We thank Dr. Seijger and colleagues for their analysis. These queries are legitimate and most of the answers are in the online repository. Indeed, in order to comply with the guidelines for letters to Thorax (no more than 1000 words and 2 tables / figures), we could not include all our descriptive and univariate analysis.

We agree that the analysis of survival of patients with type 1 myotonic dystrophy is complex. Our results in Figure 1 and Table R1 demonstrated that patients who refused to initiate NIV, or who delayed NIV initiation, had both a more severe respiratory function and a higher risk for severe event (invasive ventilation or death). Independently from determining whether these severe complications were due to the severity of the initial respiratory function, the lack of compliance to treatment or both, we believe that it was important to underline the presence of this triptych, which is not observed with other neuromuscular groups, such as Duchenne muscular dystrophy where the acceptance of NIV increases with the respiratory dysfunction severity.

Our suggestion that failure to adhere to home mechanical ventilation was associated with increased mortality (tracheostomy excluded), was based on a Cox model analysing predictors of 10-year mortality among NIV users (Table 1). The Cox model was used to evaluate death risk ratios associated with NIV adherence category and was adjusted for other risk factors described in the literature. The covariates included were sex, age at NIV introduction, and variables with a p value <0.15 in the univariate analysis identified by progressive selection (also included in the online repository).

In univariate analysis, having a pacemaker was not significantly associated with mortality. All our DM1 patients are systematically explored in a specialised cardiologic ward [1] which belongs to the same reference center for neuromuscular patients as our unit [2]; therefore patients with diagnosed heart conduction disturbances underwent pacemaker placement [3], which limited their risk of death from cardiac causes. Regarding functional status, all patients were walking.

One of the main objectives of ventilatory support is to improve gas exchanges regardless the mechanism (respiratory pump failure or respiratory drive dysfunction), which means the normalization of PaCO₂, and to improve the signs and symptoms, which has already been demonstrated by Nugent and al [4]. However, the aim of our study was to identify the long term impact of mechanical ventilation, and not its short-term effectiveness.  Our usual follow-up aims to ensure that patients are well ventilated within the first 3 months of treatment initiation. During nighttime, and daytime when required, both ventilator settings and interfaces are adjusted using repeated polygraphies (with transcutaneous PCO₂), or polysomnographies [5, 6] when necessary, until patients-ventilator interaction is correct and nocturnal transcutaneous PCO₂ improves. Moreover, we also use pharmacological treatments when residual daytime hypersomnolence is due solely to central neurological dysfunction [7, 8], as our specialised sleep laboratory is also certified as a reference centre for daytime sleepiness, where we can objectively evaluate daytime sleepiness and efficiency of different treatments by Multiple Sleep Latency Tests and/or the Maintenance of Wakefulness Tests [9]. NIV and sleep were usually efficient within the first months and were controlled every year [6] when patients accepted to continue mechanical ventilation and to come back. Therefore, it was not our objective to prove the effectiveness of mechanical ventilation in this manuscript, considering that at this stage the most important factor, in our opinion, is the adherence to treatment.

In conclusion, the main limit of this study is that it involved a single-center which limits the generalization of the findings. However, because there is no data in the literature regarding the long term impact of mechanical ventilation on DM1 patients survival, this study could be considered as the first report on which to base larger, multicenter studies as suggested by Dr. Seijger and colleagues.

Reference

[1] Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, Bécane HM, Lazarus A, Béhin A, Laforêt P, Stojkovic T, Clementy N, Dussauge AP, Gourraud JB, Pereon Y, Lacour A, Chapon F, Milliez P, Klug D, Eymard B, Duboc D. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2017 Mar 7;38(10):751-758.

[2] Boussaïd G, Wahbi K, Laforet P, Eymard B, Stojkovic T, Behin A, Djillali A,

Orlikowski D, Prigent H, Lofaso F. Genotype and other determinants of respiratory function in myotonic dystrophy type 1. Neuromuscul Disord. 2018 Mar;28(3):222-228.

[3] Wahbi K, Meune C, Porcher R, Bécane HM, Lazarus A, Laforêt P, Stojkovic T, Béhin A, Radvanyi-Hoffmann H, Eymard B, Duboc D. Electrophysiological study with prophylactic pacing and survival in adults with myotonic dystrophy and conduction system disease. JAMA. 2012 Mar 28;307(12):1292-301.

[4] Nugent AM, Smith IE, Shneerson JM. Domiciliary-assisted ventilation in patients with myotonic dystrophy. Chest. 2002 Feb;121(2):459-64.

