High prevalence of falsely declaring nicotine abstinence in lung transplant candidates.

Tobacco use after lung transplantation is associated with adverse outcome. Therefore, active smoking is regarded as a contraindication for lung transplantation and should be excluded prior to placement on the waiting list. The aim of the study was to compare self-reporting with a systematic cotinine based screening approach to identify patients with active nicotine abuse. Nicotine use was systematically assessed by interviews and cotinine test in all lung transplant candidates at every visit in our center. Patients were classified according to the stage prior to transplantation and cotinine test results were compared to self-reports and retrospectively analyzed until June 2019. Of 620 lung transplant candidates, 92 patients (14.8%) had at least one positive cotinine test. COPD as underlying disease (OR 2.102, CI 1.110-3.981; p = 0.023), number of pack years (OR 1.014, CI 1.000-1.028; p = 0.047) and a time of cessation less than one year (OR 2.413, CI 1.410-4.128; p = 0.001) were associated with a positive cotinine test in multivariable regression analysis. The majority of non-COPD patients (n = 13, 72.2%) with a positive test had a cessation time of less than one year. 78 patients (84.7%) falsely declared not consuming any nicotine-based products prior to the test. Finally, all never smokers were test negative. In conclusion, our data demonstrate that active nicotine use is prevalent in transplant candidates with a high prevalence of falsely declaring nicotine abstinence. COPD was the main diagnosis in affected patients. Short cessation time and a high number of pack years are risk factors for continued nicotine abuse.

Introduction

Smoking is the main cause for chronic lung disease and is associated with high individual and socioeconomic burden. For selected patients, lung transplantation can be offered as last treatment option. However, despite advances in transplant medicine, long-term outcome is limited due to chronic allograft dysfunction and side effects of immunosuppression with an estimated median survival of 6.7 years after transplantation. [1]

Amongst others, both recipient and donor tobacco smoking have been shown to cause allograft dysfunction and mortality in solid organ transplant recipients. [2] Smoking resumption after lung transplantation increases the risk for allograft dysfunction, cancer and vascular disease resulting in reduced overall survival. [3-6] Therefore, smoking is regarded as contraindication for lung transplantation in most centers.

Smoking status is frequently assessed on the basis of self-reporting or clinical suspicion. [4] Research has shown that a high proportion of patients with lung disease falsely declare themselves to be non-smokers. [7] This can lead to an underestimation of smoking rates and to a reduced mutual trust of the treating physician. Similarly, prior to transplantation smoking is mostly assessed by questionnaire. Objective measures of tobacco smoking could be useful in improving clinical management and counseling of patients with difficulties to quit. Due to its high sensitivity and specificity, measurement of cotinine in serum or urine is widely used for diagnosis of nicotine consumption. [8]

Several studies have addressed smoking resumption after lung transplantation. Recently, research has shown that despite the severity of illness and the knowledge that quitting would have important long-term benefits, there continues to be a high proportion of patients who resume smoking after transplantation. [9-11] Patients with chronic obstructive pulmonary disease (COPD) and a short duration of smoking cessation prior to lung transplantation were at greatest risk of smoking resumption after lung transplantation. [4]

However efforts should be made to identify patients at risk before transplantation, since smoking cessation strategies can be applied and resumption potentially prevented. The aim of the study was to describe a systematic cotinine-based assessment of transplant candidates at different stages prior to lung transplantation.

Methods

Patients and study design

All lung transplant candidates from January 2017 until June 2019 were included in the study and analysed retrospectively (since January 2017 systematic cotinine-based screening was implemented at our transplant center). The study was conducted at the University of Munich, Germany and approved by the local ethics committee (UE No. 19–346; Ethics Commission of the Faculty of Medicine at the Ludwig-Maximilians-University Munich). Ethics committee waived the requirement for informed consent since data acquisition was retrospective and observational, data were anonymized and the study relied on measurements as part of routine care.

Upon referral, all lung transplant candidates are seen in our outpatient clinic to provide detailed information for the patient and to assess indications and potential contraindications for lung transplantation. After that, patients are discussed in the multidisciplinary conference. In the case of known absolute contraindications, patients are either rejected for transplantation or reevaluation at a later time point is recommended. For potential candidates, full evaluation to identify comorbidities and contraindications is recommended as reported previously. [12] Upon that, patients are discussed once more in the multidisciplinary team and placement on the waiting list or close monitoring in our center is recommended.

For the study patients were classified according to the stage prior to transplantation:

Stage 1: referral, i.e. first visit at the transplant center

Stage 2: time after first visit until placement on the waiting list, including patients during transplant evaluation and patients who are deemed too early and are closely monitored on a regular base in the center

Stage 3: patients actively listed for lung transplantation

Severity of disease was assessed by lung function analysis including blood gas analysis, spirometry, plethysmography and 6-minute walking distance (6MWD). The clinical course from referral to our center to the end of study period or lung transplantation was assessed retrospectively and data were obtained from medical records.

