Review of biomarkers to assess the effects of switching from cigarettes to modified risk tobacco products

Figures & data

Table 1. List of biomarkers that were searched in the PubMed database and published between 2008 and 2017.

Biomarker	Abbreviation	Description
Respiratory biomarkers
Forced expiratory volume in 1 s	FEV1	Disease severity (COPD) (Aggarwal et al. 2006, Joo et al. 2013).
Biomarkers of oxidative stress
8-iso-prostaglandin F2α	8-iso-PG F2α	Related to oxidative stress and increased in smokers (Borrill et al. 2008, Hoffmeyer et al. 2009, Inonu et al. 2012).
Thromboxane B2	11-DTXB2	Related to oxidative stress and CVD. Increased in smokers (Wennmalm et al. 1991, Eikelboom et al. 2002, Calapai et al. 2009, Frost-Pineda et al. 2011).
Biomarkers of inflammation
C-reactive protein	CRP	Systemic inflammation and predictor of prognosis in COPD (Dahl et al. 2007, Mehrotra et al. 2010, Celli et al. 2012).
White blood cell count	WBC count	Systemic inflammation (Friedman et al. 1973, Yeung and Buncio 1984, Tell et al. 1985, Fernandez et al. 2012).
Soluble intercellular adhesion molecule-1	sICAM-1	Vascular inflammation. Raised in CVD (Ridker et al. 1998, Malik et al. 2001) and COPD (Riise et al. 1994, Lopez-Campos et al. 2012, Blidberg et al. 2013, Aaron et al. 2015).
Fibrinogen	FBG	Predictor of CVD (Kannel et al. 1987, Ernst and Resch 1993, Paramo et al. 2004) potential predictor of respiratory disease (Lock-Johansson et al. 2014).
Tumour necrosis factor α	TNFα	Related to inflammation in CVD (Skoog et al. 2002) and respiratory diseases (Barnes 2009) with levels increased in smokers (Bostrom et al. 1999, Tanni et al. 2010). May decrease after smoking cessation.
Myeloperoxidase	MPO	Several studies link MPO to arterial inflammation and CVD (Rudolph et al. 2008, Ikitimur and Karadag 2010, Lobbes et al. 2010, Anatoliotakis et al. 2013, Nussbaum et al. 2013) and smoking-related lung diseases (Dominguez-Rodriguez and Abreu-Gonzalez 2011, Park et al. 2013). Most studies show raised levels in smokers that do not fall following smoking cessation except after long periods of time (Andelid et al. 2007, Park et al. 2013).
Exhaled nitric oxide	FeNO	Related to airway inflammation (especially in asthma). Decreased in smoking (Kharitonov et al. 1995, Yates et al. 2001, Sundy et al. 2007, Zuiker et al. 2010) and increased following smoking cessation (Robbins et al. 1997, Hogman et al. 2002, Nadif et al. 2010), probably due to smoking-related inhibition of nitric oxide synthase.
Sputum polymorphonuclear leukocyte (PMN) content	sPMN	Related exclusively to airway inflammation, especially in COPD (Keatings et al. 1996, Tsoumakidou et al. 2003, Paone et al. 2011, Gupta and Singh 2013). Most studies show increased numbers in smokers (Swan et al. 1991, Keatings et al. 1996, Chalmers et al. 2001, Bouloukaki et al. 2009) with usually no reduction following cessation (Maestrelli et al. 1996, Paone et al. 2011).
Phospholipase A2	PLA2	Elevated levels are associated with increased risk of cardiovascular events (Lp-PLA(2) Studies Collaboration et al. 2010, Vittos et al. 2012). Levels are slightly increased in smokers (Persson et al. 2007, Tselepis et al. 2009, Fratta Pasini et al. 2013). Probably not directly implicated in smoking-related lung diseases.
Biomarkers of cardiovascular disease
Albumin	ALB	Related to CVD. May be increased in smokers (Corradi et al. 1993, Metcalf et al. 1993, Pinto-Sietsma et al. 2000) and decreased after smoking cessation (Chase et al. 1991, Metcalf et al. 1993, Ikeda et al. 1997).
High and low-density lipoprotein-cholesterol	HDL-C and LDL-C	CVD.
Apolipoprotein A1	ApoA1	Related to CVD. Lowered in smokers (Craig et al. 1989) but increases after smoking cessation (Stubbe et al. 1982, Masarei et al. 1991, Iwaoka et al. 2014).
Oxysterols	OxS	Related to CVD via oxidative stress. May be increased in smokers (Mol et al. 1997).
Homocysteine	HCY	Raised levels are associated with recurrent CVD. Some studies suggest levels rise in smokers (Nygard et al. 1997, Nygard et al. 1998, Sobczak 2003, Sobczak et al. 2007) but it is not clear in all studies that levels fall following smoking cessation (Nygard et al. 1995, O'Callaghan et al. 2002, Bazzano et al. 2003).
P-Selectin	P-Sel	Directly involved in risk of CVD (Blann et al. 2003) and most studies show increased levels in smokers (Osterud et al. 1999, Ridker et al. 2001, Bermudez et al. 2002). Long-term smoking cessation may lead to lower levels (Ridker et al. 2001, Bermudez et al. 2002).
Thiocyanate	SCN	Related to CVD (Wang et al. 2007), some cancers (Wang et al. 2001) and respiratory diseases (Shiue 2015) but is predominantly used as a marker of exposure to cigarette smoke. Levels are increased in smokers and fall to non-smoker levels 3-6 weeks after smoking cessation.
Von Willebrand factor	vWF	Related to thrombosis and CVD (O'Callaghan et al. 2005) (especially in CVD patients) as well as respiratory disease (Bartholo et al. 2014, Holz et al. 2014). Only limited evidence that smoking cessation leads to a decrease in vWF levels.
Miscellaneous biomarkers
Glycated haemoglobin	HbA1c	May indicate Increased risk of CVD (Eeg-Olofsson et al. 2010, Chamnan et al. 2013) especially in diabetics (Chamnan et al. 2013, Pacilli et al. 2013, Ohkuma et al. 2015). Increased in smokers (Vlassopoulos et al. 2013).
Blood carboxyhaemoglobin	COHb	Increased in smokers, reduced on smoking cessation or switching (Roethig et al. 2007, van Staden et al. 2013). Often used as a biomarker of exposure to carbon monoxide but is also associated with coronary artery disease and the pathogenesis of coronary atherosclerosis (Cohen et al. 1969, Whereat 1970).
Wheeze cough and sputum	W/C/S	Related to smoking-induced respiratory disease severity (Polley et al. 2008, Molassiotis et al. 2010b, Putcha et al. 2014, Vestbo 2014). Symptoms reduce after long-term smoking cessation (Viegi et al. 1988a, Toljamo et al. 2010, Bjerg et al. 2013).
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol	NNAL	Exposure marker that has been related to risk of lung cancer. Increased in smokers and is reduced following smoking cessation (Carmella et al. 2009, Goniewicz et al. 2009, Stepanov et al. 2009). Used primarily as a biomarker of exposure to NNK.

