Clinimetric properties of bronchoalveolar lavage inflammatory markers in cystic fibrosis

Michael Fayon; Lisa Kent; Stephanie Bui; Lieven Dupont; Isabelle Sermet

doi:10.1183/09031936.00017713

Tables

Additional Files

Table 1– Clinimetric properties of biomarkers

	Definition	Justification of importance
Reliability	Degree to which a measurement is consistent and free from error	Important to quantify error (systematic and random) so that true changes can be discerned from changes due to normal fluctuations
Validity		The gold standard outcome measures are often not feasible; therefore, it is important to know how an alternative outcome measure compares to the gold standard, and how different outcome measures compare It is important to know the ability of outcome measures to discriminate between different groups
Concurrent validity	Degree to which a test correlates with a “gold standard” criterion test which has been established as a valid test of the attribute of interest
Convergent validity	Degree to which a test correlates with another test which measures the same attribute
Discriminate validity	Degree to which a test differentiates between groups of individuals known to differ in the attribute of interest
Predictive validity	Degree to which an attribute can be predicted using the result of a predictor test/or degree to which prognosis can be predicted
Responsiveness	Degree to which a test changes in response to an intervention known to alter the attribute of interest	Important attribute of tests used in clinical practice or research to assess treatment benefit (e.g. to identify improvements in response to an intervention)

Reproduced from [1] with permission.

Table 2– Discriminate validity of bronchoalveolar lavage (BAL) inflammatory markers between cystic fibrosis (CF) patients and non-CF subjects

