Lung Fluid Biomarkers for Acute Respiratory Distress Syndrome

A Systematic Review and Meta-analysis

Yishan Wang; Huijuan Wang; Chunfang Zhang; Chao Zhang; Huqin Yang; Ruiyue Gao; Zhaohui Tong

Crit Care. 2019;23(43)

Abstract and Introduction

Abstract

Background: With the development of new techniques to easily obtain lower respiratory tract specimens, bronchoalveolar lavage fluid and other lung fluids are gaining importance in pulmonary disease diagnosis. We aimed to review and summarize lung fluid biomarkers associated with acute respiratory distress syndrome diagnosis and mortality.

Methods: After searching PubMed, Embase, Web of Science, and the Cochrane Library for articles published prior to January 11, 2018, we performed a meta-analysis on biomarkers for acute respiratory distress syndrome diagnosis in at-risk patients and those related to disease mortality. From the included studies, we then extracted the mean and standard deviation of the biomarker concentrations measured in the lung fluid, acute respiratory distress syndrome etiologies, sample size, demographic variables, diagnostic criteria, mortality, and protocol for obtaining the lung fluid. The effect size was measured by the ratio of means, which was then synthesized by the inverse-variance method using its natural logarithm form and transformed to obtain a pooled ratio and 95% confidence interval.

Results: In total, 1156 articles were identified, and 49 studies were included. Increases in total phospholipases A2 activity, total protein, albumin, plasminogen activator inhibitor-1, soluble receptor for advanced glycation end products, and platelet activating factor-acetyl choline were most strongly associated with acute respiratory distress syndrome diagnosis. As for biomarkers associated with acute respiratory distress syndrome mortality, interleukin-1β, interleukin-6, interleukin-8, Kerbs von Lungren-6, and plasminogen activator inhibitor-1 were significantly increased in the lung fluid of patients who died. Decreased levels of Club cell protein and matrix metalloproteinases-9 were associated with increased odds for acute respiratory distress syndrome diagnosis, whereas decreased levels of Club cell protein and interleukin-2 were associated with increased odds for acute respiratory distress syndrome mortality.

Conclusions: This meta-analysis provides a ranking system for lung fluid biomarkers, according to their association with diagnosis or mortality of acute respiratory distress syndrome. The performance of biomarkers among studies shown in this article may help to improve acute respiratory distress syndrome diagnosis and outcome prediction.

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Crit Care. 2019;23(43) © 2019 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Abstract and Introduction
Background
Methods
Results
Discussion
Conclusions
References

