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Table 2 Results of the systematic review

From: Neutrophil elastase in bronchiectasis

Author and year Study design Setting Clinical stability Sample size Assay manufacturer (methods) Quantitative findings Biological matrix Major results
Stockley, 1984 [18] Cross-sectional Monocentric, outpatients Stable state
Exacerbation
34 Bx patients Elastin-agarose diffusion plate (in-home assay) NE activity (μg x mL): grade1 19.5; grade2 48.2; grade3 62.9 Sputum Correlation with sputum macroscopic appearance
Smallman, 1984 [6] Cross-sectional/Prospective Monocentric, outpatients Stable state 8 Bx patients Elastin-agarose diffusion plate (in-home assay) NE activity (μg x mL): not quantified but evaluated as present/not present (lower limit of detection 0.8) Sputum Inverse correlation with ciliary beat frequency
NE reduction after short-term antibiotic therapy
Fujita, 1992 [60] Cross-sectional Monocentric, outpatients Stable state 9 Bx patients in a cohort of 64 chronic respiratory diseases +15 healthy subjects Elisa for NE- A1AT complex (in-home assay) NE-A1AT complex levels (μg x L): 558 ± 198; healthy subjects 122 ± 4 Blood NE- A1AT complex higher in Bx patients than in healthy subjects
Lloberes, 1992 [63] Cross- sectional Monocentric, outpatients Stable state 26 Bx patients Elastin-agarose diffusion plate (in-home assay) NE activity (μg × 100 μL): purulent 7.75 (0–21.5); mucopurulent 1.3 (0–19.5); mucoid 0 Sputum Correlation with sputum macroscopic appearance
Ip, 1993 [71] Prospective Monocentric, outpatients Exacerbation 12 Bx patients Spectrophotometry, SLAPN substrate NE activity (mU × 100 μL): baseline 50.5 ± 17.1; exacerbation before atb 51.8 ± 25.4; 1-week atb −24.3 ± 20.7; 2-week atb −35.1 ± 17.8; 2-week after atb −12.1 ± 35.6; 6-week after atb −32.8 ± 26.8 Sputum NE reduction after short-term antibiotic therapy
Llewellyn-Jones, 1995 [15] Prospective Monocentric, outpatients Stable state 9 Bx patients +8 healthy subjects Fluorescence (in-home assay) NE activity (μg x mL−1): day -7th 4.0 ± 0.46; baseline 4.15 ± 0.69; day 14th 4.25 ± 0.63; day 28th 4.39 ± 0.65; day 63th 4.03 ± 0.67 Blood No NE reduction after indomethacin
Sepper, 1995 [74] Cross-sectional Monocentric, outpatients Stable state 24 Bx patients +15 healthy subjects Spectrophotometry, SAAVNA substrate NE activity (mU x g): mild group 0.21 ± 0.09; moderate group 1.87 ± 1.12; severe group 2.64 ± 1.63; healthy subjects 0.09 ± 0.03 BAL Correlation with symptoms, exacerbation rate and radiological severity
Nakamura, 1997 [56] Cross-sectional Monocentric, outpatients Stable state 3 Bx patients in a cohort of 8 chronic respiratory diseases +15 healthy subjects Elisa (in-home assay) Quantitative findings only reported as figures BAL NE higher in Bx than in healthy subjects
Gaga, 1998 [57] Cross-sectional Monocentric, outpatients Stable state 12 Bx patients +11 healthy subjects Immunocitochemistry (in-home assay) Neutrophils (cells x mm3): Bx patients 114; healthy subjects 41 Bronchial biopsies NE higher in Bx than in healthy subjects
Nakamura, 1999 [78] Prospective Monocentric, outpatients Stable state 3 Bx patients in a cohort of 10 chronic respiratory diseases Elisa (in-home assay) NE levels (μg x mL−1): baseline 125.5 ± 47.5; 16.8 ± 7.1 after atb BAL Ne reduction after 3-month roxithromycin
