Yunnan University. Kunming, China and. State Key Laboratory of Genetic Resource and. Evolution Kunming Institute of Zoology. Chinese Academy of Sciences.
Correspondence Surfactant Composition and Biophysical Properties Are Important in Clinical Studies To the Editor:
We read with interest the article by Kesecioglu and colleagues (1). This study enrolled 418 subjects with ALI/ARDS in a randomized controlled trial (RCT) of a porcine-derived surfactant (HL-10, Leo Pharmaceuticals, Ballerup, Denmark). There was no difference in 28-day mortality and a suggestion of harm in the HL-10 surfactant–treated subjects due to hypoxia (51.9%) and hypotension (34.1%) with administration. Additionally, the direct lung injury group appeared to fare worse than those with indirect injury. These results are contrary to our findings in three pediatric calfactant studies (2–4). We have consistently demonstrated improved oxygenation with calfactant administration and our recent RCT demonstrated a survival benefit (4). Transient hypoxia (12%) and brief hypotension (9%) were seen but were not associated with adverse consequences. Furthermore, posthoc analysis demonstrated that the benefit appeared primarily in the direct lung injury group. We believe the contradictory results are due to differences in the surfactants rather than differences between children and adults. HL-10 surfactant is described in the article as ‘‘a freezedried natural surfactant isolated from pig lungs’’ that is ‘‘90–95% phospholipids and 1–2% hydrophobic proteins.’’ We are unable to find any description of its biochemical composition, biophysical properties, or in vitro or animal data beyond one paper describing the effects of reconstitution with SP-A (5), making it impossible to assess possible reasons for the trial’s failure. It is unclear whether HL-10 surfactant can reestablish a functioning surfactant film where an inflammatory injury was the etiology of the surfactant dysfunction and consequent respiratory failure. The porcine surfactant Curosurf (poractant a) preparation used successfully in RDS in infants loses its biophysical activity in the presence of low levels of plasma proteins (6). If HL-10 surfactant is similar, it could be predicted from biophysical data that is unlikely to be effective in clinical ALI/ARDS. The early unsuccessful studies of surfactant therapy in neonatal RDS demonstrated the importance of surfactant composition when used in clinical trials. We appear to be recapitulating the same error in presuming the composition and biophysical characteristics of the ‘‘surfactant’’ are of minor therapeutic importance. We suggest that the disappointing results of the trial by Kesecioglu and colleagues relative to our trials may relate to the differences in the characteristics of the surfactants and would encourage their further description of the HL-10 surfactant. Conflict of Interest Statement: D.F.W. has received industry-sponsored grants from Pneuma Pharmaceuticals (more than $100,000), and Discovery Labs ($5,001–$10,000). N.J.T. has received consultancy fees from Discovery Laboratories ($1,001–$5000); he has received advisory board fees from Discovery Laboratories ($1,001–$5,000); he has received industry-sponsored grants from Discovery Laboratories ($10,001–$50,000) and Pneuma Partners ($50,001– $100,000).
DOUGLAS F. WILLSON, M.D. University of Virginia Children’s Hospital Charlottesville, Virginia NEAL J. THOMAS, M.D. Penn State Hershey Children’s Hospital Hershey, Pennsylvania
References 1. Kesecioglu J, Beale R, Stewart TE, Findlay GP, Rouby J-J, Holzapfel L, Bruins P, Steenken EJ, Jeppesen OK, Lachmann B. Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2009;180: 989–994. 2. Willson DF, Jiao JH, Bauman L, Zaritsky A, Craft H, Dockery K, Conrad D, Dalton H. Calf’s lung surfactant extract in acute hypoxemic respiratory failure in children. Crit Care Med 1996;24:1316–1322. 3. Willson DF, Zaritsky A, Bauman LA, Dockery K, James RL, Conrad D, Craft H, Novotny WE, Egan EA, Dalton H. Instillation of calf’s lung surfactant extract (infasurf) is beneficial in pediatric acute hypoxemic respiratory failure. Crit Care Med 1999;27:188–195. 4. Willson DF, Thomas NJ, Markovitz BM, Bauman LA, DeCarlo JV, Pon S, Jacobs BR, Jefferson LS, Conaway MR, Egan EA. Effect of exogenous surfactant in pediatric acute lung injury: a randomized, controlled trial. JAMA 2005;293:470–476. 5. Larsson M, van Iwaarden JF, Haitsma JJ, Lachmann B, Wollmer P. Human SP-A and a pharmacy-grade porcine lung surfactant extract can be reconstituted into tubular myelin—a comparative structural study of alveolar surfactants using cryo-transmission electron microscopy. Clin Physiol Funct Imaging 2003;23:199–202. 6. Seeger W, Grube C, Gu¨nther A, Schmidt R. Surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations. Eur Respir J 1993;6:971–977.