Underlying diseases were categorized into interstitial lung disease (idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, cryptogenic pneumonia, hypersensitivity pneumonitis, fibrosis secondary to connective tissue disease), COPD (incl. alpha-1-antitrypsin deficiency), cystic fibrosis, and others. [13]

Smoking status, cotinine-based screening, psychiatric comorbidity and addiction

Upon referral, i.e. first visit at our center, all patients were advised to avoid active and second hand smoking as well as nicotine replacement products. All patients were informed that to be nicotine-free for a minimum of 6 months before being placed on the waiting list is mandatory, since smoking resumption is associated with unfavorable outcome after transplantation. Furthermore, patients were informed that in the case of nicotine use, support can be provided and that regular cotinine tests are performed. In the case of false self-report, exclusion from our center may result.

Smoking status, including active tobacco and/or electric cigarette use, second hand smoking and the use of nicotine-replacement products was determined on the basis of self-reports assessed in interviews and was biochemically validated by a negative urinary or blood cotinine test at every visit in our center. Patients in evaluation/preparation for transplantation or patients on the waiting list are seen at least every 3 months in the transplant center. Urinary or serum cotinine was measured as a marker of active smoking or the use of nicotine-based products. Urinary and serum cotinine levels were assessed quantitatively by gas chromatography and mass spectroscopy (Agilent Technologies, GC/MS; GC-module G1530A, MS-module G1098A, Santa Clara, California, USA). Based on urinary or serum cotinine levels, patients were categorized positive in the case of a urinary level of >50ng/ml or a serum level of >10ng/ml. [14,15]

Transplant candidates who never smoked, or who have smoked less than 100 cigarettes in their lifetime were classified as never smoker.

Medical records were screened for coexisting psychiatric comorbidities, other addictions and psychiatric treatment/findings. All patients evaluated for lung transplantation were seen by a specialist for psychiatry and psychotherapy. In case of nicotine abuse or other addictive behavior non-pharmacological and pharmacological interventions are offered or recommended.

Statistical analysis

Continuous variables are presented as the mean ± standard deviation, with categorical variables summarized by frequency and percentage. Depending on normal distributions t-test or Mann-Whitney-Wilcoxon test was used to compare continuous variables. Chi square test was used to compare categorical variables. Stepwise binary logistic regression was applied to identify the associations of certain variables on false self-reports. p < 0.05 was considered statistically significant. Data were statistically analysed by SPSS version 24.0 (IBM SPSS, Armonk, NY) statistical software.

Results

Study cohort

In total, 620 lung transplant candidates were included in the study and 1306 cotinine tests were performed during the observation period, accounting for 2.1 ± 1.7 (range 1–10) tests per patient. Underlying diseases of the study cohort were: COPD (n = 257, 41.5%), ILD (n = 228, 36.8%), CF (n = 87, 14.0%) and others (n = 48, 7.7%). The majority of the patients were male (57.3%; n = 355) with a mean age of 53.8 ± 11.9 years and a mean body mass index (BMI) of 23.4 ± 4.9 kg/m². Common comorbidities are depicted in the supplementary material (S1 Table).

In total, 92 patients (14.8%) patients had at least one positive cotinine test (Fig 1). Patients with a positive test were older (58.7 ± 6.2 vs. 52.9 ± 12.4 years, p<0.001) and had a lower Lung Allocation Score (LAS) (33.6 ± 2.5 vs. 39.5 ± 13.2, p = 0.010). Furthermore, patients with a positive test were more likely to have COPD (80.4% vs. 34.7%, p<0.0001) and have more often psychiatric comorbidities or a psychiatric disorder in the history (21.7% vs 11.3%, p = 0.011) compared to patients with only negative tests (Table 1). Finally, patients with a positive test reported more pack years (40.3 ± 19.0 vs 29.5 ± 19.4, p<0.0001) and time of smoking cessation was shorter (42.3 ± 50.1 vs 101.7 ± 104.1 weeks, p<0.0001) as shown in Table 1. The majority of non-COPD patients (n = 13, 72.2%) with a positive test had a cessation time of less than one year.

Fig 1

Classification according to cotinine results and self-reports.

Data are presented as number and percentage, respectively. NR, nicotine replacement.

Table 1

Characteristics of lung transplant candidates according to test results.