Ichikawa, 1999 [64] Cross-sectional Monocentric, outpatients Stable state 18 Bx patients in a cohort of 59 chronic respiratory diseases +28 healthy subjects Spectrofluorometry AMC substrate NE activity (U): purulent 1239.2 ± 1017.8; mucoid 45.7 ± 115.1 Sputum Inverse correlation with IgBF levels and sputum purulence
Hill, 2000 [16] Cross- sectional Monocentric, outpatients Stable state 43 Bx patients in a cohort of 160 chronic respiratory diseases Spectrophotometry NE levels (nM): mixed flora 0 (0–20); high bacterial load 21 (4–40) Sputum Correlation with sputum bacterial load
Schaaf, 2000 [68] Cross-sectional Monocentric, outpatients Stable state 11 Bx patients in a cohort of 66 chronic respiratory diseases +12 healthy subjects Immunoluminometry
Colorimetry
NE-A1AT complex levels (ng x mL): Bx patients 44 (15–152); healthy subjects 3 (0–15) BAL NE higher in Bx than in healthy subjects
Correlation with P. aeruginosa chronic respiratory infection
Tsang, 2000 [75] Cross-sectional Monocentric, outpatients Stable state 30 Bx patients Spectrophotometry, SAAVNA substrate NE levels (U x mL): 6.60 ± 3.13 Sputum Correlation with 24 h sputum volume, sputum inflammatory markers (leukocytes, IL-B and TNFa), radiological severity and spirometry (FEV1, FVC)
Zheng, 2000 [69] Cross-sectional Monocentric, outpatients Stable state 35 Bx patients +18 healthy subjects Spectrophotometry, SAAVNA substrate NE levels (Unit x mL−1): P. aeruginosa 222.6 (18.3–267.5); 8.7 (0.6–186.7) Sputum Correlation with P. aeruginosa chronic respiratory infection
Viglio, 2000 [21] Cross-sectional Monocentric, outpatients Stable state 13 Bx patients in a cohort of 54 chronic respiratory diseases +24 healthy subjects HPCE DES (μg x g creatinine−1): Bx patients 23.39 ± 2.05; CF 23.39 ± 2.02; A1AT deficiency 22.3 ± 7.74; exacerbated COPD 17.15 ± 3.42; stable COPD 14.17 ± 2.33; smokers 11.97 ± 2.75; healthy subjects 9.31 ± 2.75 Urine Desmosine higher in stable Bx than in other chronic respiratory disease and healthy subjects
Angrill, 2001 [62] Cross-sectional Monocentric, outpatients Stable state 49 Bx patients +9 healthy subjects Immunoassay (?) NE levels (μg x L): colonized patients 231 (15–2930); not colonized patients 45 (8–2280); healthy subjects 34 (9–44) BAL NE higher in Bx than in healthy subjects
Correlation with neutrophils, IL8 and TNFa in BALF
Correlation with bacterial chronic respiratory infection.
Stockley, 2001 [65] Cross-sectional Monocentric, outpatients Stable state 14 Bx patients +9 smokers Spectrophotometry, MSAPN substrate
Elisa (in-home assay)
NE levels (μM): sputum colour value-3 0.006 ± 1.0; sputum colour value-7 4.14 ± 1.0 Sputum Correlation with sputum macroscopic appearance
Correlation with MPO and 24 h sputum volume
Inverse correlation with A1AT
Zheng, 2001 [59] Cross-sectional Monocentric, outpatients Stable state 14 Bx patients +15 healthy subjects Anti-NE antibodies Median neutrophils x mm−2: Bx patients 608 (101–1013); healthy subj. 127 (24–630) Endobronchial biopsies NE higher in bronchiectatic lamina propria than in healthy subjects
Vandivier, 2002 [58] Prospective Monocentric, outpatients Exacerbation 6 Bx patients in a cohort of 18 chronic respiratory diseases Spectrophotometry NE (U x mL): Bx patients 10; CF 3 Sputum NE higher in Bx
NE as cause of delay in apoptotic cell clearance
Chan, 2003 [12] Cross-sectional Monocentric, outpatients Stable state 10 Bx patients Spectrophotometry NE activity range (mM): 0.9–1.2 Sputum NE not only as free but complexed with polyanionic partners (syndecan-1) and A1AT
