https://links.lww.com/QAD/C27

Supplemental Table 1. I AM OLD Cohort Demographics, San Francisco & Seattle (N=200) n (%) or Median [P25-P75]

Age 53 [47, 60]

Male Gender 168 (84.0%)

Race/Ethnicity

White 78 (39.0%)

African American 68 (34.0%)

Hispanic 26 (13.0%)

Other 28 (14.0%)

Ever Smoke(n = 197) 130 (66.0%)

Current Smoker(n = 192) 71 (37.0%)

Pack Years(n = 190) 10 [0, 26]

Marijuana Ever(n = 189) 164 (86.8%)

Smoke Crack Ever(n = 190) 89 (46.8%)

Injection Drug Use Ever(n = 196) 71 (36.2%)

Current ART use (n=195) 163 (83.6%)

CD4 count, cells/µL(n = 197) 474 [270, 682]

CD8count, cells/µL(n = 184) 782 [521, 1,076]

CD4/CD8(n = 182) 0.65 [0.38, 1.03]

HIV Viral Load, copies/mL(n = 195) 0 [0, 39]

HIV Viral Load not detected or detected <40 158 (81.0%) Bacterial Pneumonia Ever(n = 192) 120 (62.5%)

PCP Ever(n = 191) 52 (27.2%)

TB Ever(n = 192) 13 (6.8%)

Hepatitis C Ever (n = 187) 61 (32.6%)

Pneumonia 3 months prior 75 (37.5%)

Post-BD FEV1% predicted (n = 177) 90 (78, 101) Post-BD FVC% predicted (n = 177) 92 (80, 103) Post-BD FEV1/FVC (n = 177) 0.79 (0.71, 0.84)

Post-BD FEV1/FVC <0.70 39 (22.0%)

Post-BD FEV1/FVC <LLN 44 (24.9%)

DLco% predicted (n = 199) 69 (60, 80)

DLco% predicted ≤80.00 150 (75.4%)

DLco% predicted ≤60.00 54 (27.1%)

DLco% predicted <LLN 106 (53.3%)

I AM OLD = Inflammation, Aging, Microbes and Obstructive Lung Disease

PCP = Pneumocystis pneumonia TB = Tuberculosis

Post-BD = Post-bronchodilator

FEV1/FVC = Forced expiratory volume in one second/forced vital capacity

DLco = Diffusion capacity for carbon monoxide adjusted for hemoglobin and carboxyhemoglobin measured on day of PFTs

LLN = Lower limit of normal

Supplemental Table 2. Associations between Plasma Biomarkers and Post- Bronchodilator FVC% predicted (N=177)

Adjusted for pack years, CD4/CD8 ^S, Bacterial Pneumonia ever, PCP ever Adjusted Estimate

[95% CI]

(% predicted) p-value Gut barrier integrity IFABP^T,1 -0.07 [-3.74, 3.60] 0.97 Monocyte/Macrophage

activation

sCD14^T,2 -1.42 [-5.46, 2.62] 0.49 sCD163^T,3 -2.65 [-6.53, 1.24] 0.18 Interferon response IP10^T,4 1.13 [-5.96, 8.22] 0.75 Lymphocyte activation sCD27^T,5 -2.38 [-6.28, 1.53] 0.23

Non-specific inflammation

IL-6^T,6 -5.97 [-12.00, 0.06] 0.05 hsCRP^T,7 -9.64 [-15.69, -3.58] 0.002 Fibrinogen^T 3.68 [-1.75, 9.12] 0.18 sTNFR-I^T,8 -3.75 [-8.16, 0.65] 0.09 sTNF-R-II^T,9 -2.76 [-7.49, 1.97] 0.25 Fibrin breakdown D-Dimer^T -4.54 [-11.02, 1.94] 0.17 Marker of fibrosis Hyaluronic Acid^T 1.40 [-3.07, 5.86] 0.54

FVC = Forced vital capacity

S Square Root Transformed for Regression Analysis

T Log Transformed and divided by IQR for Regression Analysis

1intestinal fatty acid binding protein

2soluble CD14

3soluble CD163

4interferon gamma-inducible protein-10

5soluble CD27

6interleukin-6

7high-sensitivity C-reactive protein

8soluble tumor necrosis factor receptor 1

Supplemental Table 3a. Comparison of FEV1/FVC<0.7 vs. FEV1/FVC≥0.7 Post- Bronchodilator (N=177)

Adjusted for age, pack years, CD4 count ^S, Bacterial Pneumonia ever, PCP ever Adjusted OR [95% CI] p- value