[5] Nardi J, Prigent H, Garnier B, Lebargy F, Quera-Salva MA, Orlikowski D, Lofaso F. Efficiency of invasive mechanical ventilation during sleep in Duchenne muscular dystrophy. Sleep Med. 2012 Sep;13(8):1056-65.

[6] Annane D, Quera-Salva MA, Lofaso F, Vercken JB, Lesieur O, Fromageot C, Clair B, Gajdos P, Raphael JC. Mechanisms underlying effects of nocturnal ventilation on daytime blood gases in neuromuscular diseases. Eur Respir J. 1999 Jan;13(1):157-62.
[7] Orlikowski D, Chevret S, Quera-Salva MA, Laforêt P, Lofaso F, Verschueren A, Pouget J, Eymard B, Annane D. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial. Clin Ther. 2009 Aug;31(8):1765-73.

[8] Hilton-Jones D, Bowler M, Lochmueller H, Longman C, Petty R, Roberts M, Rogers M, Turner C, Wilcox D. Modafinil for excessive daytime sleepiness in myotonic dystrophy type 1--the patients' perspective. Neuromuscul Disord. 2012 Jul;22(7):597-603.

[9] Orlikowski D, Chevret S, Quera-Salva MA, Laforêt P, Lofaso F, Verschueren A, Pouget J, Eymard B, Annane D. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial. Clin Ther. 2009 Aug;31(8):1765-73.

We appreciate the points raised by the commentator about our study (Zeng et al.)[1] published in June 2018 issue of Thorax that (1) the prevalence of abnormal residual volume to total lung capacity ratio (RV:TLC) in our study of ever-smokers with preserved spirometry is substantially higher than that observed in the commentator’s past studies,[2-4] and (2) an assumption by the commentator that stringent exclusion of those with abnormally low TLC and those with diagnosis codes of interstitial lung diseases (ILD) in their electronic health records (EHR) may have resulted in overestimation of the prevalence of abnormally high RV:TLC among smokers with preserved spirometry.

We would like to draw the attention of commentator and readers to the following points:

1- The studies referenced by the commentator used pulmonary function tests (PFT) data collected from 708 patients in 2013 across 5 clinical sites associated with University of Minnesota Medical Center with inclusion criteria of patients 18 years of age or older with or without history of smoking.[2] They included about 50% women and 3 African Americans. Our study was performed on PFT data obtained from 1985 through 2017 through the United States Veterans Affairs (VA) nationwide EHR from 7,479 patients across 37 VA medical centers in the United States with inclusion criteria of patients 40 years of age or older with an EHR diagnosis code of smoking, which likely suggests heavy smoking for VA patients. Our study included only 7.5% women but 8.8% African Americans. The populations in our study and that of the commentator’s study are very different. Given the heavier smoking burden at the VA,[5] it is not unexpected to identify higher smoking-related pathology including higher prevalence of air trapping among the VA patients. Of note, through their deployments, veterans are also exposed to high levels of air pollutants,[6] which have been shown to contribute considerably to development of chronic obstructive pulmonary disease (COPD).[7]
2- As mentioned in our article, a limitation of our study was that spirometries, and specifically full PFT, were likely done due to clinical concerns for respiratory diseases, and given the inclusion of plethysmography, the likely existence of concerns for ILD. This selection bias may then contribute to a higher prevalence of receiving an ILD diagnosis in those patients’ records in our study.
3- Abnormally low TLC could occur for reasons other than ILD including obesity, which is a common health problem and thus may have resulted in exclusions of many patients from our study.
4- It is important to note that the assumption of stringent exclusion of those with ILD and abnormally low TLC should result in the remaining included patients to have higher than expected TLC, and should not result in the remaining patients to have high RV; that is, the remaining subjects should have the same level RV but higher TLC, and hence lower RV:TLC ratio. Thus, if the commentator’s assumption that “stringent exclusion criteria resulted in a very small denominator” were correct, then the algorithm of our study indeed would have been biased towards generating lower than expected prevalence of abnormally high RV:TLC, leading to an underestimation, not overestimation, of the prevalence of abnormally high RV:TLC.
5- Most remarkably, a finding that we would like to emphasize and should not be overlooked is that regardless of whether the RV:TLC ratio was normal or abnormal, it was linearly and directly associated with respiratory morbidity and progression to spirometric COPD. No threshold level was observed.
6- It is now estimated that approximately 20% of COPD is caused by exposure to air pollutants (including pollutants other than biomass smoke such as the daily air pollution experienced by all across the globe).[8] Given above, the use of “normal” or “abnormal” values and reference equations should be approached cautiously as it is potentially extremely difficult if not impossible to develop a “normal” cohort when all earth inhabitants are being exposed to air pollutants. This is consistent with our related findings in a previous article showing that in never-smokers with history of exposure to air pollutants, all with preserved spirometry AND normal range of RV:TLC, higher RV:TLC ratio was associated with worse physiologic performance.[9]
7- Finally, the commentator’s statement about lesser reliability and lack of rationale for use of lung volumes in smokers at risk for COPD is fascinating. Spirometry is an extremely important tool in assessment of respiratory diseases including COPD. It is easier to use than plethysmography and more widely available. However, COPD is a complex disease and reducing it to one or two dimensions is unhelpful.[10] As demonstrated in our article, lung volumes, regardless of whether in the normal or abnormal range, provide an additional dimension to help prognosticate in early obstructive lung disease in those at risk for COPD. In their study of 708 patients with normal spirometry,[2] the commentator and colleagues did conclude that their “findings point out the importance of measuring lung volumes in symptomatic patients who have normal spirometry.” We fully agree with them.