First author [ref.]	Aliquot fraction analysed	CF		Non-CF		PMN cell counts ×10³ cells·mL⁻¹, unless otherwise stated	PMN cells %	Neutrophil elastase	IL-6 ×10³·mL⁻¹, unless otherwise stated	IL-8 ×10³·mL⁻¹, unless otherwise stated	Statistical tests	Data presentation
		Subjects n	Age	Subjects n	Age
Armstrong [26]	F	50 infected	19.1 (1.5–71) months	19	12.4±11.8 months	CF 50 (39–65) versus non-CF 8.2 (4.6–15)***	CF 80 (66–90) versus non-CF 32 (13–57)***		CF 1153 (754–1762) versus non-CF 24 (12–47)***	CF 50 (39–65) versus non-CF 8.2 (4.6–15)***	Wald test	Geometric mean (95% CI)
Armstrong [26]	F	28	Infants (age not reported)	10	Infants (age not reported)			CF 11 (8.7–13) versus non-CF 2.1 (0.95–4.7) μg·mL⁻¹***			Wald test	Geometric mean (95% CI)
Muhlebach [38]	Not specified	17	25±4 months	25	15±3 months	CF 41.2±7.0 versus non-CF 21.8±5.2*			CF 6868±2065 pg·mL⁻¹ versus non-CF 1434±362 pg·mL^−1¶	CF 41.2±7.0 versus non-CF 21.8±5.2*	Mann–Whitney U-test	Mean±sem
Armstrong [39]	F	5 virus infected	Infants (age not reported)	13	Infants (age not reported)	CF 169 (16–1809) versus non-CF 7 (2–22)***				CF 1372 (561–3358) versus non-CF 32 (12–84)***	ANCOVA	Geometric mean (95% CI)
Khan [31]	P	16	0.48 (0.08–0.97) years	11	1.02 (0.25–2.7) years	CF 673.6±367.9 versus non-CF 6.9±1.7⁺		CF 1.18±0.46 μg·mL⁻¹ versus non-CF 0 μg·mL^−1§		CF 1298±338 pg·mL⁻¹ versus non-CF 92±25 pg·mL⁻¹***	Independent t-test	Mean±sem
Kirchner [40]	P	16	10.5 (2–25) months	9 (disease)	11.7 (3–30) months	^¶					Kruskal–Wallis	Values not reported
Muhlebach [41]^#,¶	Not specified	51	1.8 years (3 weeks–13 years)	50 (disease)	1.0 years (2 weeks–8.3 years)	***	*			***	Independent t-test	Values not reported
Muhlebach [42]^#	Not specified	55	3.7 (0.1–13) years	56	2.1 (0.04–9) years	*				*	Independent t-test	Values not reported
Noah [43]	P	15 (infected)	2.4 (0.1–13) years	12 (uninfected)	1.4 (0.1–8.8) years	CF 3358 (100–11 520) versus non-CF 10 (1–117)*	CF 84 (16–96) versus non-CF 5 (1–51)*		CF 56 (17–681) versus non-CF 10 (2–59)*	CF 11 614 (1424–71 100) versus non-CF 459 (21–2040)*	Kruskal–Wallis	Median (range)
Noah [43]	P	15 (infected)	2.4 (0.1–13) years	12 (infected)	1.4 (0.1–8.8) years	CF 3358 (100–11 520) versus non-CF 229 (1–2976)*	CF 84 (16–96) versus non-CF 46 (1–93)*		ns	CF 11 614 (1424–71 100) versus non-CF 1860 (18–6224)*	Kruskal–Wallis	Median (range)
MacGregor [44]	P	39	6.4±0.7 years	38	6.1±0.6 years		ns			CF 1308.1±56.4 versus non-CF 716±89.9***	Mann–Whitney U-test	Mean±sem
Hilliard [45]	P	43	6.2 (0.3–16.8) years	7 (PCD)	9.2 (5.7–14.8) years	ns		ns		ns	Nonparametric tests