Table 1. Demographic variables
Reference	Biomarkers	Diagnostic criteria for ARDS	Study size	Male (%)	Age	Mortality (%)	Sample retrieved time	Sample retrieved location	Sample type (vol. of irrigation solution)
Studies related to diagnosis
Armstrong [14]	Procollagen peptide I	AECC	66	66.7	64.65	48.5 (nsp.)	Within 48 h of ICU admission	Right middle lobe	BALF (20 mL*6)
Bersten [15]	Total phospholipids	Clinical criteria	21	np.	np.	np.	Within 7 h of study entry	np.	LAF
Calfee [16]	Soluble intercellular adhesion molecule-1	Clinical criteria	67	59.84	50.63	44.79 (hosp mort)	Within 4 h of intubation	np.	PEF
Chollet-Martin [18]	Interleukin-8	LIS	29	np.	62.12	np.	Within 72 h of ARDS diagosis	np.	ELF
	Tumor necrosis factor-α
	Interleukin-6
Conner [20]	Soluble intercellular adhesion molecule-1	Clinical criteria+EF/plasma protein	27	np.	np.	np.	Within 1 h of intubation	np.	PEF
Delclaux [21]	Albumin	Clinical criteria	29	71.43	54	64.29 (nsp.)	np.	np.	BALF (3*50mL)
El Solh [22]	Plasminogen activator inhibitor-1	AECC	51	43.14	36.57	5.88 (hosp mort)	Within 8 h of intubation	Blind BAL	PEF
Prabhakaran [52]	Plasminogen activator inhibitor-1	AECC	51	58	50	47 (hosp mort)	Within 12h of intubation	np.	PEF
Song [56]	Plasminogen activator inhibitor-1	Clinical criteria	33	39	70	15 (28-day mort)	When patients were suspected to have VAP	np.	BALF (20mL*3)
Farjanel [23]	Procollagen peptide III	LIS	61	60.7	49.23	47.5 (hosp mort)	3 days after intubation	A subsegmental of middle lobe	BALF (3*50mL)
	Procollagen peptide I
	Albumin
Geerts [25]	Club cell protein	AECC	26	73.1	51	np.	Within 12 h of ARDS diagnosis	Right middle lobe	BALF (50mL*3)
Geerts [25]	Total protein
González-López [26]	Interleukin-8	AECC	22	np.	50.1	31.8 (ICU mort)	np.	np.	BALF (20mL*3)
	Matrix metalloproteinases-9
	Procollagen peptide III
	Interleukin-6
	Vascular endothelial growth factor
Hallgren [27]	Albumin	Clinical criteria	40	66.67	46.87	25 (nsp.)	np.	Right middle lobe	BALF (3*20mL)
Hamacher [28]	Tumor necrosis factor-α	AECC	56	75	45.41	25.07 (hosp mort)	np.	np.	BALF (nsp.)
	Soluble TNF-α receptors II
	Transforming growth factor-β1
Idell [29]	Total protein	Clinical criteria	16	np.	np.	np.	Within 96 h of ARDS diagnosis	Right middle lobe/right lower lobe/lingula	BALF (30mL*5)
Jabaudon [60]	Soluble receptor for advanced glycation end products	AECC	60	55	61	66.67	Within 24 h of disease onset.	np.	LAF
Karagiorga [32]	Total protein	Clinical criteria	31	64.52	41.43	22.58 (nsp.)	Within 72 h of ARDS diagnosis	np.	BALF (20mL*6)
	Platelet activating factor-acetyl choline
	Total phospholipids
	Total phospholipases A2 activity
Keane [33]	Interleukin-8	AECC	9	np.	np.	np.	np.	np.	BALF (nsp.)
	Procollagen peptide III
	Procollagen peptide I
Kurdowska [36]	Interleukin-8	LIS	26	np.	np.	41.2 (nsp.)	Upon ICU admission	Right middle lobe	BALF (60mL*3)
Lanchou [37]	Matrix metalloproteinases-9	AECC	21	47.6	54	33.3 (nsp.)	Within 24 h of ARDS diagnosis	Right middle lobe	BALF (20mL*3)
Lanchou [37]	Matrix metalloproteinases-2
Martin [44]	Total protein	AECC	69	68	45	56 (nsp.)	Within 72 h of ARDS diagnosis	Right middle lobe/lingula	BALF (30mL*5)
Martin [43]	Soluble receptor for advanced glycation end products	AECC	69	59	53.9	46 (nsp.)	np.	np.	BALF (nsp.)
Medford [45]	Vascular endothelial growth factor	AECC	70	40	59.37	38.57 (28-day mort)	With 72 h of intubation	np.	ELF
Miller [46]	Interleukin-8	AECC	35	np.	48.54	np.	Within 30 min of intubation	np.	PEF
Nakos [49]	Total protein	AECC	21	76.2	61	np.	Within 24 h of intubation	Right middle lobe/lingula.	BALF (20mL*6)
	Albumin