Gut barrier integrity IFABP ^T,1 0.99 [0.58, 1.74] 0.97 Monocyte/Macrophage

activation

sCD14^T,2 0.76 [0.41, 1.38] 0.38

sCD163 ^T,3 1.06 [0.59, 1.91] 0.83

Interferon response IP10 ^T,4 1.49 [0.53, 4.14] 0.44 Lymphocyte activation sCD27 ^T,5 0.60 [0.33, 1.05] 0.08 Non-specific

inflammation

IL-6^T,6 3.14 [1.19, 9.00] 0.03

hsCRP ^T,7 1.82 [0.68, 5.03] 0.24

Fibrinogen ^T 1.51 [0.69, 3.35] 0.30 sTNF-RI ^T,8 1.22 [0.71, 2.08] 0.46 sTNF-RII ^T,9 1.17 [0.59, 2.28] 0.64

Fibrin breakdown D-Dimer ^T 1.20 [0.46, 3.09] 0.70

Marker of fibrosis Hyaluronic Acid ^T 0.49 [0.21, 1.02] 0.07

FEV1/FVC = Forced expiratory volume in one second/forced vital capacity

S Square Root Transformed for Regression Analysis

T Log Transformed and divided by IQR for Regression Analysis

1intestinal fatty acid binding protein

2soluble CD14

3soluble CD163

4interferon gamma-inducible protein-10

5soluble CD27

6interleukin-6

7high-sensitivity C-reactive protein

8soluble tumor necrosis factor receptor 1

9soluble tumor necrosis factor receptor 2

Supplemental Table 3b. Comparison of FEV1/FVC<LLN vs. FEV1/FVC≥LLN Post- Bronchodilator (N=177)

Adjusted for pack years, CD4 count ^S, Bacterial Pneumonia ever, PCP ever Adjusted OR [95% CI] p-value Gut barrier integrity IFABP ^T,1 1.11 [0.65, 1.92] 0.71 Monocyte/Macrophage

activation

sCD14^T,2 0.81 [0.46, 1.41] 0.46

sCD163 ^T,3 1.13 [0.66, 1.94] 0.66

Interferon response IP10 ^T,4 1.53 [0.58, 3.98] 0.38 Lymphocyte activation sCD27 ^T,5 0.67 [0.41, 1.12] 0.13 Non-specific

inflammation

IL-6^T,6 2.67 [1.12, 6.82] 0.03

hsCRP ^T,7 2.01 [0.84, 5.32] 0.12

Fibrinogen ^T 2.11 [1.00, 4.58] 0.05 sTNF-RI ^T,8 1.23 [0.74, 2.09] 0.42 sTNF-RII ^T,9 1.20 [0.64, 2.28] 0.56

Fibrin breakdown D-Dimer ^T 1.67 [0.69, 4.03] 0.25

Marker of fibrosis Hyaluronic Acid ^T 0.61 [0.31, 1.16] 0.15 FEV1/FVC = Forced expiratory volume in one second/forced vital capacity

LLN = Lower limit of normal

T Log Transformed and divided by IQR for Regression Analysis

S Square Root Transformed for Regression Analysis

1intestinal fatty acid binding protein

2soluble CD14

3soluble CD163

4interferon gamma-inducible protein-10

5soluble CD27

6interleukin-6

7high-sensitivity C-reactive protein

9soluble tumor necrosis factor receptor 2

Supplemental Table 4a. Comparison of DLco% predicted≤80% vs. DLco%

predicted>80% (N=199)

Adjusted for pack years, CD4/CD8^S, PCP ever, TB ever, Hepatitis C ever Adjusted OR [95% CI]

(% predicted)

p-value Gut barrier integrity IFABP ^T,1 1.14 [0.70, 1.85] 0.59 Monocyte/Macrophage

activation

sCD14^T,2 2.13 [1.11, 4.40] 0.03

sCD163 ^T,3 2.09 [1.18, 3.82] 0.01

Interferon response IP10 ^T,4 6.30 [2.07, 22.40] 0.002 Lymphocyte activation sCD27 ^T,5 2.10 [1.18, 3.93] 0.02 Non-specific

inflammation

IL-6^T,6 1.64 [0.68, 4.05] 0.27

hsCRP ^T,7 0.99 [0.43, 2.30] 0.99

Fibrinogen ^T 1.15 [0.55, 2.40] 0.70 sTNF-RI ^T,8 2.07 [1.02, 4.64] 0.06 sTNF-RII ^T,9 5.50 [2.26, 15.01] 0.0004