Hilliard [45]	P	43	6.2 (0.3–16.8) years	26 (CRD)	4.8 (0.9–15.2) years	CF 0.7 (0.02–23.97)×10⁶·mL⁻¹ versus non-CF 0 (0–17.91)×10⁶·mL⁻¹ ***		CF 201 (100–5000) μm·mL⁻¹ versus non-CF 100 (100–1297) μm·mL⁻¹ ***		CF 1340 (31–1760) pg·mL⁻¹ versus 703 (31–1560) pg·mL⁻¹ ***	Nonparametric tests	Median (range)
Hilliard [45]	P	43	6.2 (0.3–16.8) years	7 (disease control)	5.8 (0.3–16.3) years	CF 0.7 (0.02–23.97)×10⁶·mL⁻¹ versus non-CF 0 (0–0.01)×10⁶·mL⁻¹ ***		CF 201 (100–5000) μm·mL⁻¹ versus non-CF 100 (100–100) μm·mL⁻¹ ***		CF 1340 (31–1760) pg·mL⁻¹ versus 64 (31–221) pg·mL⁻¹**	Nonparametric tests	Median (range)
Harris [46]	F	29 (during exacerbation)	9.1±12 years	12	6.0±1.4 years	CF 6.1±0.12 log₁₀ versus 4.9±0.17 log₁₀***	CF 68.8±3.6 versus 16.4±3.8***				Wilcoxon rank sum test	Mean±sem
Dean [37]	svBAL, F	5	8 (4–18) years	8 (asthma)	Adults (age not reported)					CF 6618 (1200–11 136) pM versus non-CF 302.4 (48–984) pM*	Not reported	Mean (range)
Dean [37]	svBAL, F	5	8 (4–18) years	6 (PCD)	Children (age not reported)					CF 6618 (1200–11 136) pM versus non-CF 302.4 (48–984) pM*^ƒ	Not reported	Mean (range)
Reeves [47]	Not specified	15	Children and adolescents	12	8.21±1.22 years						Mann–Whitney U-test	Values not reported
Ratjen [48]	F	105	5–37 years	48	3–15 years		First aliquot CF 52±30 versus non-CF 4±5^##				Mann–Whitney U-test	Mean±sd
Ratjen [48]	P (aliquots 2 and 3)	105	5–37 years	48	3–15 years		Pooled CF 29±23 versus non-CF 2±3^##¶				Mann–Whitney U-test	Mean±sd
Reeves [49]	F	18	19.6±5.2 years	14 (other disease)	50.14±10.5 years					CF 325±81.96 pg·mg⁻¹ versus 125.92±43.95 pg·mg⁻¹ *	Independent t-test	Mean±sem
McGarvey [6]	F (cytology), P (remaining)	11	22.7±3.8 years	9 (mild asthma)	24.1±3.9 years			ns		ns	ANOVA
				11 (healthy)	24.3±2.8 years
Bonfield [33]	P	22	20±2 years	13	29±6 years	CF 41±10×10⁶·mL⁻¹ versus non-CF 0.09±0.02×10⁶·mL⁻¹ *	CF 60±5 versus non-CF 1±0.3*	CF 1.9±0.5 μM versus non-CF 0 μM*	p=0.06 CF 287±104 versus non-CF 0	CF 32 565±9686 versus non-CF 0*	Kruskal–Wallis	Mean±sem
Konstan [50]	P	18	20±1 years	23	25±1 years	CF 38±14 (1–222)×10⁶·mL⁻¹ versus non-CF 0.1±0.04 (0–0.6)×10⁶·mL⁻¹ *					Independent t-test	Mean±sem (range)
Meyer [35]	P	14 (exacerbation)	17–40 years	8	19–24 years		CF 51.1±5.2 versus non-CF 0.3±0.4*	CF 323±127 nM·min⁻¹·mL⁻¹ versus non-CF 0 nM·min⁻¹·mL⁻¹*			Independent t-test	Mean±sem
Nakamura [51]	Not specified	8	28±2 years	7	29±3 years	CF 101±26 versus non-CF 0.4±0.3*		CF 31±10 versus non-CF 0*		CF 35±13 versus non-CF 0*	Not reported	Mean (range)