	Platelet activating factor-acetyl choline
	Total phospholipids
Nakos [48]	Total protein	AECC	19	66.67	45	33.33 (nsp.)	Within 12 h of intubation	np.	BALF (20mL*6)
	Albumin
	Platelet activating factor-acetyl choline
	Total phospholipids
Nakos [47]	Platelet activating factor-acetyl choline	AECC	31	29	55.54	32.2 (ICU mort)	Upon ARDS diagnosis	np.	BALF (20mL*6)
Nakos [47]	Total phospholipases A2 activity
Park [51]	Tumor necrosis factor-α	AECC	54	59.1	44.67	20.1 (nsp.)	Within 24 h of ARDS diagnosis	Right middle lobe/lingula	BALF (30mL*5)
	Soluble TNF-α receptors II
	Interleukin-1β
	Interleukin-6
Pugin [53]	Interleukin-8	AECC	31	54.84	48.87	57.65 (nsp.)	np.	blind BAL	PEF
	Matrix metalloproteinases-2
	Procollagen peptide III
Ricou [55]	Interleukin-6	Clinical criteria+LIS	24	79.2	50.5	33.3 (nsp.)	Within 24 h of ARDS diagnosis	np.	BALF (nsp.)
Stern [57]	Procollagen peptide III	AECC	25	64	67.08	60 (30-day mort)	Within 72 h of ARDS diagnosis	The abnormal area on the chest radiography	BALF (20mL*6)
	Albumin
	Hepatic growth factor
Uchida [58]	Soluble receptor for advanced glycation end products	AECC	33	57.67	43	51.33 (hosp mort)	np.	np.	PEF
Studies related to mortality
Adamzik [12]	Tumor necrosis actor-α	AECC	47	68.09	44.53	36.17 (30-day mort)	Within 24 h of ICU admission	np.	BALF (40mL*4)
	Total protein
	Interleukin-6
	Interleukin-2
	Interleukin-1β
	Interleukin-10
Clark [19]	Procollagen peptide III	AECC	117	64.1	42.78	41 (hosp mort)	Within 72h of ARDS diagosis	Right middle lobe/lingula	BALF (30mL*5)
Frenzel [24]	Interleukin-6	AECC	46	60.9	62	45.7 (28-day mort)	Within 96h of intubation	Right middle lobe/lingula	BALF (20mL*5)
	Interleukin-8
	Tumor necrosis factor-α
	Interleukin-1β
	Interleukin-10
Kondo [34]	Kerbs von Lungren-6	AECC	32	84.38	70.1	31.3 (hosp mort)	Within 24 h of ARDS diagnosis	Right middle lobe	ELF
Lee [38]	Interleukin-8	AECC	31	51.6	54.5	51.6 (28-day mortality)	Within 48 h of ARDS diagnosis	Right middle lobe/lingular	BALF (30mL*5)
Lin [41]	Interleukin-6	AECC	39	69.2	68	43.6 (hosp mort)	Within 24h of ARDS diagnosis	Right middle lobe/lingula	BALF (20mL*6)
Lin [41]	Interleukin-8
Nathani [50]	Kerbs von Lungren-6	AECC	42	57.1	60.13	np.	Upon study entry	Middle lobe	BALF (50mL*3)
Ishizaka [30]	Kerbs von Lungren-6	AECC	38	77%	68	32 (hosp mort)	Upon onset of ARDS	Right middle lobe	ELF
Studies related to diagnosis and mortality
Agouridakis [13]	Interleukin-2	AECC	34	74.42	47.79	27.9 (nsp.)	Within 2h of ICU admission	np.	BALF (nsp.)
Chesnutt [17]	Procollagen peptide III	AECC+EF/plasma protein	44	47.73	56.25	63.64 (hosp mort)	Within 1h of intubation	np.	PEF
Jorens [31]	Club cell protein	Fowler+LIS	35	88.6	55	42.9 (nsp.)	Within 12 h of ARDS diagnosis	Right middle lobe	BALF (50mL*3)
Kropski [35]	Club cell protein	AECC+EF/plasma protein	32	46.9	48	56.5 (nsp.)	Within 24 h of intubation	np.	PEF
Lee [39]	IL-8	Clinical criteria	112	78.6	66.5	77.3 (nsp)	With 24h of ICU admission	The most abnormal area on the chest radiography/right middle lobe/lingula	BALF (20mL*6)
	Tumor necrosis factor-α
	Interleukin-1β
	Interleukin-6
	Interleukin-10
Lesur [40]	Interleukin-2	AECC	33	36.4	51.52	24.2 (hosp mort)	Within 72h of intubation	Right middle lobe/lingula	BALF (20mL*5)
Marshall [42]	Procollagen peptide III	AECC	60	53.33	51.35	31.67 (nsp.)	Within 24h of ARDS diagnosis	np.	BALF (nsp.)
Quesnel [54]	Interleukin-8	AECC	122	64.8	67	33.6 (28-day mort)	np.	np.	BALF (20mL*6)
	Procollagen peptide I
	Transforming growth factor-β1
	Hepatic growth factor
Ware [59]	Vascular endothelial growth factor	AECC	102	62.8	49	60 (nsp.)	np.	np.	PEF