Fibrin breakdown D-Dimer ^T 1.56 [0.62, 4.13] 0.36

Marker of fibrosis Hyaluronic Acid ^T 1.37 [0.78, 2.42] 0.27

DLco = Diffusion capacity for carbon monoxide adjusted for hemoglobin and carboxyhemoglobin measured on day of PFTs

T Log Transformed and divided by IQR for Regression Analysis

S Square Root Transformed for Regression Analysis

1intestinal fatty acid binding protein

2soluble CD14

3soluble CD163

4interferon gamma-inducible protein-10

5soluble CD27

6interleukin-6

7high-sensitivity C-reactive protein

9soluble tumor necrosis factor receptor 2

Supplemental Table 4b. Comparison of DLco% predicted<LLN vs. DLco%

predicted≥LLN (N=199)

Adjusted for pack years, CD4/CD8^S, PCP ever, TB ever, Hepatitis C ever Adjusted OR [95% CI]

(% predicted)

p-value Gut barrier integrity IFABP ^T,1 1.51 [0.97, 2.40] 0.07 Monocyte/Macrophage

activation

sCD14^T,2 1.81 [1.08, 3.16] 0.03

sCD163 ^T,3 1.63 [1.01, 2.67] 0.048

Interferon response IP10 ^T,4 3.34 [1.43, 8.31] 0.007 Lymphocyte activation sCD27 ^T,5 1.42 [0.87, 2.40] 0.17 Non-specific

inflammation

IL-6^T,6 1.49 [0.70, 3.25] 0.30

hsCRP ^T,7 1.43 [0.68, 3.05] 0.35

Fibrinogen ^T 1.69 [0.91, 3.21] 0.10 sTNF-RI ^T,8 1.59 [0.92, 2.90] 0.11 sTNF-RII ^T,9 2.96 [1.54, 6.05] 0.002

Fibrin breakdown D-Dimer ^T 1.76 [0.80, 3.91] 0.16

Marker of fibrosis Hyaluronic Acid ^T 1.05 [0.67, 1.66] 0.84

DLco = Diffusion capacity for carbon monoxide adjusted for hemoglobin and carboxyhemoglobin measured on day of PFTs

LLN = Lower limit of normal

T Log Transformed and divided by IQR for Regression Analysis

S Square Root Transformed for Regression Analysis

1intestinal fatty acid binding protein

2soluble CD14

3soluble CD163

4interferon gamma-inducible protein-10

5soluble CD27

6interleukin-6

8soluble tumor necrosis factor receptor 1

9soluble tumor necrosis factor receptor 2

Supplemental Table 5. Associations between Plasma Biomarkers and Emphysema Lung Function Phenotype (DLco% predicted≤80% with Post-Bronchodilator FEV1/FVC<0.7)^R

Adjusted for pack years, CD4 count ^S, PCP ever Adjusted OR

[95% CI]

(% Predicted)

p-value

Gut barrier integrity I-FABP^T,1 1.98 [0.74, 5.83] 0.19

Monocyte/Macrophage activation

sCD14^T,2 1.38 [0.46, 4.85] 0.59 sCD163^T,3 1.56 [0.54, 4.80] 0.41

Interferon response IP10^T,4 16.39 [2.29, 224.26] 0.02

Lymphocyte activation sCD27^T,5 1.15 [0.51, 2.87] 0.75

Non-specific inflammation IL-6^T,6 34.53 [3.45, 670.29] 0.007 hsCRP^T,7 4.73 [1.05, 27.37] 0.06 Fibrinogen^T 7.84 [1.70, 50.66] 0.02 sTNFR-1^T,8 1.85 [0.71, 8.62] 0.34 sTNFR-II^T,9 8.91 [1.78, 71.82] 0.02

Fibrin breakdown D-dimer^T 2.17 [0.40, 11.84] 0.36

Marker of fibrosis Hyaluronic Acid ^T 0.72 [0.23, 2.16] 0.56

Post-BD = Post-bronchodilator

FEV1/FVC = Forced expiratory volume in one second/forced vital capacity

DLco = Diffusion capacity for carbon monoxide adjusted for hemoglobin and carboxyhemoglobin measured on day of PFTs

R Reference = Participants with normal spirometry and normal DLco

S Square Root Transformed for Regression Analysis

T Log Transformed and divided by IQR for Regression Analysis

2soluble CD14

3soluble CD163

4interferon gamma-inducible protein-10

5soluble CD27

6interleukin-6

7high-sensitivity C-reactive protein

8soluble tumor necrosis factor receptor 1

9soluble tumor necrosis factor receptor 2