The

n e w e ng l a n d j o u r na l

prescription-drug abuse should not be discounted but rather examined to identify effective methods, and policy should be formed to implement the effective responses. We share the concerns of Bolash as well. Prescription-monitoring programs have tremendous potential that is not fully realized in most states. One solution is PMP Interconnect, an effort of the National Association of Boards of Pharmacy to link these programs (www.nabp.net/programs/ pmp-interconnect/nabp-pmp-interconnect). There are currently 28 states participating in PMP Interconnect, with more enrolling. Another important challenge for prescription-monitoring programs is the reluctance of physicians to use

of

m e dic i n e

these programs. The ultimate solution will be multifactorial, but integrated prescription-monitoring programs could develop into an effective tool to reduce doctor-shopping. Richard C. Dart, M.D., Ph.D. S. Geoff Severtson, Ph.D. Becki Bucher-Bartelson, Ph.D. Denver Health and Hospital Authority Denver, CO [email protected] Since publication of their article, the authors report no further potential conflict of interest. 1. Dasgupta N, Davis J, Jonsson Funk M, Dart R. Using poison

center exposure calls to predict methadone poisoning deaths. PLoS One 2012;7(7):e41181.

DOI: 10.1056/NEJMc1501822

Origins of Cystic Fibrosis Lung Disease To the Editor: On the basis of their seminal findings in models of disease in large animals, Stoltz and colleagues (Jan. 22 issue)1 report that the origins of cystic fibrosis lung disease result from impaired chloride and bicarbonate epithelial transport, defective mucociliary transport, and acidification of the airway-surface liquid. The pathophysiology of cystic fibrosis is deduced from the loss or dysfunction of CFTR in the apical epithelial membrane. However, this exclusive focus on the epithelial membrane ignores the roles of CFTR in intracellular compartments and in nonepithelial cells. An attenuated bacteria-killing capability has been reported in monocytes and macrophages isolated from people with cystic fibrosis.2,3 Similarly, when mice with a deficiency of Cftr in myeloid cells but a sufficiency of Cftr in epithelial cells were challenged with the major cystic fibrosis pathogen Pseudomonas aeruginosa, the animals had sustained neutrophilic inflammation, and their ability to resolve the airway infection was compromised.4,5 These data from studies in humans and mice show the dysfunction of CFTR in nonepithelial host-defense cells. Cystic fibrosis lung disease is not exclusively a consequence of the loss of CFTR channels in airway epithelial cells. Antje Munder, M.D. Burkhard Tümmler, M.D., Ph.D. Hanover Medical School

Hannover, Germany [email protected] No potential conflict of interest relevant to this letter was reported.

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1. Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibro-

sis lung disease. N Engl J Med 2015;372:351-62. 2. Del Porto P, Cifani N, Guarnieri S, et al. Dysfunctional CFTR alters the bactericidal activity of human macrophages against Pseudomonas aeruginosa. PLoS One 2011;6(5):e19970. 3. Van de Weert-van Leeuwen PB, Van Meegen MA, Speirs JJ, et al. Optimal complement-mediated phagocytosis of Pseudomonas aeruginosa by monocytes is cystic fibrosis transmembrane conductance regulator-dependent. Am J Respir Cell Mol Biol 2013; 49:463-70. 4. Ng HP, Zhou Y, Song K, Hodges CA, Drumm ML, Wang G. Neutrophil-mediated phagocytic host defense defect in myeloid Cftr-inactivated mice. PLoS One 2014;9(9):e106813. 5. Bonfield TL, Hodges CA, Cotton CU, Drumm ML. Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloidderived cells slows resolution of inflammation and infection. J Leukoc Biol 2012;92:1111-22. DOI: 10.1056/NEJMc1502191

The Authors Reply: We agree with Munder and Tümmler that abnormal function in myeloid cells (i.e., neutrophils, monocytes, or macrophages) may contribute to impaired host defense in cystic fibrosis. In our article, we said that the “loss of CFTR  .  .  .  reduces the effectiveness of at least two defenses — mucociliary transport and antimicrobial activity — and other defenses may also be degraded” and referenced a review. Although not highlighted, additional nonepithelial cells, including neurons and airway smooth muscle, might also contribute to the pathogenesis of cystic fibrosis.1,2 Specific cell types involved (monocytes, neutrophils, or macrophages) and proposed mechanisms for defects (e.g., organelle acidification, complement-mediated phagocytosis, and intraphagosomal production of hypochlorous acid) vary

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correspondence

substantially among studies. Which cells and mechanisms are key is uncertain. In addition to the work that Munder and Tümmler referenced, other research has not detected defects in myeloid cells.3-5 As we stated in our article, we focused “primarily on the newborn period, because this time window is key to discovering the origins of cystic fibrosis airway disease.” Myeloid cells from humans or animals with chronic infection, inflammation, or both might have altered function. Perhaps that explains, at least in part, why results vary among studies. David A. Stoltz, M.D., Ph.D. David K. Meyerholz, D.V.M., Ph.D. Michael J. Welsh, M.D.