ARDS acute respiratory distress syndrome, AECC American-European Consensus Conference, EFedema fluid, LIS lung injury score, np not provided, nsp not specific, mort mortality, hosp morthospital mortality, ICU intensive care unit, BALF bronchoalveolar lavage fluid, LAF lung aspirational fluid, ELF epithelial lining fluid, PEF pulmonary edema fluid

Table 2. Biomarkers associated with ARDS diagnosis
Biomarker	No. of study	No. of patients	RoM (95% CI)	p	Heterogeneity
Biomarker	No. of study	No. of patients	RoM (95% CI)	p	Q (pvalue)	I ²(%)
Total phospholipases A2 activity	2[32, 47]	62	17.995 (11.381, 28.454)	< 0.05	10.54 (0.001)	90.50
Total protein	5[25, 29, 32, 44, 48]	179	9.299 (7.575, 11.414)	< 0.05	40.48 (< 0.1)	90.10
Albumin	5[21, 23, 27, 48, 57]	191	6.544 (4.908, 8.725)	< 0.05	27.35 (< 0.1)	85.40
Plasminogen activator inhibitor-1	3[22, 52, 56]	135	5.525 (3.876, 7.877)	< 0.05	3.69 (0.158)	45.8
Soluble receptor for advanced glycation end products	3[43, 58, 60]	162	4.901 (3.603, 7.673)	< 0.05	31.19 (0.000)	93.6
Platelet activating factor-acetyl choline	4[32, 47, 48, 49]	120	4.783 (3.495, 6.545)	< 0.05	71.83 (< 0.1)	95.80
Soluble TNF-α receptors II	2[28, 51]	110	3.253 (1.765, 5.993)	< 0.05	4.95 (0.026)	79.80
Hepatic growth factor	2[54, 57]	144	3.199 (1.668, 6.135)	< 0.05	0.02 (0.892)	0
Interleukin-8	7[18, 26, 36, 39, 46, 53, 54]	377	3.008 (2.322, 3.896)	< 0.05	62.08 (< 0.1)	90.30
Soluble intercellular adhesion molecule-1	2[16, 20]	96	2.952 (1.902, 4.581)	< 0.05	0.28 (0.6)	0
Procollagen peptide I	2[14, 23]	133	2.949 (1.867, 4.659)	< 0.05	0.11 (0.743)	0.00
Interleukin-2	2[13, 40]	67	2.761 (1.508, 5.057)	0.001	17.34 (< 0.1)	94.20
Procollagen peptide III	6[17, 23, 26, 42, 53, 57]	195	2.328 (1.456, 3.723)	< 0.05	2.81 (0.729)	0
Interleukin-6	5[18, 26, 39, 51, 55]	250	1.826 (1.170, 2.852)	0.008	9.1 (0.0059)	56
Club cell protein	3[25, 31, 35]	93	0.553 (0.369, 0.827)	0.004	3.6 (0.166)	44.40
Matrix metalloproteinases-9	2[26, 37]	43	0.548 (0.336, 0.893)	0.016	15.45 (< 0.1)	93.50
Transforming growth factor-β1	2[28, 54]	116	1.32 (0.575, 3.034)	0.513	0.93 (0.334)	0
Tumor necrosis factor-α	4[18, 28, 39, 51]	247	1.3 (0.917, 1.843)	0.14	2.97 (0.397)	0
Matrix metalloproteinases −2	2[37, 53]	52	1.066 (0.889, 1.278)	0.493	0.06 (0.814)	0
Total phospholipids	4[15, 32, 48, 49]	110	1.003 (0.862, 1.166)	0.973	34.25 (< 0.1)	91.20
Interleukin-1β	2[39, 51]	166	0.952 (0.628, 1.444)	0.817	4.23 (0.04)	76.30
Vascular endothelial growth factor	3[26, 45, 59]	194	0.812 (0.544, 1.212)	0.309	3.4 (0.183)	41.20

Numbers within the square brackets were reference numbers
RoM ratio of means, CI confident interval