	Patients with positive tests (n = 92)	Patients with negative tests (n = 528)	p-value
Age (years)	58.7 ± 6.2	52.9 ± 12.4	0.000
Sex (male), n (%)	57 (62.0)	298 (56.4)	0.362
BMI (kg/m2)	22.3 ± 4.7	23.6 ± 4.9	0.017
Underlying diseases
COPD, n (%)	74 (80.4)	183 (34.7)	0.000
ILD, n (%)	14 (15.2)	225 (42.6)	0.000
CF, n (%)	1 (1.1)	86 (16.3)	0.000
Others, n (%)	3 (3.3)	34 (6.4)	0.235
Smoking history
Former smoker	76 (82.6)	337 (63.8)	0.000
Packyears, n	40.3 ± 19.0	29.5 ± 19.4	0.000
<1 year smokingcessation, n (%)	64 (80.0)	75 (23.1)	0.000
Time of smoking cessation (weeks) a	42.3 ± 50.1	101.7 ± 104.1	0.000
Lung Allocation Score	33.6 ± 2.5	39.5 ± 13.2	0.010
Psychiatric disorder, n (%)	20 (21.7)	60 (11.3)	0.011

Data are presented as number and percentage, respectively.

a Available in 404 patients (80/324). BMI, body mass index; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; ILD, interstitial lung diseases.

In addition, 193 patients (31.1%) reported never smoking. All were tested negative. Only 4 patients with negative cotinine test admitted smoking or use of nicotine replacement several days prior to screening (Fig 1).

To assess risk factors for a positive cotinine test multivariable regression analysis was performed while controlling for age, sex, underlying lung disease, coexisting psychiatric comorbidities or a history of psychiatric disorders, pack years and cessation time. COPD as underlying disease (odd ratio 2.102, CI 1.110–3.981; p = 0.023), the number of pack years (odd ratio 1.014, CI 1.000–1.028; p = 0.047) and a time of less than 1 year of smoking cessation (odd ratio 2.413, CI 1.410–4.128; p = 0.001) were independently associated with a positive cotinine test. Coexisting psychiatric comorbidities or a history of psychiatric disorders were not statistically significant associated with a positive test (odd ratio 1.291, CI 0.681–2.447; p = 0.434).

Of all positive tested patients, only 11 patients (12.0%) admitted active smoking and 3 patients (3.3%) reported the use of nicotine replacement therapy as shown in Fig 1. 78 patients (84.7%) falsely declared not consuming any nicotine-based products prior to the test. Of those, the cause of positive cotinine could not be assessed.

Recurrent positive tests occurred in 12 patients (13.0%) with 8 patients (66.7%) suffering from COPD, 3 patients (25.0%) from ILD and 1 patient (8.3%) from pulmonary hypertension. 10 patients (83.3%) with a recurrent positive test declared falsely not using nicotine-based products.

The majority of patients with a positive test were patients at stage 1 (n = 53, 57.6%), i.e. at the first presentation in our center. However, 29 patients (31.5%) were already in stage 2 and 10 patients (10.9%) in stage 3, i.e. in preparation for listing and on the waiting list respectively. They were tested positive despite detailed information about smoking regulations at our center. The distribution of tests according to transplant stage is shown in Table 2. Positive tested patients are depicted in Fig 2 according to cotinine values and pre-transplant stage. Whereas medium serum cotinine decreased over the stages, no clear signal was found for urine cotinine levels. However, the medium cotinine values were lowest in stage 3 in both, serum (58.0 ng/ml [53.4–260.0]) and urine (105.0 ng/ml [90.8–322.5]) as shown in Fig 2.

Table 2

Distribution of tests and patients according to transplant stage.

Stage	All 1–3	1	2	3
Number of test (%)	1306	272 (20.8)	551 (42.2)	483 (37.0)
Number of patients (%)	620	272 (43.7)	361 (58.2)	186 (30.0)
Positive tested patients, n (%*)	92 (14.8)	53 (19.5)	29 (8.0)	10 (5.4)
Self-reported smoking, n (%#)	11 (12.0)	8 (15.1)	3 (10.3)	0 (0.0)
Self-reported NR, n (%#)	3 (3.3)	1 (1.9)	1 (3.4)	1 (10.0)
False self-report, n (%#)	78 (84.8)	44 (83.0)	25 (86.2)	9 (90.0)

Data are presented as number and percentage, respectively. NR, nicotine replacement.

* percent of all tested patients.

# percent of positive tested patients.

Fig 2

Distribution of cotinine values over stages 1–3.

(A) serum levels of cotinine; (B) urinary levels of cotinine. The horizontal lines represent the medium values for each stage.

Furthermore, calculations for sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) over different stages prior to lung transplantation were performed (Fig 3). Specificity (true negative reports) was high and remained stable over the stages. Sensitivity (true positive reports) was low, however, decreased towards transplantation, suggesting that the number of cotinine positive patients falsely declaring nicotine abstinence increased over the stage, towards transplantation. If a patients reported active nicotine use the test was likely positive (PPV) and if a patient declared nicotine abstinence the test was likely negative (NPV).

Fig 3

Accuracy of reporting nicotine use of transplant candidates.

Definition of abbreviation. PPV: positive predictive value; NPV negative predictive value.