References:

1. Zeng, S., et al., Lung volume indices predict morbidity in smokers with preserved spirometry. Thorax, 2018.
2. Fortis, S., E.O. Corazalla, and H.J. Kim, Does normal spirometry rule out an obstructive or restrictive ventilatory defect? Respir Investig, 2017. 55(1): p. 55-57.
3. Fortis, S., et al., The difference between slow and forced vital capacity increases with increasing body mass index: a paradoxical difference in low and normal body mass indices. Respir Care, 2015. 60(1): p. 113-8.
4. Fortis, S., et al., Persistent Empiric COPD Diagnosis and Treatment After Pulmonary Function Test Showed No Obstruction. Respir Care, 2016. 61(9): p. 1192-200.
5. Odani, S., et al., Tobacco Product Use Among Military Veterans - United States, 2010-2015. MMWR Morb Mortal Wkly Rep, 2018. 67(1): p. 7-12.
6. Falvo, M.J., et al., Airborne hazards exposure and respiratory health of Iraq and Afghanistan veterans. Epidemiol Rev, 2015. 37: p. 116-30.
7. van Koeverden, I., et al., Secondhand Tobacco Smoke and COPD Risk in Smokers: A COPDGene Study Cohort Subgroup Analysis. COPD, 2015. 12(2): p. 182-9.
8. Eisner, M.D., et al., An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2010. 182(5): p. 693-718.
9. Arjomandi, M., et al., Lung volumes identify an at-risk group in persons with prolonged secondhand tobacco smoke exposure but without overt airflow obstruction. BMJ Open Respir Res, 2018. 5(1): p. e000284.
10. Agusti, A., B. Celli, and R. Faner, What does endotyping mean for treatment in chronic obstructive pulmonary disease? Lancet, 2017. 390(10098): p. 980-987.

The global increase in air travel, with over 3.97 billion people traveling by air each year, and the ageing population, increase the number of those with an illness who wish to travel (1). Even more, in countries like Greece with hundreds of islands, health professionals are frequently asked to assess a patient’s fitness to fly. Doctors can receive advice and guidance mainly from two sources: the IATA passenger medical clearance guidelines (2) and the Aerospace Medical Association in which the British Thoracic Society’s recommendations for air travel (3) are suggested.
Many respiratory conditions can affect a passenger’s fitness to fly with pulmonary embolism being the most debatable (3). A major question that respiratory physicians frequently have to answer, mostly with visitors from overseas who need to be repatriated following diagnosis of pulmonary embolism, is about the right time to “fly with a clot”. The British Thoracic Society guidelines recommend against airline travel during the first four weeks following pulmonary embolism (3). On the other hand, in the IATA medical guidelines published in 2018 it is suggested that patients can fly 5 days after an acute pulmonary embolism episode, if they receive anticoagulation and their PaO2 is normal on room air (2). Although there is little scientific evidence to support the above mentioned recommendations, the huge difference in the suggested period can really confuse healthcare professionals. Moreover, asking patients-tourists to remain in a travel destination one month more than scheduled, launches their cost of stay and many times they are proven unable to follow this recommendation.
In our opinion, one size does not fit all. The 4-week period seems too long for a patient with pulmonary embolism severity index I or II, no evidence of right ventricular dysfunction on an imaging test, negative laboratory biomarkers on presentation (low risk patient) and a normal PaO2 on room air (4). On the other hand, the 4-week period and even more the 5-day period may be too short for a patient with pulmonary embolism severity index III-V, evidence of right ventricular dysfunction on an imaging test and positive laboratory biomarkers on presentation (intermediate high risk patient), who has a significantly higher mortality rate during the first thirty days even without traveling (4).
Thus, we believe that the risk of flying after being diagnosed with pulmonary embolism is not the same for all patients and in every case we should take into consideration the risk stratification on presentation and the PaO2 level. Further carefully designed studies taking into account risk stratification will give the answer to the tough question “should I stay or should I go” after pulmonary embolism.