Table 3. Biomarkers associated with ARDS mortality
Biomarker	No. of study	No. of patients	RoM (95% CI)	p	Heterogeneity
Biomarker	No. of study	No. of patients	RoM (95% CI)	p	Q (pvalue)	I ²(%)
Interleukin-1β	3[12, 24, 39]	137	4.617 (4.331, 4.921)	< 0.05	11.24 (0.004)	82.20
Interleukin-6	4[12, 24, 39, 41]	176	3.882 (3.270, 4.608)	< 0.05	41.09 (< 0.1)	92.70
Interleukin-8	4[24, 38, 39, 41]	160	3.679 (3.414, 3.964)	< 0.05	20.59 (< 0.1)	85.40
Kerbs von Lungren-6	2[30, 34]	65	3.178 (2.931, 3.446)	< 0.05	0.83 (0.363)	0.00
Plasminogen activator inhibitor-1	2[52, 56]	32	2.085 (2.039, 2.133)	< 0.05	1.31 (0.252)	23.70
Tumor necrosis factor-α	3[12, 24, 39]	137	1.923 (1.656, 2.233)	< 0.05	11.47 (0.003)	82.60
Procollagen peptide III	3[17, 19, 42]	194	1.714 (1.613, 1.822)	< 0.05	34.08 (< 0.1)	94.10
Total protein	3[12, 19, 42]	208	1.667 (1.595, 1.742)	< 0.05	82.47 (< 0.1)	97.60
Interleukin-2	2[13, 40]	27	0.828 (0.715, 0.959)	0.012	1.49 (0.223)	32.70
Club cell protein	2[31, 35]	37	0.406 (0.362, 0.405)	< 0.05	21.08 (< 0.1)	95.30
Interleukin-10	3[12, 24, 39]	137	1.019 (0.922, 1.127)	0.709	54.54 (< 0.1)	96.30

Numbers within the square brackets were reference numbers
RoM ratio of means, CI confident interval

Table 1. Etiology of ARDS
Etiology of ARDS	N (%)
Sepsis	409(30.87)
Pneumonia	314(23.70)
Trauma	145(10.94)
Aspiration	113(8.53)
Transfusion	56(4.23)
Major surgery	46(3.47)
not provided	162(12.23)
Other	80(6.04)

ARDS=Acute Respiratory Distress Syndrome

Table 2. Influence analysis
							corrected heterogeneity
Biomarker	Removed studies		No. of patients removed	Remaining studies	No. of patients remaining	Corrected RoM(95%CI)	I²%	P
Total protein		2	106	3	73	9.391(6.866,12.845)	0	0.404
Albumin		1	37	4	154	1.962 (1.136,3.388)	0	0.683
Platelet Activating Factor-acetyl choline		2	58	2	62	4.046 (2.718,6.024)	7.3	0.299
Interleukin-8		2	234	5	143	3.985 (2.762,5.751)	0	0.908
Interleukin-6		1	112	4	138	3.833 (1.958,7.502)	0	0.865

No. = Number, RoM=Ratio of means, CI=Confident Interval

Table 3. Subgroup analysis for biomarkers associated with diagnosis
				Heterogeneity
	No. of studies	RoM (95%CI)	P value	Q(P value)	I²%
Design type Total protein	2	6.949(3.999, 12.077)	<0.05	0.13(0.72)	0
Albumin	2	0.76(-1.28,2.80)	0.057	15(0)	93.3
Interleukin-8	5	5.734(4.098,8.022)	<0.05	11.26(0.024)	64.5
Interleukin-6	3	3.551(1.741,7.236)	<0.05	0.33(0.848)	0
Diagnositic criteria
Interleukin-6	2	4.442(1.373,14.369)	0.013	0.31(0.576)	0
Sample type
Interleukin-8	3	4.219(2.641,6.738)	<0.05	0.12(0.941)	0

No. =Number, RoM=Ratio of means, CI=Confident Interval

Table 4. Subgroup analysis for biomarkers associated with mortality
				Heterogeneity
	No. of studies	RoM (95%CI)	P value	Q(P value)	I²%
Diagnositic criteria
Tumor Necrosis Factor-α	2	1.452(1.158,1.819)	0.001	0.86(0.355)	0

No. =Number, RoM=Ratio of means, CI=Confident Interval

Table 5. Publication bias
	Egger's regression		Duval & Tweedie's trim and fil
Biomarkers	Z	P value	Original RoM(95%CI)	studies trimmed	Adjusted RoM(95%CI)
Interleukin-6	1.47	0.032	1.826(1.170,2.852)	3	1.423(0.948, 2.136)

RoM=Ratio of means, CI= Confident Interval

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Lung Fluid Biomarkers for Acute Respiratory Distress Syndrome

A Systematic Review and Meta-analysis

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