Discussion

Smoking in solid organ transplant recipients is associated with an increase in graft loss, cardiovascular events, malignancy, and mortality and is therefore regarded as absolute contraindication for lung transplantation. [16-19] Active smoking is a risk factor for early resumption after transplantation. [20] Therefore, attempts should be made to identify lung transplant candidates with active smoking behavior to provide support for smoking cessation or to not place patients on the waiting list. Self-reported smoking status may be particularly prone to false reports, since exclusion from transplantation may be life threatening in selected patients. [4]

In our cross-sectional observational study almost 15% of lung transplant candidates were tested positive for cotinine, indicating active smoking or nicotine replacement therapy. Most of the patients were positive at the first presentation at our center. However, patients during evaluation, follow-up, or even on the waiting list have been tested positive, despite detailed explanation about strict smoking regulations.

Approximately 85% of patients who smoke or use nicotine products do not accurately self-report use, supporting the previous finding that active smoking in underreported by patients with chronic lung disease. [7] In our study, the number of false self-reports of active nicotine use was particularly high, most likely due to the fact that the patients are aware of direct consequences, including postponing listing or ultimately exclusion from transplantation permanently. This is a potentially live threatening situation, which might force the patient to a false self-report. In this context, the number true positive reports decreased over the pre-transplant stages, suggesting that the number of cotinine positive patients falsely declaring nicotine abstinence increased towards transplantation. However, the numbers of positive tested patients is low, therefore a proper statistical comparison is not possible and interpretation should be performed cautiously.

COPD as underlying disease was identified as a risk factor for a positive cotinine test. However, our data demonstrated that also non-COPD patients can be affected and should be screened on a regular base. The number of individuals was too low to prove an association, but the majority of non-COPD patients had smoking cessation time less than one year, which should draw attention in affected patients.

In this line, the number of pack years and a duration of smoking cessation of less than one year were independently associated with a positive cotinine test in the entire cohort. This is in accordance with previous reports, demonstrating that a short duration of smoking cessation before transplantation is a risk for tobacco use after lung transplantation. [10]

On the other hand all never smoker were tested negative. Therefore, regular cotinine test in never smoker did not provide additional information and could be waived.

Psychiatric disorder or a history of psychiatric disorders, including addictive behavior were more often found in patients with a positive cotinine test compared to respective controls. However, in multivariable analysis an independent association could not be confirmed. Previous reports have shown that patients with psychiatric disorders demonstrate greater rates of tobacco use and nicotine dependence and quitting rates are lower. [21] Lung transplant candidates with a psychiatric and addictive history might benefit from targeted cessation intervention.

The results of our study should be interpreted in view of the study design and its limitations, which include a single‐center cross-sectional study. Furthermore, despite providing data of a systematic cotinine screening we cannot prove that our approach would influence smoking resumption after transplantation. Furthermore, cotinine as biomarker does not allow to distinguish between surreptitious use of combustible tobacco versus pharmacologic use of NRT. In this context, exhaled carbon monoxide (CO) can be measured in expired air or in the blood, carboxyhemoglobin (COHb) in the blood using spectrophotometry. Both levels are highly correlated. [22,23] CO has limited sensitivity in detection of light smoking because CO levels from smoking are low and can be influenced by environmental sources (i.e. air pollution, open fires). [4,24] However, CO in addition to continine test could be used to distinguish between tobacco exposure and NRT. Several other tobacco exposure biomarkers, have been reported but may not always be practical to measure. [25]

In conclusion, our data demonstrate that lung transplant candidates who smoke or use nicotine products do not accurately self-report use. COPD was the most frequent diagnosis in affected patients. Patients with a history of heavy smoking and a short cessation time are at particular risk. Therefore, in patients at risk for active nicotine use a systematic cotinine based screening might improve optimal candidate selection and preparation for transplantation, which has to be proven in prospective controlled trials.

Anonymized data set.

(SAV)

Click here for additional data file.

Comorbidities of the study cohort.

(DOCX)

Click here for additional data file.

18 Mar 2020

PONE-D-20-02858

High prevalence of false reporting of smoking in lung transplant candidates

PLOS ONE

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Reviewer #1: The authors used urinary cotinine levels to confirm tobacco abstinence among subjects being evaluated, and/or listed for lung transplantation. They report that active smoking (as evidenced by cotinine levels) is prevalent (~15%) in their lung transplant candidates, and that reliance upon self-reported abstinence is inaccurate for detecting tobacco use.

The study is well done, though I do not believe the study design allows them to faithfully backup their conclusions. Most importantly, though patients are restricted from using nicotine replacement therapy, it is possible (perhaps very likely) that many of the positive urinary screens could be related to individuals self-medicating with over-the-counter nicotine replacement therapy. What the finding of this paper illustrates to me is how profoundly addicting nicotine is, as evidenced by patient factors associated with positive nicotine test (those with psychiatric comorbidities, patients with heavier-pack-year exposure, and more recent quit dates). These factors are known to be associated with both higher prevalence of tobacco use, and greater risk of relapse. It is precisely these individuals, who are more susceptible to nicotine withdrawal symptoms, that might self-medicating with over-the-counter nicotine replacement products in order to avoid relapse to combustible tobacco.

