)
    Demographics
    Age (years)58.3 (50.0 to 65.1)52.5 (48.9 to 70.5)48.8 (40.3 to 70.3)0.69
    BMI (kg m-2)30.7 (27.3 to 35.4)31.0 (24.7 to 36.5)35.0 (29.5 to 38.6)0.52
    Ethnicity, Hispanic or Latino13 (22.0%)9 (26.5%)4 (40%)0.47
    Male, gender30 (50.9%)26 (76.5%)5 (50%)0.04
    Race0.74
     Black or African American22 (37.3%)10 (29.4%)3 (30%)
     White or Caucasian30 (50.9%)22 (64.7%)6 (60%)
     Other7 (11.9%)2 (5.9%)1 (10%)
    Clinical presentation
    Blood pressure, systolic (mm Hg)131 (116 to 148)129 (119 to 147)128 (114 to 132)0.74
    Blood pressure, diastolic (mm Hg)75 (69 to 86)78 (69 to 88)65 (56 to 69)0.04
    Clinical Score3 (3 to 5)4 (3 to 5)3 (2 to 4)0.61
    Respiratory rate20 (18 to 20)20 (18 to 26)23 (19 to 25)0.07
    SpO2 (%)97 (95 to 98)93 (90 to 94)89 (87 to 94)<0.001
    Comorbidities
    Comorbidity Score1 (1 to 3)2 (1 to 2)2 (1 to 2)0.96
     Asthma8 (13.6%)2 (5.9%)0 (0%)0.36
     CAD5 (8.5%)3 (8.8%)2 (20%)0.47
     Cancer8 (13.6%)2 (5.9%)0 (0%)0.36
     COPD6 (10.2%)1 (2.9%)0 (0 %)0.41
     Diabetes19 (32.2%)12 (35.3%)3 (30%)0.95
     Hypertension36 (61.0%)17 (50.0%)6 (60%)0.61
     Renal disease9 (15.3%)9 (26.5%)0 (0%)0.14
     Smoker15 (25.4%)13 (38.2%)4 (40.0%)0.36
    Laboratory features
    Albumin (on admission) (g/dL)3.4 (3.2 to 3.9)3.6 (3.0 to 3.9)2.8 (2.3 to 3.3)0.02
     Albumin change (baseline to nadir) (g/dL)−0.5 (–0.7 to −0.4)−0.6 (−1.0 to –0.4)−0.7 (−1.0 to −0.4)0.18
    Alkaline phosphatase (U/L)81 (61 to 103)78 (55 to 96)70 (54 to 85)0.66
    ALT (U/L)32 (23 to 59)33 (27 to 48)44 (37 to 63)0.79
    AST (U/L)39 (23 to 58)41 (29 to 55)60 (41 to 134)0.23
    BNP (pg/mL)51 (18 to 118)48 (22 to 124)82 (48 to 129)0.61
    Creatinine (mg/dL)1.0 (0.5 to 3.0)1.5 (1.0 to 2.0)1.5 (1.0 to 2.0)0.96
    C reactive protein (mg/dL)5.9 (2.5 to 10.1)11.1 (4.0 to 16.2)16.2 (6.8 to 17.2)0.03
    Ferritin (ng/mL)360 (166 to 707)531 (302 to 1183)761 (210 to 1682)0.27
    Lymphocytes (%)20 (13 to 29)12 (9 to 19)12 (9 to 18)0.006
    Neutrophils (%)69 (61 to 79)74 (70 to 85)80 (72 to 84)0.007
    Admission details
    DNAR status3 (5.1%)2 (5.9%)1 (10.0%)0.63
    ICU admission20 (33.9%)19 (55.9%)10 (100%)<0.001
    Critical outcomes
    Invasive mechanical ventilation4 (6.8%)14 (41.2%)6 (60.0%)<0.001
    Multiorgan failure5 (8.5%)13 (38.2%)7 (70%)<0.001
     Heart failure3 (5.1%)9 (26.5%)6 (60%)<0.001
     Hepatic failure5 (8.5%)3 (8.8%)1 (10%)1.00
     Kidney failure3 (5.1%)7 (20.6%)3 (30.0%)0.01
     Respiratory failure7 (11.9%)15 (44.1%)7 (70%)<0.001
    Shock4 (7.0%)9 (25.0%)10 (100%)<0.001
    Mortality, inpatient4 (6.8%)7 (20.6%)5 (50%)0.003
    • ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BNP, B-type natriuretic peptide; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; DNAR, do not attempt resuscitation; ICU, intensive care unit; NAA, nucleic acid amplification test; SpO2, pulse oximeter oxygen saturation.