Table 2. Numbers of publications (2008–2017) and the reasons for their exclusion.

Biomarker	Search number				Exclusion criteria
	1	2	3	Total	E1	E2	E3	E4	E5	E6	E7	E8	E9	Total	Used
Forced expiratory volume (FEV1)	1914	43	1215	2815	561	287	921	22	255	8	20	490	204	2768	47
C-reactive protein (CRP)	363	265	80	708	24	52	394	3	48	5	4	93	13	633	75
(Soluble intercellular adhesion molecule-(1) sICAM-1	80	185	31	292	3	27	144	3	29	12	1	28	10	257	35
White blood cell count (WBC)	416	370	145	931	275	90	250	4	29	13	37	46	18	762	168
Fibrinogen (FBG)	112	91	43	246	4	35	124	2	10	6	11		10	202	50
Carboxyhaemoglobin (COHb)	112	3	4	119	19	23	29	6	3	11	10	2	13	116	3
Glycated Haemoglobin (HbA1c)	306	265	58	935	14	45	446	1	14					516	113
High-density lipoprotein-cholesterol (HDL-C)	560	848	28	1436	371	245	175	8	156	8		113	53	1129	307
Low-density lipoprotein-cholesterol (LDL-C)	93	262	28	383	19	57	260		4	1		1		338	45
Oxysterols (OxS)	4	17	40	61	3	4	1		3	7		7		25	36
Apolipoprotein A1 (ApoA1)	19	28	24	71	6	1	27		7		3	4		47	24
8-iso-15(S)-Prostaglandin F2α (8-epi-PGF2α/8-iso-PGF2α)	52	17	15	84	8	6	24	1	18	1	4	1		61	23
11-Dehydrothromboxane_B2 (11-DTXB2)	60	52	15	127	11	9	49		8	14		26		117	10
Albumin (ALB)	217	290	52	559	3	21	478		6	6	9	7	13	533	16
Fractional exhaled nitric oxide (FeNO)	61	6	34	101	2	18	28		21	7	9			75	26
Homocysteine (HCY)	113	113	18	244	14	45	113		22	3	3		1	201	43
Myeloperoxidase (MPO)	77	39	40	156	9	8	30	0	8	24		9	13	101	55
Phospholipase A2 (PLA2)	21	26	10	57	4	1	13		6		1			25	32
P-Selectin (P-Sel)	118	68	2	188	37	50	28		18	3		2		138	50
Sputum polymorphonuclear neutrophils (sPMN)	23	0	18	41	2	2	6		1			1		12	29
Thiocyanate (SCN)	25	10	18	53	4	3	6		3	8	1		2	27	26
Von Willibrand Factor (vWF)	18	53	53	124	7	22	35		7	5		2		78	46
Tumour necrosis factor α (TNFα)	212	143	69	424	14	15	155	1	27	66	3	48	47	376	42
Wheeze, cough, sputum (W/C/S)	277	29	175	481	3	28	223	4	16		4		2	280	35
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)	15	99	9	123	15			21	3	5		15		59	64

