RIZZO, Manfredi

SCICHILONE, Nicola Alessandro

Archivio istituzionale della ricerca - Università di Palermo

drugs, such as age, bronchodilator reversibility, and history of orcurrent tobacco use. Naturally, some criteria may be warrantedby the trial methodology to reach the primary endpoint. For example,the minimum exacerbation rate in the previous year may guaranteea sufﬁcient number of events to avoid studies being prolonged ifthe primary endpoint is the time until the ﬁrst exacerbation. Theseadministrative and ﬁnancial constraints should not, however,affect the scientiﬁc value of these studies, and the results should remainable to be extrapolated to excluded populations.Patients included in RCTs are young, are recently diagnosed,are healthy other than their asthma, have moderate to severe ratherthan very severe asthma, and have never been heavy smokers.Because current guidelines such as GINA rely on results from suchexclusive RCTs, this calls into question the extent to which theseguidelines are applicable to daily practice. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Laurie Pahus, Pharm.D.Khuder Alagha, M.D.Tu¨nde Sofalvi, M.D.Assistance Publique-Hoˆpitaux de MarseilleMarseille, FranceandAix Marseille Universite´Marseille, FranceIsabelle Vachier, Ph.D.Hoˆpital Arnaud de VilleneuveMontpellier, FranceArnaud Bourdin, M.D., Ph.D.Hoˆpital Arnaud de VilleneuveMontpellier, FranceUniversite´ de Montpellier 1, 2Montpellier, FranceandInstitut National de la Sante´ et de la Recherche Me´dicale U1046–CentreNational de Recherche Scientiﬁque Unite´ Mixte de Recherche 9214Montpellier, FranceNicolas Molinari, Ph.D.Hoˆpital la Colombie`reaMontpellier, FrancePascal Chanez, M.D., Ph.D.Assistance Publique-Hoˆpitaux de MarseilleMarseille, FranceInstitut National de la Sante´ et de la Recherche Me´dicale U1067–CentreNational de Recherche Scientiﬁque Unite´ Mixte de Recherche 7333Marseille, FranceandAix Marseille Universite´Marseille, FranceOn behalf of the COBRA consortiumReferences1. Rothwell PM. External validity of randomised controlled trials: “to whomdo the results of this trial apply?” Lancet 2005;365:82–93.2. Town I. Applying the results of randomised control trials on asthma.Thorax 2007;62:195–196.3. Costa DJ, Amouyal M, Lambert P, Ryan D, Schu¨nemann HJ, Daures JP,Bousquet J, Bousquet PJ; Languedoc-Roussillon TeachingGeneral Practitioners Group. How representative are clinical studypatients with allergic rhinitis in primary care? J Allergy Clin Immunol2011;127:920–926.4. Scichilone N, Basile M, Battaglia S, Bellia V. What proportion of chronicobstructive pulmonary disease outpatients is eligible for inclusion inrandomized clinical trials? Respiration 2014;87:11–17.5. Dowd R, Recker RR, Heaney RP. Study subjects and ordinary patients.Osteoporos Int 2000;11:533–536.6. Ha C, Ullman TA, Siegel CA, Kornbluth A. Patients enrolled inrandomized controlled trials do not represent the inﬂammatorybowel disease patient population. Clin Gastroenterol Hepatol2012;10:1002–1007.7. Global Initiative for Asthma. Global strategy for asthma management andprevention 2011 [accessed 2014 Aug 18]. Available from: http://www.ginasthma.org/guidelines-gina-report-global-strategy-for-asthma.html8. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Developmentand validation of a questionnaire to measure asthma control. EurRespir J 1999;14:902–907.Copyright © 2015 by the American Thoracic SocietyA Potential Link between Serum Low-DensityLipoproteins and AsthmaTo the Editor:We read with great interest the article by Barochia and colleaguesabout the relationship between serum lipid and apolipoproteinlevels and asthma (1). As highlighted by the authors, althoughapolipoproteins and lipoproteins are important modulators ofinﬂammation, varying relationships exist between these parametersand asthma (2), and the data are still not conclusive. Indeed, it isstill not fully clear which lipoproteins are more strictly associatedwith asthma development and progression (severity).Barochia and colleagues report a positive correlation betweenFEV1% predicted and high-density lipoprotein (HDL)-cholesterolor apolipoprotein A-I in atopic asthma, and they also suggest thatthis correlation may be largely mediated by the subfraction oflarge HDL particles. This ﬁnding seems to complement what weTable 1. Ranking of the Most Discriminating Criteria Used inRandomized Controlled Severe Asthma TrialsCriterionPatients Excluded Because ofthe Criterion (%)Reversibility 73Exacerbation rate 58Absence of oralcorticosteroid treatment50No ICU admission history 31Maximum FEV1 24Minimum FEV1 23Smoking status 23Age 10BMI/weight 3Comorbidities 2Definition of abbreviations: BMI = body mass index; ICU = intensive careunit.Percentages are out of the total number of patients in the COBRA (CohorteObstruction Bronchique et Asthme) cohort.CORRESPONDENCECorrespondence 261reported in 2013 in another study on the association betweenasthma and low-density lipoprotein (LDL) subclasses (3): Wefound a positive correlation between FEV1% predicted and largerLDL particles (LDL-1), as well as negative correlation betweenFEV1% predicted and smaller, more dense LDL particles (LDL-3).In that study, we hypothesized that LDL could represent a potenttrigger for the inﬂammatory changes of the airways. It wassomewhat surprising that the Barochia and colleagues did notmention our study, as it still represents the only study that hasassessed the full spectrum of all