  • Table 2

    Comparison of demographic, clinical, and laboratory factors by progression of disease

    VariableDisease progressionP value
    Remained non-critical (n=75)Progressed to critical (n=18)
    Demographics
    Age (years)57 (49 to 65)60 (52 to 69)0.48
    BMI (kg m-2)30.9 (26.9 to 35.9)30.9 (24.6 to 35.5)0.67
    Ethnicity, Hispanic or Latino17 (22.7%)5 (27.8%)0.76
    Male gender42 (56.0%)14 (77.8%)0.15
    Race0.39
     Black or African American28 (37.3%)4 (22.2%)
     White or Caucasian39 (52.0%)13 (72.2%)
     Other8 (10.7%)1 (5.6%)
    Admission clinical presentation
    Blood pressure, systolic (mm Hg)129 (116 to 144)142 (123 to 155)0.27
    Blood pressure, diastolic (mm Hg)76 (68 to 87)81 (73 to 85)0.51
    Clinical Score3 (3 to 5)4 (3 to 4)0.60
     Anorexia11 (14.7%)7 (38.9%)0.04
     Chest pain13 (17.3%)0 (0%)0.07
     Cough58 (77.3%)16 (88.9%)0.35
     Diarrhea20 (26.7%)3 (16.7%)0.55
     Fever61 (81.3%)14 (77.8%)0.74
     Headache12 (16.0%)3 (16.7%)1.00
     Myalgia22 (29.3%)7 (38.9%)0.62
     Rash0 (0%)1 (5.6%)0.19
     Shortness of breath53 (70.7%)12 (66.7%)0.96
     Nausea/Vomiting18 (24%)5 (27.8%)0.77
    Respiratory rate19 (18 to 22)20 (18 to 22)0.36
    SpO2 (%)96 (95 to 97)94 (90 to 96)0.001
    Comorbidities
    Comorbidity Score1 (1 to 3)2 (1 to 4)0.36
     Asthma10 (13.3%)0 (0%)0.20
     CAD6 (8.0%)2 (11.1%)0.65
     Cancer9 (12.0%)1 (5.6%)0.68
     COPD5 (6.7%)2 (11.1%)0.62
     Diabetes21 (28.0%)10 (55.6%)0.05
     Hypertension42 (56.0%)11 (61.1%)0.90
     Renal disease14 (18.7%)4 (22.2%)0.74
     Smoker21 (28.0%)7 (38.9%)0.54
    Disease severity on admission<0.001
     Moderate55 (73.3%)4 (22.2%)
     Serious20 (26.7%)14 (77.8%)
    Laboratory results
    Albumin (on admission) (g/dL)3.5 (3.1 to 3.9)3.4 (3.0 to 3.9)0.72
     Albumin change (baseline to nadir) (g/dL)−0.5 (–0.7 to –0.3)−0.9 (–1.1 to –0.5)0.001
    Alkaline phosphatase (U/L)81 (60 to 99)73 (57 to 106)0.91
    ALT (U/L)32 (24 to 52)39 (27 to 80)0.32
    AST (U/L)39 (25 to 56)42 (31 to 124)0.15
    BNP (pg/mL)53 (20 to 123)38 (21 to 76)0.46
    Creatinine (mg/dL)1.0 (0.8 to 1.3)1.1 (1.0 to 1.8)0.28
    C reactive protein (mg/dL)4.7 (2.4 to 9.0)16.2 (12.6 to 21.4)<0.001
    Ferritin (ng/mL)391 (170 to 576)970 (369 to 1741)0.03
    Lymphocytes (%)19 (12 to 27)11 (9 to 19)0.01
    Neutrophils (%)70 (62 to 79)79 (71 to 87)0.006
    Total bilirubin (mg/dL)0.5 (0.4 to 0.7)0.6 (0.6 to 0.9)0.04
    Troponin-I (ng/mL)0.02 (0.02 to 0.03)0.02 (0.01 to 0.04)0.90
    • ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BNP, B-type natriuretic peptide; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; SpO2, pulse oximeter oxygen saturation.

  • Table 3

    Multivariable logistic model estimates of risk for development of critical disease

    VariableEstimateSEOR (95% CI)P value
    Intercept−1.770.940.17 (0.02 to 0.99)0.06
    Baseline lymphocyte (%)−0.100.040.91 (0.83 to 0.97)0.01
    Total albumin change (baseline to nadir) (g/dL)−3.070.980.05 (0.01 to 0.26)0.002

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    [jim-2020-001525supp001.pdf]

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    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

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ALLY in fighting COVID-19: magnitude of albumin decline and lymphopenia (ALLY) predict progression to critical disease
Johanna S van Zyl, Amit Alam, Joost Felius, Ronnie M Youssef, Dipesh Bhakta, Christina Jack, Aayla K Jamil, Shelley A Hall, Göran B Klintmalm, Cedric W Spak, Robert L Gottlieb
Journal of Investigative Medicine Mar 2021, 69 (3) 710-718; DOI: 10.1136/jim-2020-001525

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ALLY in fighting COVID-19: magnitude of albumin decline and lymphopenia (ALLY) predict progression to critical disease
Johanna S van Zyl, Amit Alam, Joost Felius, Ronnie M Youssef, Dipesh Bhakta, Christina Jack, Aayla K Jamil, Shelley A Hall, Göran B Klintmalm, Cedric W Spak, Robert L Gottlieb
Journal of Investigative Medicine Mar 2021, 69 (3) 710-718; DOI: 10.1136/jim-2020-001525
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ALLY in fighting COVID-19: magnitude of albumin decline and lymphopenia (ALLY) predict progression to critical disease
Johanna S van Zyl, Amit Alam, Joost Felius, Ronnie M Youssef, Dipesh Bhakta, Christina Jack, Aayla K Jamil, Shelley A Hall, Göran B Klintmalm, Cedric W Spak, Robert L Gottlieb
Journal of Investigative Medicine Mar 2021, 69 (3) 710-718; DOI: 10.1136/jim-2020-001525
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