Table 3. Literature retrieved from monographs and review articles.

	Monographs				Reviews			Both (Mongraphs + Reviews)
Biomarker	Monographs	Articles	Excluded	Used	Reviews	Excluded	Used	Total (all)	Excluded (all)	Used
CRP	2	22	5	17	14	0	14	36	5	31
FBG	2	34	1	33	42	27	15	76	28	48
HbA1c	2	4	0	4	79	34	45	83	34	49
LDL-C	2	17	1	16	63	41	22	80	42	38
OxS	2	2	0	2	26	2	24	28	2	26
ApoA1	2	16	4	12	16	1	15	32	5	27
Alb	2	3	0	3	26	12	14	29	12	17
FeNO	2	16	0	16	30	15	15	46	15	31
HCY	2	4	1	3	15	0	15	19	1	18
MPO	2	11	2	9	23	6	17	34	8	26
PLA2	2	0			11	0	11	11	0	11
P-Sel	2	6	3	3	42	28	14	48	31	17
sPMN	2	16	4	12	10	2	8	26	6	20
SCN	2	10	0	10	16	4	12	26	4	22
vWF	2	6	0	6	28	8	20	34	8	26
TNFα	2	23	3	20	53	17	36	76	20	56
W/C/S	2	5	3	2	4	3	1	9	6	3

Monographs searched for biomarkers of effect and smoking were the US Surgeon General’s report 2010 (Centers for Disease Control and Prevention et al. 2010) and the Life Sciences Research Office Report (Life Sciences Research Office 2007). The articles possibly extracted from reviews were not separately counted, but the reviews themselves were include or excluded.

Table 4. Association of TXB2 metabolites with smoking status.

No.	Study	Sample size	Metabolite	Results
1	Nowak et al. (1987)	6 smokers, 6 non-smokers	2.3-dinor-TXB2	Levels higher in smokers than in non-smokers (p < 0.05).
2	Barrow et al. (1989)	30 smokers, 37 non-smokers	2,3-dinor-TXB2, 11-dehydro-TXB2	Levels of both metabolites higher in smokers than in non-smokers (p < 0.001).
3	Wennmalm et al. (1991)	73 smokers, 377 non-tobacco users	2,3-dinor-TXB2	Levels higher in smokers than in non-tobacco users (p < 0.001).
4	Uedelhoven et al. (1991)	13 smokers, 15 non-smokers	2,3-dinor-TXB2, 11-dehydro-TXB2	Levels of both metabolites higher in smokers compared to non-smokers (p < 0.0001 and p < 0.005, respectively).
5	Rangemark and Wennmalm, (1991)	13 female smokers, 13, female non-smokers	2,3-dinor-TXB2	Levels higher on day 3 (p < 0.01), day 10 (p < 0.05) and day 20 (p < 0.05) of the menstrual cycle in smokers compared to non-smokers.
6	Rangemark et al. (1992)	125 smokers, 125 non-smokers	2,3-dinor-TXB2	Levels higher in smokers compared to non-smokers (p < 0.001).
7	Dotevall et al. (1992)	18 smokers and 17 non-smokers	2,3-dinor-TXB2	Levels higher in smokers than in non-smokers (p < 0.05).
8	Rangemark and Wennmalm (1996)	23 smokers and 26 non-smokers	2,3-dinor-TXB2	Levels higher in smokers than in non-smokers (p < 0.001).
9	Weber et al. (2000)	10 smokers and 10 non-smokers	2,3-dinor-TXB2	Levels higher in smokers than in non-smokers (p < 0.05).
10	McAdam et al. (2005)	17 smokers and 15 non-smokers	11-dehydro-TXB2	Levels higher in smokers than in non-smokers (p value not given).
11	Ikonomidis et al. (2005)	30 smokers, 30 non-smokers all with active CAD	11-dehydro-TXB2	Levels higher in smokers than in non-smokers (p < 0.01).
12	Calapai et al. (2009)	20 smokers, 20 never smokers	2,3-dinor-TXB2, 11-dehydro-TXB2	Levels of 2.3-dinor-TXB2 higher in smokers compared to never smokers (p < 0.01), levels of 11-dehydro-TXB2 higher in smokers (N = 18) compared to never smokers (N = 17) (p < 0.05).
13	Frost-Pineda et al. (2011)	3346 smokers, 1051 non-smokers	11-dehydro-TXB2	Levels higher in smokers than in non-smokers (p < 0.0001).
14	Prasad et al. (2016)	40 smokers, 40 non-smokers	11-dehydro-TXB2	Levels higher in smokers than in non-smokers, but the difference was not statistically significant.