All four biomarkers are present at higher levels in patients with CF. All samples are BAL, unless otherwise stated. PMN: polymorphonuclear; IL: interleukin; F: first; P: pooled; svBAL: small volume BAL; ns: not significant; PCD: primary ciliary dyskinesia; CRD: chronic respiratory disease. ^#: [42] includes patients previously reported in [41]; *: p<0.05; **: p<0.01; ***: p<0.001; ^¶: p<0.005; ⁺: p=0.002; ^§: p=0.03; ^ƒ: p=0.02; ^##: p<0.0001.

Table 3– Discriminate validity of bronchoalveolar lavage (BAL) inflammatory markers between groups of patients with cystic fibrosis (CF) with different phenotypes

First author [ref.]	Aliquot fraction analysed	Group 1		Group 2		PMN cell counts ×10³ cells·mL⁻¹, unless otherwise stated	PMN cells %	Neutrophil elastase	IL-6 ×10³·mL⁻¹, unless otherwise stated	IL-8 ×10³·mL⁻¹, unless otherwise stated	Statistical tests	Data presentation
		Subjects n	Age	Subjects n	Age
Sly [9]	F (microbiology), P (aliquots 2 and 3)	48 asymptomatic	Infants	9 symptomatic	Infants	ns	Group 1 14.5 (9.0–27.1) versus Group 2 39.7 (28.3–65.0)^#	Group 1 100 (100–143) ng·mL⁻¹ versus Group 2 100 (100–2025) ng·mL^−1#		ns	Independent t-tests	Median (IQR)
Sly [9]	F (microbiology), P (aliquots 2 and 3)	45 uninfected	Infants	12 infected	Infants	Group 1 31.3 (11.3–76.3) versus Group 2 169 (72.2–208.5)^#	Group 1 13.5 (8.3–26.1) versus Group 2 35.7 (25.3–44.7)^¶	Group 1 100 (100–100) ng·mL⁻¹ versus Group 2 350 (100–1330) ng·mL⁻¹⁺		Group 1 260 (128–630) pg·mL⁻¹ versus Group 2 770 (420–2120) pg·mL^−1§	Independent t-tests	Median (IQR)
Armstrong [13]	svBAL, P	18 infected	2.6±1.1 months	10 noninfected, nonsymptomatic	2.6±1.1 months	Group 1 153 (52–449) versus Group 2 15 (8–29)***		Group 1 78 (52–94)% versus Group 2 0 (0–31)%***		Group 1 1112 (582–2126) versus Group 2 24 (9–63)***	Independent t-test	Mean (95% CI)
Sly [9]	F (microbiology), P (aliquots 2 and 3)	24 no antistaphylococcal prophylaxis	3.6 (3.4–4.8) months	33 antistaphylococcal prophylaxis	3.6 (2.8–4.7) months	ns	ns	ns		ns	Independent t-tests
Armstrong [26]	F	28 infected	Infants (age not reported)	7 pristine 17 uninfected	Infants (age not reported)				Group 1 11 (8.7–13) pg·mL⁻¹ versus Group 2 pristine 2.2 (0.48–10) pg·mL⁻¹ and uninfected 2.2 (1.8–2.6) pg·mL⁻¹ ***		Wald test	Geometric mean (95% CI)
Armstrong [26]	F	50 infected		13 pristine		Group 1 562 (407–777) versus Group 2 pristine 127 (76–210) and uninfected 106 (67–168)***	Group 1 50 (39–65) versus Group 2 pristine 8.4 (5.2–14) and uninfected 7.1 (4.4–12)***	Group 1 80 (66–90)% versus Group 2 pristine 0 (0–25)% and uninfected 20 (6–44)% of patients with free NE activity***		Group 1 1153 (754–1762) pg·mL⁻¹ versus Group 2 pristine 32 (15–72) pg·mL⁻¹ and uninfected 49 (23–101) pg·mL⁻¹***	Wald test	Geometric mean (95% CI)
Rosenfeld [52]	Not specified	31 (≥10⁵ CFU·mL⁻¹)	≤15 months at study entry	29 (<10⁵ CFU·mL⁻¹)	≤15 months at study entry	ns				ns	Generalised estimating equation
Rosenfeld [52]	Not specified	31 (≥10⁵ CFU·mL⁻¹)	≤15 months at study entry	30 no pathogen	≤15 months at study entry	Group 1 1145 (580–2264) versus Group 2 114 (63–206)***				Group 1 1802 (1104–2942) versus Group 2 427 (269–679)^ƒ¶	Generalised estimating equation	Geometric mean (95% CI)
Rosenfeld [52]	Not specified	Not specified P. aeruginosa positive	≤15 months at study entry	Not specified other pathogen	≤15 months at study entry	ns					Generalised estimating equation
Nixon [53]	F	20 symptomatic	20.7±10.6 months	34 asymptomatic	15.7±9.7 months		ns	ns		ns	Generalised estimating equation
Nixon [53]	F	15 infected	22.8±6.7 months	39 uninfected	15.9±10.9 months		Group 1 59 (47–70) versus Group 2 28 (21–35) ***	ns		Group 1 641 (305–1350) versus Group 2 253 (158–406)^##¶	Generalised estimating equation	Mean and geometric mean (95% CI)