Major:

These individuals should be supported in their attempts at tobacco cessation by any means necessary. Apparently their transplant program prohibits the use of nicotine replacement therapy, which is true of some other programs, but not universally the case for all transplant centers. Apart from the ethical issue of prohibiting use of an effective treatment for an addiction, this prohibition of nicotine replacement therapy probably limits the validity of their conclusions, in that the study as described could not reliably distinguish between surreptitious use of combustible tobacco versus pharmacologic use of NRT. There are alternative biomarkers which, though more expensive, are also more specific to combustible tobacco.

Minor:

the statement in the 2nd to final paragraph of the Results section indicates that the "...number of patients falsely declaring nicotine abstinence increased over the transplant stage" but the data shown in this regard in table 4 do not appear to have appropriate statistical confirmation. While the numbers do increase, the confidence intervals about these averages are likely too large to support a 'trend'.

Reviewer #2: Authors present an interesting manuscript on misreporting of smoking status in lung transplant patients. Data have some unique findings and the cohort represents the most recent analysis for this type of cohort. There are several areas where presentation of data in a different format would make information much more useful and clear. Standard calculations for sensitivity, specificity, NPV, and PPV would help as would a flowchart and breakdown of cotinine values. There are suggestions for reanalysis that could make this manuscript much more interesting and valuable, but the value of the data could be very high.

References for urinary and serum cotinine values should be noted.

Most of Table 1 is not useful to the manuscript. PFTs could be eliminated and simple description of age, sex, and BMI could be presented as a single line of text. Table 2 is also not particularly helpful and may be more useful as a supplementary table in lieu of suggestions below.

The presentation of results is somewhat confusing. The most interesting findings are in Table 4. It would be much more intuitive if the following were presented perhaps as a flowchart:

Number of patients screened

Number tested

Number with positive cotinine vs. negative cotinine

Number who reported no smoking who tested positive vs. number who reported smoking and tested positive AND number who reported no-smoking who tested negative vs. number who reported smoking who tested negative

How many patients reported never smoking according to cotinine results?

Authors should strongly consider a simple 2x2 table with calculations for sensitivity, specificity, NPV, and PPV according to self-report vs. cotinine positive. Consideration for these according to Stage 1-3 might be interesting as it appears these change closer to waitlisting.

In the results, the statement “patients with a positive test were more often former smokers (82.6% vs 63.8%, p<0.001)” does not make sense.

Throughout the manuscript, statements are slightly misleading regarding percentages. For example, in the 6th paragraph of the Results there is a statement “The number of patient falsely declaring nicotine abstinence increased over the transplant stage, with 83%, 86.2% and 90% in stage 1, 2 and 3, respectively.” I believe this should state “The number of cotinine positive patients falsely declaring nicotine abstinence…” These statements need correction throughout including in the abstract.

In Table 3, annotation “a” is not in the table.

The binary selection of positive cotinine values provides limited information. A scatterplot of cotinine values for serum and urine over Stage 1-3 would provide significant useful information to see distribution of values change over stage. This would provide an indirect representation of whether cotinine values are generally large, small, or somewhere in between.

The last paragraph of the Results is not particularly useful.

The final sentence of the abstract is not well supported. From the data, it appears that 85% of patients did not smoke with 81/92/95% of patients not smoking at Stage 1/2/3. Of patients who smoked, the accuracy did not appear to change much during stage. It is possible that patients who were never smokers (not clearly presented here) could be very accurate as would patients who report current smoking. Data suggest that quitting more than 1 year ago resulted in clearly more accuracy than quitting within the past year. Authors need to better consider the data for more representative conclusions.

It is anticipated that the above changes may result in more definitive discussion measures including where measuring cotinine is most useful.

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Reviewer #1: No

Reviewer #2: No

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17 Apr 2020

Dear Editors, dear Reviewers,

we thank both reviewers and the editor for reviewing our manuscript so carefully and raising important issues that helped us to improve the manuscript. To us, by presenting data in a different format and by clarifying misleading information, the manuscript is now more consistent and gives the reader a more thorough picture of our patients.

Sincerely,

Nikolaus Kneidinger and co-authors

REVIEWER COMMENTS:

The full comments of the reviewers were the following:

Reviewer: #1

Comments to the Author

GENERAL

The authors used urinary cotinine levels to confirm tobacco abstinence among subjects being evaluated, and/or listed for lung transplantation. They report that active smoking (as evidenced by cotinine levels) is prevalent (~15%) in their lung transplant candidates, and that reliance upon self-reported abstinence is inaccurate for detecting tobacco use.