Watt, 2004 [72] Prospective Monocentric, outpatients Exacerbation 15 Bx patients +10 healthy subjects Kinetic assays (?) NE levels (ng x mL): after atb −73,451 (135,495–12,303) Sputum NE reduction after short-term antibiotic therapy
Chan, 2009 [61] Cross-sectional Monocentric, outpatients Stable state 12 Bx patients Spectrophotometry, MSAPN substrate
ELISA (in-home assay)
NE activity (mM): 1.3 (1–2) Sputum NE complexed with syndecan-1
Description of protease/anti-protease balance
Murray, 2010 [77] RCT Monocentric, outpatients Stable state 65 Bx patients Elastin-agarose diffusion plate (in-home assay) NE activity gentamicin group vs placebo: (U x mg): baseline 3.6 (0–17.6) vs 4.1 (0–19); 3-month 0 (0–0) vs 0 (0–20.4); 6-month 0 (0–2.9) vs 0 (0–29.1); 9-month 0 (0–7.6) vs 0.9 (0–19.4); 12- month 0 (0–1.8) vs 1.8 (0.17–16); 15-month 7.1 (0–56) vs 2.8 (0.9–18.2) Sputum NE reduction after 3-month inhaled gentamicin
Chalmers, 2012 [67] Prospective Monocentric, outpatients Stable state
Exacerbation
385 Bx patients Elastin-agarose diffusion plate (in-home assay) NE activity (μg x mL): P. aeruginosa infected 4.9 (1.2–68); P. aeruginosa not infected 1.2 (0.4–147.2); other quantitative findings only reported as figures Sputum Correlation with bacterial load and radiological severity
Mandall, 2013 [73] Prospective Monocentric, outpatients Stable state 163 Bx patients Spectrophotometry NE activity (U x mL): GERD group 5; non-GERD group 3 Sputum Correlation with GERD
Stockley, 2013 [55] RCT Multicentric, outpatients Stable state 38 Bx patients Custom-made immunoassay (in-home assay) for both NE and desmosine NE activity AZD9668 group vs placebo (μM x L): baseline 24.54 vs 7.28; end of treatment 15.92 vs 7.49 Sputum
Urine
NE reduction after 28-day of oral AZD9668
No difference in desmosine between AZD9668 and placebo
Goeminne, 2014 [66] Cross-sectional Monocentric, outpatients Stable state 49 Bx patients +12 healthy subjects Enzymatic assay NE activity (μg x mL): Bx patients 15 (3–23); healthy subject 0.8 (0.4–1.2) Sputum Correlation with TNFA, CXCL8 and MMP-9
Inverse correlation with FVC
Liu, 2014 [14] RCT Monocentric, outpatients Stable state 43 Bx patients ELISA (in-home assay) Quantitative findings only reported as figures Sputum NE reduction after 6-month roxythromicin
Aliberti, 2016 [70] Prospective Multicentric, outpatients Stable state 1145 Bx patients different assays according to different centers Quantitative findings only reported as figures Sputum Correlation with ‘P. aeruginosa‘cluster and ‘Other chronic infection’ cluster
Chalmers, 2016 [17] Prospective   Stable state
Exacerbation
381 Bx patients Immunoassay (ProAxsis LTD) Kinetic assay (Sigma Aldrich)
LC-MS for desmosine
NE levels (μg x mL): baseline 0.39 (0–23.5); onset of exacerbation 57.0 (3.3–145); after 14-day atb 0 (0–125.8); 1-month later 1.3 (0–29.9) Sputum
Serum
Correlation with BSI, MRC, FEV 1 , bacterial load, radiological severity
Correlation with higher exacerbation rate, FEV1 decline, all-cause mortality during 3-year follow up
NE increase during exacerbations and NE reduction after short-term antibiotic therapy
Serum desmosine is associated with age and disease severity
  1. Definitions: atb antibiotics, A1AT alpha-1 anti-trypsin, BAL broncho-alveolar lavage, Bx bronchiectasis, DES desmosine, NE neutrophil elastase, SLAPN succinyl-trialanine-nitroanilide, SAAVNA succinyl-Ala-Ala-Val-nitroanilide, MSAPN methoxysuccinyl-Ala-Ala-Pro-Val-paranitroanilide, HPCE high-performance capillary electrophoresis, LC-MS liquid chromatography-mass spectrometry