Dakin [54]	F	8 infected	23 months	14 uninfected	23 months		90.8% >10⁵ pathogens versus 24.1% <10⁵ pathogens^¶¶			4600 pg·mL⁻¹ >10⁵ pathogens versus 1627 pg·mL⁻¹ <10⁵ pathogens⁺⁺	Independent t-test/ANOVA
Brennan [30]	F (microbiology), P (aliquots 2 and 3)	9 infected	1.55 (1.11–2.51) years	15 uninfected	1.58 (1.12–2.91) years	667 (58–5342) infected versus 60 (39–91) noninfected^ƒ	52 (38–81)% infected versus 17.3 (9–29)% noninfected ***			ns	Not reported	Median (IQR)
Gutierrez [55]	F	6 (≥10⁵ CFU·mL⁻¹)	35.3±21.3 months	24 (<10⁵ CFU·mL⁻¹)	22.1±13.3 months		*** (right middle lobe) ns (lingula)			^§§ (right middle lobe) ^¶¶ (lingula)	Independent t-test
Armstrong [39]	F	5 virus-infected	6.5±5.3 months	22 noninfected	2.6±1.5 months	169 (16, 1809) virus infected versus 16 (8, 34) noninfected***				1372 (561, 3358) virus-infected versus 47 (21, 108) noninfected***	ANCOVA	Geometric mean (95% CI)
Brennan [30]	F (microbiology), P (aliquots 2 and 3)	14 asymptomatic	<6 years	11 symptomatic	<6 years	Group 1 60.3 (38.45–90.55) versus Group 2 667.58 (64.3–5341.48)^ƒƒ,¶	Group 1 16.5 (10.5–26.5) versus Group 2 53 (49.67–80.5)***			ns	Not reported	Median (IQR)
Sagel [56]	P	59 P. aeruginosa positive	6 months–6 years	31 no pathogens	6 months–6 years	Group 1 5.6±0.7 log₁₀·mL⁻¹ versus Group 2 4.8±0.6 log₁₀·mL⁻¹***	Group 1 49.3±25.9 versus Group 2 22.1±14.4***	Group 1 41% of patients versus Group 2 0% of patients with NE detected in BAL***	ns	Group 1 3.1±0.6 pg·mL⁻¹ versus Group 2 2.3±0.6 pg·mL⁻¹***	Linear regression	Mean±sd
Sagel [56]	P	21 P. aeruginosa negative, other pathogen present	6 months–6 years	31 no pathogens	6 months–6 years	Group 1 59±0.3 log₁₀·mL⁻¹ versus Group 2 5.6±0.3 log₁₀·mL⁻¹***	Group 1 33.6±17.6 versus Group 2 22.1±14.4*	ns	ns	Group 1 2.8±0.7 pg·mL⁻¹ versus Group 2 2.3±0.6 pg·mL⁻¹**	Linear regression	Mean±sd
Sagel [56]	P	59 P. aeruginosa positive	6 months–6 years	21 P. aeruginosa negative, other pathogen present	6 months–6 years	ns	Group 1 33.6±17.6 versus Group 2 22.1±14.4⁺	ns	ns	ns	Linear regression	Mean±sd
Sagel [57]	P	44 nonmucoid P. aeruginosa	6 months–6 years	15 mucoid P. aeruginosa	6 months–6 years	Group 1 5.9±0.6 log₁₀·mL⁻¹ versus 5.5±0.7 log₁₀·mL^−1#	Group 1 62.7±22.1 versus Group 2 44.5±25.7^###	ns	ns	ns	Linear regression	Mean±sd
Sagel [56]	P	Not specified S. aureus present	6 months–6 years	Not specified S. aureus not present	6 months–6 years	***	^¶¶¶		⁺	***	Linear regression	Values not reported
Hilliard [45]	P	31 exacerbation	6.2 years	12 clinically well	6.2 years	Group 1 1.0×10⁶·mL⁻¹ versus Group 2 0.4×10⁶·mL⁻¹*					Nonparametric tests	Median
Muhlebach [41]	Not specified	Not specified P. aeruginosa positive	Mean 7.6 years	Not specified other pathogen	Mean 1.9 years	ns				ns	Independent t-test
Armstrong [15]	Not specified	14 infected	Children (age not reported)	20 noninfected	Children (age not reported)	Group 1 259 (70–968)×10⁶·L⁻¹ versus 17 (8–36)×10⁶·L⁻¹***				Group 1 2013 (1164–3784) ng·L⁻¹ versus Group 2 26 (13–51) ng·L⁻¹***	Independent t-test	Mean (95% CI)
Noah [43]	P	15 infected	<13 years	10 uninfected	<13 years	Group 1 3358 (100–11 520) versus Group 2 291 (25–952)*	Group 1 84 (16–96) versus Group 2 40 (4–62)*		ns	ns	Kruskal–Wallis	Median (range)
Regamey [28]	P	36 during exacerbation		10 stable		Group 1 970 (287–1584) versus Group 2 222 (21–380)^¶¶¶					Independent t-test	Median (IQR)
Regamey [28]	P	13 Aspergillus present		13 Aspergillus not present		ns					Independent t-test
Regamey [28]	P	11 P. aeruginosa positive		15 P. aeruginosa negative		ns					Independent t-test
Bonfeld [33]	P	17 P. aeruginosa positive	Adolescents and adults (age not reported)	5 P. aeruginosa negative	Adolescents and adults (age not reported)					ns	Kruskal–Wallis
Kirchner [40]	P	7 older patients	Mean (range) 18.6 (13.5–31) years	16 younger patients	Mean (range) 10.5 (2–25) months	ns					Kruskal–Wallis