Table 5. Changes in levels of TXB2 metabolites following smoking cessation.

No	Study	Sample size	Study type	Study period	Metabolite	Results
1	Wennmalm et al. (1993)	43 smokers	Prospective	31–44 months	2,3-dinor-TXB2	Levels were significantly lower in individuals who stopped smoking (N = 9) compared to continuing smokers (p < 0.002).
2	Rangemark et al. (1993)	8 smokers	RCT [a]	3 days	2,3-dinor-TXB2, 11-dehydro-TXB2	Both metabolites were significantly lower at day 3 following smoking cessation (2,3-dinor-TXB2, p < 0.02; 11-dehydro-TXB2, p = 0.02).
3	Saareks et al. (2001)	60 smokers	RCT [a]	14 days	11-dehydro-TXB2	Levels had decreased to the levels measured in non-smokers (p < 0.0001).

^a RCT: Randomized controlled trial.

Table 6. Summary of findings for each biomarker investigated with respect to its relationship to smoking, smoking cessation and two smoking-related disease groups.

				Disease related to the biomarker
Biomarker	Change caused by smoking	Relationship to smoking	Relationship to cessation	Resp	CVD	Time to normalise
Forced expiratory volume (FEV1)	↓	+++	++	+++	−	Months
Iso-prostaglandin (8-iso-PGF2α)	↑	+	+/−	+/−	++	Weeks
Thromboxane B2 (11-DTXB2)	↑	++	+	−	++	Days–weeks
C-Reactive protein (CRP)	↑	++	+/−		+++	Years
White blood cell count (WBC)	↑	++	++	++	+++	Weeks–months
Soluble intracellular adhesion molecule (s-ICAM-1)	↑	++	+	++	++	Weeks
Fibrinogen (FBG)	↓↑	+/−	+/−	++	++	–
Tumour necrosis factor (TNFα)	↑↓	+	+/−	++	++	–
Myeloperoxidase (MPO)	↑↓	+/−	+/−	+++	+++	–
Exhaled nitric oxide (FeNO)	↓	+	+	++	−	–
Sputum Neutrophils	↑	+	+/−	++	−	No change
Phospholipase A2 (Lp-PLA2)	↑	+/−	−	−	++	Months
Albumin (ALB)	↑	+	+	−	+	Months–years
Low-density lipoprotein-cholesterol (LDL-C)	↓↑	++	+/−	−	+++	–
High density lipoprotein-cholesterol (HDL-C)	↓	+++	+++	+/−	+++	Months
Apolipoprotein A1 (ApoA1)	↓	+	+	−	++	Weeks–months
Oxysterols (OxS)	↑?	−	−	−	++	–
Homocysteine (HCY)	↑	−	−	−	+/−	Months
P-Selectin (P-Sel)	↑	+	+/−	−	+	Weeks–months
Thiocyanate (SCN)	↑	++	+	+	++	Weeks
Von Willebrand factor (vWF)	↑	+	+	−	+	Weeks
Glycated Haemoglobin (HbA1c)	↑	++	++	−	++	Weeks–months
Carboxyhaemoglobin (COHb)	↑	+++	+++	+	+++	Days
Wheeze, cough and sputum (W/C/S)	↑	+++	++	+++	−	Months–years
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)	↓	+++	+++	(cancer)	−	Weeks–months

Resp: respiratory diseases; CVD: cardiovascular diseases; arrows indicate increase or decrease in biomarker levels caused by smoking; time to normalize is an indication of how long following smoking cessation the biomarker returns to normal levels (for some biomarkers this is not clear from the literature).

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