Since publication of their article, the authors report no further potential conflict of interest.

University of Iowa Carver College of Medicine

DOI: 10.1056/NEJMc1502191

1. Reznikov LR, Dong Q, Chen JH, et al. CFTR-deficient pigs

display peripheral nervous system defects at birth. Proc Natl Acad Sci U S A 2013;110:3083-8. 2. Meyerholz DK, Stoltz DA, Namati E, et al. Loss of cystic fibrosis transmembrane conductance regulator function produces abnormalities in tracheal development in neonatal pigs and young children. Am J Respir Crit Care Med 2010;182:125161. 3. Haggie PM, Verkman AS. Cystic fibrosis transmembrane conductance regulator-independent phagosomal acidification in macrophages. J Biol Chem 2007;282:31422-8. 4. Barriere H, Bagdany M, Bossard F, et al. Revisiting the role of cystic fibrosis transmembrane conductance regulator and counterion permeability in the pH regulation of endocytic organelles. Mol Biol Cell 2009;20:3125-41. 5. Steinberg BE, Huynh KK, Brodovitch A, et al. A cation counterflux supports lysosomal acidification. J Cell Biol 2010;189:117186.

Iowa City, IA

More on Hidden Formaldehyde in E-Cigarette Aerosols To the Editor: The data presented by Jensen et al. (Jan. 22 issue)1 in their recent letter to the Editor do not support their conclusion that e-cigarette use presents a likely risk of excessive exposure to formaldehyde. The 5-V puff topography used by Jensen et al. appears to have overheated the coil, resulting in excessive breakdown of propylene glycol to formaldehyde. This phenomenon is readily detected by the consumer by virtue of an exceedingly unpleasant burning taste, commonly referred to as a “dry puff.” It has been described in detail in the literature.2,3 The consumer can address this issue by discontinuing use of the unit or reducing puff duration while increasing the interval between puffs.3 Thus, taste prevents e-cigarette users from exposing themselves to excessive formaldehyde from overheating of the coil. Joel L. Nitzkin, M.D., M.P.H. JLN, MD Associates

New Orleans, LA [email protected]

Konstantinos Farsalinos, M.D. Onassis Cardiac Surgery Center

Athens, Greece

Michael Siegel, M.D., M.P.H. Boston University School of Public Health

Boston, MA Dr. Nitzkin reports receiving partial funding for some of his tobacco policy work from the R Street Institute. Dr. Farsalinos reports that some of his studies on electronic cigarettes were performed with unrestricted funds provided to the Onassis Car-

diac Surgery Center by FlavourArt and Nobacco. No other potential conflict of interest relevant to this letter was reported. 1. Jensen RP, Luo W, Pankow JF, Strongin RM, Peyton DH. Hid-

den formaldehyde in e-cigarette aerosols. N Engl J Med 2015;372: 392-4. 2. Farsalinos KE, Romagna G, Allifranchini E, et al. Comparison of the cytotoxic potential of cigarette smoke and electronic cigarette vapour extract on cultured myocardial cells. Int J Environ Res Public Health 2013;10:5146-62. 3. Farsalinos K, Romagna G, Tsiapras D, Kryzopoulos S, Voudris V. Evaluation of electronic cigarette use (vaping) topography and estimation of liquid consumption: implications for research protocol standards definition and for public health authorities’ regulation. Int J Environ Res Public Health 2013;10:2500-14. DOI: 10.1056/NEJMc1502242

To the Editor: The letter by Jensen and colleagues discusses the concentration of formaldehyde-releasing agents that are present in e-cigarette aerosols in relation to applied voltage. The heat required to generate the e-cigarette aerosol is provided by applying a voltage to a resistive element. Importantly, the magnitude of temperature increase is related to the total power dissipated in the element, a product of both the applied voltage and element resistance. The authors reported that 3.3 V did not produce detectable levels of formaldehyde-releasing agents. A brief review of the websites of several e-cigarette manufacturers reveals variable-voltage devices with element resistances ranging from 0.5 to 6.5 Ω. Critically, applying 3.3 V to a

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Origins of cystic fibrosis lung disease.

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