Biomarkers are present at higher levels in patients with more severe lung disease. All samples are BAL, unless otherwise stated. PMN: polymorphonuclear; IL: interleukin; F: first; P: pooled; svBAL: small volume BAL; IQR: interquartile range; ns: not significant; P. aeruginosa: Pseudomonas aeruginosa; S. aureus: Staphylococcus aureus; NE: neutrophil elastase. *: p<0.05; **: p<0.01; ***: p<0.001; ^#: p=0.0001; ^¶: p=0.027; ⁺: p=0.003; ^§: p=0.036; ^ƒ: p=0.04; ^##: p=0.03; ^¶¶: p=0.01; ⁺⁺: p=0.0001; ^§§: p=0.05; ^ƒƒ: p= 0.002; ^###: p=0.02; ^¶¶¶: p=0.004.

Table 4– Discriminate validity of bronchoalveolar lavage (BAL) inflammatory markers

First author [ref.]	Aliquot fraction analysed	Subjects	Age	Participants	Results	Statistics
Khan [31]	P	16	0.08–0.97 years	Neutrophil count PMN cell count above controls (n=11) PMN cell count overlapping controls (n=5)	Lower S_pO₂ in group with elevated PMN cell count (mean±SEM 92.8±0.9 versus 96.6±0.7, p=0.0097) Weight-for-age ns Respiratory rate ns Wisconsin chest computed tomography score ns	Independent t-test
Sagel [57]	P	111	6 months–6 years	Neutrophil elastase	Lower Shwachman scores in group with detectable free neutrophil elastase activity (63.5±8.8 versus 69.7±5.5, p<0.0001)	Not reported
Hull [58]	F	32		Presence of inflammation (PMN cell count and IL-8) Inflammation (n=13) No inflammation (n=19)	Higher lipid hydroperoxide concentration in group with detectable inflammation (geometric mean 97.7 versus 21.9 μM, p<0.05) Higher γ-GT in group with detectable inflammation (geometric mean 104.2 versus 20.2 U·L⁻¹, p<0.05)	Independent t-test

Data are presented as n, range or mean±sd, unless otherwise stated. Patients grouped by level of inflammation (from BAL biomarkers) differ in clinical presentation (including oxidative stress). P: pooled; F: first; PMN: polymorphonuclear; S_pO₂: arterial oxygen saturation measured by pulse oximetry; ns: nonsignificant; IL: interleukin; γ-GT: gamma glutamyl transpeptidase.