The study is well done, though I do not believe the study design allows them to faithfully backup their conclusions. Most importantly, though patients are restricted from using nicotine replacement therapy, it is possible (perhaps very likely) that many of the positive urinary screens could be related to individuals self-medicating with over-the-counter nicotine replacement therapy. What the finding of this paper illustrates to me is how profoundly addicting nicotine is, as evidenced by patient factors associated with positive nicotine test (those with psychiatric comorbidities, patients with heavier-pack-year exposure, and more recent quit dates). These factors are known to be associated with both higher prevalence of tobacco use, and greater risk of relapse. It is precisely these individuals, who are more susceptible to nicotine withdrawal symptoms, that might self-medicating with over-the-counter nicotine replacement products in order to avoid relapse to combustible tobacco.

MAJOR Comment:

These individuals should be supported in their attempts at tobacco cessation by any means necessary. Apparently their transplant program prohibits the use of nicotine replacement therapy, which is true of some other programs, but not universally the case for all transplant centers. Apart from the ethical issue of prohibiting use of an effective treatment for an addiction, this prohibition of nicotine replacement therapy probably limits the validity of their conclusions, in that the study as described could not reliably distinguish between surreptitious use of combustible tobacco versus pharmacologic use of NRT. There are alternative biomarkers which, though more expensive, are also more specific to combustible tobacco.

Response: We thank the reviewer for these important comments.

Patients are informed that nicotine addiction is a risk factor for tobacco smoking resumption after transplantation and that nicotine replacement and active tobacco use are equally regarded is a contraindication. In the context of pre-transplant psychiatric evaluation patients are evaluated regarding addictive behaviour and in case non-pharmacological and pharmacological interventions are offered by our institution.

We agree that a clear differentiation between nicotine replacement and active tobacco use is not possible in our study. In total, 92 patients were tested positive and thereof 14 patients truly reported nicotine use (new Figure 1). Thereof, 11 patients reported tobacco and only 3 patients reported to use nicotine replacement products. We cannot conclude that the distribution is similar in patients falsely reporting not using nicotine-based products. However, this could indicate that among positive tested patients there is a considerable number of patients actively using tobacco.

However, we completely agree that this is a limitation; therefor through out the manuscript the assumption of “false reporting smoking” was changed to “false reporting nicotine use” to avoid confusion. Furthermore, the limitation is discussed in the revised version of the manuscript.

In this line, as suggested, we agree with the referee that more sophisticated methods to directly detect active tobacco use in contrast to nicotine replacement products would facilitate patient selection and cessation in patients with addictive behavior. In particular the use of carbon monoxide (CO) or carboxyhemoglobin (COHb) is widely available and could be used to distinguish between active tobacco and nicotine replacement therapy. This is acknowledged in the revised version of the manuscript.

Minor Comment:

the statement in the 2nd to final paragraph of the Results section indicates that the "...number of patients falsely declaring nicotine abstinence increased over the transplant stage" but the data shown in this regard in table 4 do not appear to have appropriate statistical confirmation. While the numbers do increase, the confidence intervals about these averages are likely too large to support a 'trend'.

Response: We thank both reviewers for this important comment. As suggested by referee #2 we performed 2x2 tables with calculations for sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) over different stages prior to lung transplantation (new Figure 3).

Specificity (true negative reports) was high and remained stable over the stages. Sensitivity (true positive reports) was low, and decreased towards transplantation, suggesting that the number of cotinine positive patients falsely declaring nicotine abstinence increased over the stages, towards transplantation. If a patient reports active nicotine use the test is likely positive (PPV) and if a patient declares nicotine abstinence the test is likely negative (NPV).

We agree with the reviewer that the number of patients, in particular of positive tested patients over the stages towards transplantation decrease, therefore, a proper statistical comparison is not possible and interpretation should be performed cautiously. This limitation is acknowledged in the revised version of the manuscript.

Reviewer: #2

Comments to the Author

Authors present an interesting manuscript on misreporting of smoking status in lung transplant patients. Data have some unique findings and the cohort represents the most recent analysis for this type of cohort. There are several areas where presentation of data in a different format would make information much more useful and clear. Standard calculations for sensitivity, specificity, NPV, and PPV would help as would a flowchart and breakdown of cotinine values. There are suggestions for reanalysis that could make this manuscript much more interesting and valuable, but the value of the data could be very high.

1/. References for urinary and serum cotinine values should be noted.

Response: We thank the reviewer for this request. As suggest, references for urinary and serum cotinine values were added to the revised version of the manuscript.

Jarvis, M.J., et al., Comparison of tests used to distinguish smokers from nonsmokers. Am J Public Health, 1987. 77(11): p. 1435-8.

Benowitz, N.L., et al., Optimal serum cotinine levels for distinguishing cigarette smokers and nonsmokers within different racial/ethnic groups in the United States between 1999 and 2004. Am J Epidemiol, 2009. 169(2): p. 236-48.