seven LDL subclasses in asthma.As highlighted by the European Panel on LDL Subclasses(4), the methodology used for assessing lipoprotein subclasses iscrucial. In the present study, Barochia and colleagues used nuclearmagnetic resonance spectroscopy to assess the lipoprotein particles;yet with this methodology, they were able to assess only a fewsubclasses with low resolution (e.g., three very-low-densitylipoprotein subclasses [large, medium, and small very-low-densitylipoprotein], two LDL subclasses [large and small LDL], and threeHDL subclasses [large, medium, and small HDL]). Methodologiesare available to assess lipoprotein subfractions with a higher degreeof resolution, and in our study, we used a methodology of gelelectrophoresis (Lipoprint; Quantimetrix Corporation, RedondoBeach, CA) that is able to distinguish seven LDL subclasses (3) aswell as 10 HDL subclasses (5).Of interest, in our study (3), we reported that asthma wasassociated with smaller LDL particles, which are proinﬂammatoryparticles (6), and in the present study, Barochia and colleaguesreported that asthma was associated with larger HDL particles,which seem to be dysfunctional HDLs with proinﬂammatoryproperties (7). We therefore believe that the ﬁndings of the twostudies support the concept that small LDLs could lead to theampliﬁcation of the inﬂammatory cascade in asthma, and weadvocate for larger studies speciﬁcally designed to conﬁrm theassociation between asthma and dyslipidemia and to elucidate theunderlying mechanisms. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Nicola Scichilone, M.D.Manfredi Rizzo, M.D.University of PalermoPalermo, ItalyandIstituto Euro-Mediterraneo di Scienza e TecnologiaPalermo, ItalyReferences1. Barochia AV, Kaler M, Cuento RA, Gordon EM, Weir NA, Sampson M,Fontana JR, MacDonald S, Moss J, Manganiello V, et al. Serumapolipoprotein A-I and large high-density lipoprotein particles arepositively correlated with FEV1 in atopic asthma. Am J Respir Crit CareMed 2015;191:990–1000.2. Gowdy KM, Fessler MB. Emerging roles for cholesterol and lipoproteinsin lung disease. Pulm Pharmacol Ther 2013;26:430–437.3. Scichilone N, Rizzo M, Benfante A, Catania R, Giglio RV, Nikolic D,Montalto G, Bellia V. Serum low density lipoprotein subclasses inasthma. Respir Med 2013;107:1866–1872.4. Mikhailidis DP, Elisaf M, Rizzo M, Berneis K, Grifﬁn B, Zambon A,Athyros V, de Graaf J, Ma¨rz W, Parhofer KG, et al. “European panelon low density lipoprotein (LDL) subclasses”: a statement on thepathophysiology, atherogenicity and clinical signiﬁcance of LDLsubclasses. Curr Vasc Pharmacol 2011;9:533–571.5. Fendler W, Rizzo M, Borowiec M, Malachowska B, Antosik K,Szadkowska A, Banach M, Urbanska-Kosinska M, Szopa M, MaleckiM, et al. Less but better: cardioprotective lipid proﬁle of patients withGCK-MODY despite lower HDL cholesterol level. Acta Diabetol 2014;51:625–632.6. Norata GD, Raselli S, Grigore L, Garlaschelli K, Vianello D, Bertocco S,Zambon A, Catapano AL. Small dense LDL and VLDL predict commoncarotid artery IMT and elicit an inﬂammatory response in peripheralblood mononuclear and endothelial cells. Atherosclerosis 2009;206:556–562.7. Rizzo M, Otvos J, Nikolic D, Montalto G, Toth PP, Banach M.Subfractions and subpopulations of HDL: an update. Curr Med Chem2014;21:2881–2891.Copyright © 2015 by the American Thoracic SocietyReplyFrom the Authors:We thank Drs. Scichilone and Rizzo for bringing to our attentiontheir study investigating the association between lung function inpatients with asthma and subclasses of low-density lipoproteins(LDLs), as measured by gel electrophoresis (1). In particular, theﬁnding that the LDL-3 subclass is negatively correlated with FEV1after adjusting for differences in age, sex, and body mass index isintriguing. We believe their result is consistent with the negativeassociation we found between percentage predicted FEV1 andsubgroups of LDL particles, as measured by nuclear magneticresonance (NMR) spectroscopy in atopic patients with asthma.We respectfully point out that we did not report an associationbetween asthma and large high-density lipoprotein (HDL) particlesbut, rather, a positive association between FEV1% predicted andthe concentration of large HDLNMR particles in patients withasthma (2). Thus, we postulate that large HDLNMR particles maymodulate the severity of airﬂow obstruction in atopic patientswith asthma.The study of the signiﬁcance of lipoproteins in asthma is in itsearly stages yet. We agree with Drs. Scichilone and Rizzo thatadditional studies investigating the composition and function ofsubclasses of lipoprotein molecules, and the various methods used tomeasure them, will be necessary to better characterize the preciseroles they may be playing in the pathogenesis of asthma. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Amisha V. Barochia, M.B. B.S.Stewart J. Levine, M.D.National Institutes of HealthBethesda, MarylandReferences1. Scichilone N, Rizzo M, Benfante A, Catania R, Giglio RV, Nikolic D,Montalto G, Bellia V. Serum low density lipoprotein subclasses inasthma. Respir Med 2013;107:1866–1872.2. Barochia AV, Kaler M, Cuento RA, Gordon EM, Weir NA, Sampson M,Fontana JR, MacDonald S, Moss J, Manganiello V, et al. SerumCORRESPONDENCE262 American Journal of Respiratory and Critical Care Medicine Volume 192 Number 2 | July 15 2015

A Potential Link between Serum Low-Density Lipoproteins and Asthma

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