Table 5– Responsiveness of bronchoalveolar lavage (BAL) inflammatory markers

First author [ref.]	Aliquot fraction analysed	Subjects n	Age	Intervention	Results					Statistical test Presentation of data
					PMN cell counts	PMN cell %	NE	IL-6	IL-8
Response to treatment with antibiotics
Armstrong [26]	F	13	22.1 (14–44) months	Eradication of infection Follow-up BAL at 6–18 months	Decreased T1 56.6% T2 21.2%		Decreased T1 13.6 μg·mL⁻¹ T2 8.5 μg·mL⁻¹		Decreased T1 1782 pg·mL⁻¹ T2 307 pg·mL⁻¹	Mean
Noah [18]	Not specified	15	14–133 months	TIS (inhaled 300 mg twice daily, 28 days) (n=6) versus ceftazidime and tobramycin (i.v., 14 days) (n=9) Follow-up BAL at 4–6 weeks	p=0.02 Inhaled +0.9 (0.6–5.4) Systemic -0.26 (0.03–2.26)	ns Inhaled +5.4 (-11–15.3) Systemic -7.0 (-34.5–19.1)		ns	ns	Mann–Whitney U-test Median (range) ratio post versus pre
Gibson [17]	Not specified	21	6 months–6 years	TIS (inhaled, 28 days) versus placebo Follow-up BAL at day 28	ns			ns	ns	Not reported
Gibson [16]	Not specified	9	6 months–6 years	TIS (28 days) Follow-up BAL at day 56	ns	ns		ns	ns	One-sample t-test
Gibson [16]	Not specified	9	6 months–6 years	TIS (28 days) Follow-up BAL at day 84	ns	p=0.01 T1 60.5 (29.4) T2 38.8 (18.2)		ns	ns	One-sample t-test
Gibson [16]	Not specified	12	6 months–6 years	TIS (56 days) Follow-up BAL at day 112	ns	p=0.01 T1 53.4 (13.5) T2 35.4 (20.3)		ns	ns	One-sample t-test
Gibson [16]	Not specified	8	6 months–6 years	TIS (28 days) Follow-up BAL at day 112	ns	ns		ns	ns	One-sample t-test
Meyer [61]	P	11	17–40 years	i.v. antibiotics for respiratory exacerbation BAL start and end of 2 weeks admission	ns		p=0.017			Not reported
Acquisition of infection
Armstrong [26]	F	8	20 (13–50) months	No infection in first BAL (T1) but present in second Follow-up BAL at 6–18 months (T2)	Increased T1 9.7% T2 55%		Increased T1 3.3 μg·mL⁻¹ T2 10.3 μg·mL⁻¹		Increased T1 88 pg·mL⁻¹ T2 1206 pg·mL⁻¹	Mean
Armstrong [13]	F	9	27±12 months	No infection in first BAL, but present in second Follow-up BAL at 6–18 months		ns	p<0.05 Fold change 2.0 (95% CI 1.2–3.2)		p<0.05 Fold change 2.3 (95% CI -1.06–5.2)	ANCOVA
DNase
Ratjen [21]	F, P (2 and 3)	29 Treated group	5–25 years	Treated group (DNase inhaled 2.5 mg once daily, 18 months) versus untreated group (no DNase) Follow-up BAL at 18 months		ns				Unpaired t-test
		19 Untreated group	5–25 years
Paul [19]	F, P (2 and 3)	46 Treated group	11.3±5.1 years	Treated group (DNase inhaled, 36 months) versus untreated group (no DNase) Follow-up BAL at 18 and 36 months		Increase more pronounced in untreated group (p<0.005) than the treated group (p<0.01)	Increased in untreated group (p<0.007) but remained stable in treated group		Increased in untreated group (p<0.02) but remained stable in treated group	Nonparametric repeated measures analyses of variance
		39 Untreated group	12.2±4.4 years
Ratjen [20]	F, P (2 and 3)	13 Treated group	6–18 years	Treated group (DNase inhaled 2.5 mg once daily, 18 months) versus untreated group (no DNase) Follow-up BAL at 18 months		Decreased in treated group -15 (-40–58) Increased in untreated group 20 (-49–48) ns between groups				Median (range) Mann–Whitney U-test
		10 Untreated group	6–18 years
rSLPI
McGarvey [6]	P	16	27±2 years	rSLPI (nebuliser 100 mg, twice daily, 1 week) Follow-up BAL 12 after the last aerosol			p<0.03 Average decrease 68%			Not reported

All samples are BAL unless stated. PMN: polymorphonuclear; NE: neutrophil elastase; IL: interleukin; F: first; NS: not specified; P: pooled; T1: first paired (range: 6–18 months) BAL sample; T2: second paired (range: 6–18 months) BAL sample; TIS: tobramycin inhalation solution; rSLPI: recombinant secretory leukocyte protease inhibitor.

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M. Fayon