2/. Most of Table 1 is not useful to the manuscript. PFTs could be eliminated and simple description of age, sex, and BMI could be presented as a single line of text. Table 2 is also not particularly helpful and may be more useful as a supplementary table in lieu of suggestions below.

Response: As suggest by the reviewer, the comments are addressed in the revised version of the manuscript. Table 1 was deleted from the manuscript and demographic characteristics are provided in the Results of the manuscript. Table 2 is provided as new Table S1 in the supplement material.

3/. The presentation of results is somewhat confusing. The most interesting findings are in Table 4. It would be much more intuitive if the following were presented perhaps as a flowchart:

Number of patients screened

Number tested

Number with positive cotinine vs. negative cotinine

Number who reported no smoking who tested positive vs. number who reported smoking and tested positive AND number who reported no-smoking who tested negative vs. number who reported smoking who tested negative

Response: We thank the reviewer for this comment. As suggested the results are presented as a flowchart. Since 2016 the German Medical Association request from all German lung transplant centers to provide evidence for nicotine abstinence in lung transplant candidates and suggest to routine use of cotinine measurements. Therefor, from all lung transplant candidates seen in our outpatient clinic from January 2017 until the end of the observation period (June 2019) cotinine tests were available.

New Figure 1

4/. How many patients reported never smoking according to cotinine results?

Response: In total, 193 patients (31.1%) reported never smoking, defined as a candidate who has never smoked, or who has smoked less than 100 cigarettes in his or her lifetime. All patients were tested negative. Therefore, routine testing in this never smokers seems not to be mandatory. Results are included and discussed in the revised version of the manuscript.

5/. Authors should strongly consider a simple 2x2 table with calculations for sensitivity, specificity, NPV, and PPV according to self-report vs. cotinine positive. Consideration for these according to Stage 1-3 might be interesting as it appears these change closer to waitlisting.

Response: We thank the reviewer for this important comment. We performed 2x2 tables with calculations for sensitivity, specificity, NPV, and PPV over different stages prior to lung transplantation (new Figure 3). Specificity (true negative reports) was high and remained stable over the stages. Sensitivity (true positive reports) was low, however, decreased towards transplantation, suggesting that the number of cotinine positive patients falsely declaring nicotine abstinence increased over the stage, towards transplantation. If a patient reports active nicotine use the test is likely positive (PPV) and if a patient declares nicotine abstinence the test is likely negative (NPV).

The number of patients, in particular of positive tested patients over the stages towards transplantation decrease, therefore, a proper statistical comparison is not possible and interpretation should be performed cautiously.

6/. In the results, the statement “patients with a positive test were more often former smokers (82.6% vs 63.8%, p<0.001)” does not make sense.

Response: We thank the reviewer for this comment and apologize for confusion. We have deleted that part of the statement from the manuscript.

7/. Throughout the manuscript, statements are slightly misleading regarding percentages. For example, in the 6th paragraph of the Results there is a statement “The number of patient falsely declaring nicotine abstinence increased over the transplant stage, with 83%, 86.2% and 90% in stage 1, 2 and 3, respectively.” I believe this should state “The number of cotinine positive patients falsely declaring nicotine abstinence…” These statements need correction throughout including in the abstract.

Response: We thank both reviewers for this important comment and refer to request #5. Changes have been made as suggested throughout the revised manuscript.

8/. In Table 3, annotation “a” is not in the table.

Response: We apologize; the annotation “a” was added in the table (new Table 1).

9/. The binary selection of positive cotinine values provides limited information. A scatterplot of cotinine values for serum and urine over Stage 1-3 would provide significant useful information to see distribution of values change over stage. This would provide an indirect representation of whether cotinine values are generally large, small, or somewhere in between.

Response: Thank you for this comment. As suggest the serum and urine cotinine values of positive tested patients are provided as a scatterplot over the stages in the revised version of the manuscript (Table 2 and new Figure 2).

Whereas medium serum cotinine decreased over the stages, no clear signal was found for urine cotinine. However, the medium cotinine value was lowest in Stage 3 in both, serum and urine. This might indicate that active smoking or nicotine replacement is stopped before follow-up visit in the transplant center in patients active listed for lung transplantation. However, the number of tests, in particular of positive tests is low and decreased over the stages towards transplantation, therefore interpretation should be performed cautiously.

Results and limitations are incorporated and discussed in the revised version of the manuscript.

10/. The last paragraph of the Results is not particularly useful.

Response: Thank you for this comment. The paragraph was deleted from the manuscript.

11/. The final sentence of the abstract is not well supported. From the data, it appears that 85% of patients did not smoke with 81/92/95% of patients not smoking at Stage 1/2/3. Of patients who smoked, the accuracy did not appear to change much during stage. It is possible that patients who were never smokers (not clearly presented here) could be very accurate as would patients who report current smoking. Data suggest that quitting more than 1 year ago resulted in clearly more accuracy than quitting within the past year. Authors need to better consider the data for more representative conclusions.