References
The World Bank. Air transport, passengers carried. https://data.worldbank.org/indicator/IS.AIR.PSGR Date last accessed: December 7, 2018.
International Air Transport Association. Medical manual 11th edition. https://www.iata.org/publications/Documents/medical-manual.pdf 2018
Ahmedzai S1, Balfour-Lynn IM, Bewick T, Buchdahl R, Coker RK, Cummin AR, Gradwell DP, Howard L, Innes JA, Johnson AO, Lim E, Lim WS, McKinlay KP, Partridge MR, Popplestone M, Pozniak A, Robson A, Shovlin CL, Shrikrishna D, Simonds A, Tait P, Thomas M; British Thoracic Society Standards of Care Committee. Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations. Thorax. 2011 Sep;66 Suppl 1:i1-30.
Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69, 3069a-3069k.

According to recent study published by Sebastian et al., (1) electronic cigarette vapor impairs the activity of alveolar macrophages, which engulf and remove dust particles, bacteria, and allergens that have evaded the other mechanical defenses of the respiratory tract. This study finding is important and it shows that the long term health impact of e-cigarettes use may be more harmful than we know (2).

Meanwhile, industry, tobacco research community and the online information are promoting electronic cigarette as a less harmful tobacco cessation tool. However, before more leeway to advertise the harm-reduction benefits of vaping products, we believe that the first step would be to establish whether vaping products are indeed safer tobacco cessation device or harm reduction tool (3). Moreover, currently available evidence (including clinical guidelines and position statements of credible medical organizations) based information need to ensure that people are protected from commercial interests and are able to make informed decisions based on current best evidence on electronic cigarette and its long term health effects (3). It is our moral obligation that we should not be promoted electronic cigarette to our children and people those who never wanted to smoke tobacco. At the same time, it is important to promote the proven non-tobacco nicotine products such as Nicotine Replacement Therapy (gum or inhalators) to smokers those who are sincerely wanted to quit.

A new congressionally mandated National Academies of Sciences, Engineering and Medicines’ (NASEM) comprehensive review of more than 800 peer reviewed scientific studies on health effects of vaping on adolescents concluded that “There is moderate evidence for increased cough and wheeze in adolescents who use electronic-cigarettes, and an increase in asthma exacerbations” (4).

The harms that e-cigarettes currently pose to non-smoking teens and young adults (those who never wanted to smoke) far outweigh the potential benefits (5).Therefore, the NASEM (5) recommendations and emerging research on electronic cigarette use and potential long term harm (1) should be appropriately reflect in the future clinical guidelines and position statements of credible medical organizations.

REFERENCES:
(1). Scott A, Lugg ST, Aldridge K, Lewis KE, Bowden A, Mahida RY, Grudzinska FS, Dosanjh D, Parekh D, Foronjy R, Sapey E, Naidu B, Thickett DR. Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages. Thorax. 2018 Aug 13. pii: thoraxjnl-2018-211663. doi: 10.1136/thoraxjnl-2018-211663.

(2). Huang SJ, Xu YM, Lau ATY. Electronic cigarette: A recent update of its toxic effects on humans. J Cell Physiol. 2018 Jun;233(6):4466-4478. doi: 10.1002/jcp.26352

(3). Bandara AN, Mehrnoush V. Electronic cigarettes: adolescent health and wellbeing. Lancet. 2018; 11;392(10146):473. doi: 10.1016/S0140-6736(18)31177-2.

(4). National Academies of Sciences and Engineering and Medicine. Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems. Public health consequences of e-cigarettes. The National Academies Press, Washington, DC; 2018. Available at: https://www.nap.edu/catalog/24952/public-health-consequences-of-e-cigare...

(5). Soneji S, Sung HY, Primack BA, Pierce JP, Sargent JD. "Quantifying population-level health benefits and harms of e-cigarette use in the United States" PLOS ONE 2018; DOI: 10.1371/journal.pone.0193328.