Response: We agree with the referee that our statement is misleading and not supported by the presented data. As suggested the majority of the patients did report truly not to use nicotine based products and even some patients did report active tobacco use or nicotine replacement products. We agree that there are patients at risk, as assessed by regression analysis (cessation<1 year, high number of pack years, COPD) where regular cotinine tests might be useful. On the other hand, in never-smokers regular cotinine tests seem not to be mandatory. Therefore, our conclusion was revised accordingly and the sentence deleted. To avoid misinterpretation, we clarified that most patients report not to use nicotine based products and were consecutively tested negative. However, even the proportion of patients tested positive (14,8%) was low, the number seems to be high in the context of imminent lung transplantation. Furthermore, of patients tested positive there was a high prevalence of falsely declaring nicotine abstinence (84,8%). Accordingly, title and wording was revised throughout the manuscript.

It is anticipated that the above changes may result in more definitive discussion measures including where measuring cotinine is most useful.

Submitted filename: Response to reviewers.docx

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19 May 2020

PONE-D-20-02858R1

High prevalence of falsely declaring nicotine abstinence in lung transplant candidates

PLOS ONE

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Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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Reviewer #1: Though I am still concerned that the study design does not permit fully addressing the study question, I believe the authors have raised valid points and acknowledged the limitations of their data in support of the conclusions. IN doing so the paper has been strengthened and I support the authors interpretation of their findigs.

Reviewer #2: Results are much clearer and findings are very interesting. From the revised manuscript, the significant finding is that 85% of patients who smoked (or used NRT) did not report this. This is striking and I would offer that the opening to the Discussion could better reflect this finding. This is certainly more interesting than higher rates in COPD or pack years. I would recommend reorganizing the Discussion around this theme and opening with this finding, but otherwise much improved.

In the discussion, paragraph starting with “interestingly, approximately 85% of patients…” this sentence doesn’t make sense. I think the authors are trying to state “Approximately 85% of patients who smoke or use nicotine products do not accurately self-report use, supporting the previous finding that active smoking in underreported by patients with chronic lung disease”

In the final paragraph of the discussion, the first sentence appears incorrect and could perhaps conclude that while active smoking is present in a minority of patients, there is a high rate of misrepresentation that warrants biochemical confirmation, particularly in patients reporting an ever-smoking history or quitting smoking within the past year.

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21 May 2020

Dear Editors, dear Reviewers,

we thank both reviewers and the editor for reviewing our manuscript once more. We have addressed the comments and adopted suggestions accordingly. To us, the manuscript now has improved further and gives the reader a thorough picture of our patients.

Sincerely,

Nikolaus Kneidinger and co-authors

REVIEWER COMMENTS:

The full comments of the reviewers were the following:

Reviewer: #1

Though I am still concerned that the study design does not permit fully addressing the study question, I believe the authors have raised valid points and acknowledged the limitations of their data in support of the conclusions. IN doing so the paper has been strengthened and I support the authors interpretation of their findings.

Response: Thank you for your willingness to review and help to improve our manuscript.

Reviewer #2:

Results are much clearer and findings are very interesting. From the revised manuscript, the significant finding is that 85% of patients who smoked (or used NRT) did not report this. This is striking and I would offer that the opening to the Discussion could better reflect this finding. This is certainly more interesting than higher rates in COPD or pack years. I would recommend reorganizing the Discussion around this theme and opening with this finding, but otherwise much improved.

Response: We thank the referee for his comments to further improve our manuscript. As suggested we reorganized the Discussion accordingly.

In the discussion, paragraph starting with “interestingly, approximately 85% of patients…” this sentence doesn’t make sense. I think the authors are trying to state “Approximately 85% of patients who smoke or use nicotine products do not accurately self-report use, supporting the previous finding that active smoking in underreported by patients with chronic lung disease”

Response: Thank you for this comment; we adopted the sentence as suggested.

In the final paragraph of the discussion, the first sentence appears incorrect and could perhaps conclude that while active smoking is present in a minority of patients, there is a high rate of misrepresentation that warrants biochemical confirmation, particularly in patients reporting an ever-smoking history or quitting smoking within the past year.

Response: Thank for this suggestion. To avoid misinterpretation, the first sentence of the last paragraph was deleted and replaced by “In conclusion, our data demonstrate that lung transplant candidates who smoke or use nicotine products do not accurately self-report use….”

Submitted filename: Response to reviewers2.docx

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3 Jun 2020

High prevalence of falsely declaring nicotine abstinence in lung transplant candidates

PONE-D-20-02858R2

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9 Jun 2020

PONE-D-20-02858R2

High prevalence of falsely declaring nicotine abstinence in lung transplant candidates

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