From the Authors:
We thank Dr. Willson and Dr. Thomas for their comments in relation to our study (1). They have highlighted the importance of surfactant composition and biophysical properties for the improvement of oxygenation and potential survival benefit in clinical ALI/ARDS. A similar situation was demonstrated by Ainsworth and colleagues in a study performed in neonates with respiratory distress syndrome (2). Mortality was lower among neonates who received poractant alfa, an animal-derived surfactant, than among those who received pumactant, a synthetic surfactant. The information related to the exact composition of the porcine-derived surfactant, HL 10, is the property of the surfactant-making company and is at this point unavailable for public disclosure. However, experiments in surfactantdeficient animal models preceding the clinical trials have shown that HL 10 was at least as effective as Curosurf, Alveofact, or Survanta (unpublished data). Moreover, the mortality between the large bolus HL10 and the usual care group started to diverge 3 weeks after beginning the trial and was consistent up to day 180 (1). Therefore, we have considered that the outcomes were related to factors other than the surfactant used or ALI/ARDS. We agree that our results were disappointing. However, we also believe (which we think the authors are alluding to) that the issue of the use of surfactant for ALI/ARDS is not dead. In fact there are many unanswered questions including the best formulation, concentration and total volume of surfactant, administration route, timing of therapy, and subset of patients most likely to benefit. Conflict of Interest Statement: J.K. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.E.S. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.J.S. has received more than $100,001 employed as the Head of Medical Department at LEO Pharma A/S. B.L. has been reimbursed by Draeger for giving talks at scientific meetings and received a research grant from Lyomark Pharma GmbH, Germany (10,000 euros) in 2009.
Correspondence
JOZEF KESECIOGLU, M.D., PH.D. Department of Intensive Care Medicine University Medical Center Utrecht, The Netherlands THOMAS E. STEWART, M.D. Department of Medicine Mount Sinai Hospital and University Health Network, University of Toronto Toronto, Canada EDMEE J. STEENKEN, M.SC. LEO Pharma A/S Ballerup, Denmark BURKHARD LACHMANN, M.D., PH.D Department of Anesthesia and Intensive Care Medicine Charite, Humboldt–University Berlin, Germany
References 1. Kesecioglu J, Beale R, Stewart TE, Findlay GP, Rouby JJ, Holzapfel L, Bruins P, Steenken EJ, Jeppesen OK, Lachmann B. Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2009;180: 989–994. 2. Ainsworth SB, Beresford MW, Milligan DW, Shaw NJ, Matthews JN, Fenton AC, Ward Platt MP. Pumactant and poractant alfa for treatment of respiratory distress syndrome in neonates born at 25–29 weeks’ gestation: a randomised trial. Lancet 2000;355:1387–1392.
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suggested by Reference (9), and the results indicated that OR1 and OR3 were significant (P , 0.005), but OR2 was not (P 5 0.35), suggesting that the genetic effect was most likely to be recessive (V/V vs. V/I 1 I/I). Under this circumstance, no correlation was observed among Asians (P 5 0.21; OR 5 1.49; 95%CI, 0.98–2.27; see Figure 1b). For the white population, we excluded the result from van Diemen and colleagues (unpublished) due to lack of detailed genotype data but included another one (10). Moreover, the genotype data from Reference (11) was provided by the author (personal communication) instead of imputed by the Hardy-Weinberg equilibrium as done by Smolonska and colleagues (1). The subsequent meta-analysis yielded a significant correlation (P 5 0.001; OR 5 1.59; 95%CI, 1.20–2.11; Figure 1b). In summary, our results suggested that GSTP1 I105V may correlate with COPD by a recessive model in a white population, but not in Asians. However, because the V/V genotype is present in human populations with very low frequency, the sample size for V/V genotype, even after combining all published literature, was still modest, which, to some extent, lowered the power of our analysis. To solidify this conclusion, it is essential to investigate the association in more populations with much larger sample sizes independently and perform further meta-analyses. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
LI ZHONG*, PH.D. YA-PING ZHANG, PH.D. Laboratory for Conservation and Utilization of Bio-resource Yunnan University Kunming, China and State Key Laboratory of Genetic Resource and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Kunming, China
The Relationship between GSTP1 I105V Polymorphism and COPD: A Reappraisal To the Editor:
In a recent issue of the Journal, Smolonska and colleagues (1) performed a meta-analysis on the relation between the glutathione S-transferase P1 (GSTP1) I105V polymorphism (rs1695) and chronic obstructive pulmonary disease (COPD [MIM 606963]) and suggested that this variation was protective in Asians but not associated with COPD in white populations. However, a careful audit indicated that their result was not accurate: the genotype count in cases and controls from References 71 and 78 (2, 3) were improperly reversed in Smolonska and colleagues’ report (1), which seriously biased the result. When this error was corrected, no correlation was observed in the Asian population (P 5 0.35; OR 5 0.82; 95%CI, 0.53–1.25). Furthermore, we genotyped this polymorphism in 325 patients with COPD and 349 healthy smokers from a Han population from Southwest China (more information on the samples can be found in Reference 4). The genotype frequencies were 65.2, 32.0, and 2.8% in patients, and 69.6, 28.1, and 2.3% in controls for I/I, I/V, and V/V, respectively, and no correlations were observed (P 5 0.223; OR 5 1.22; 95%CI, 0.89–1.69). When our result and two other genotyping efforts among Chinese (5, 6) were also incorporated in the metaanalysis, the conclusion still persisted (P 5 0.64; OR 5 0.93; 95%CI, 0.68–1.27; see Figure 1a), which was consistent with most previous studies in Asian populations (3, 7, 8). All analyses above and in Smolonska and colleagues (1) were based on the assumption that GSTP1 I105V was correlated with COPD in a dominant model, which, however, was actually ambiguous. We evaluated the pairwise odds ratio, that is, OR1 (V/V vs. I/I), OR2 (V/I vs. I/I) and OR3 (V/V vs. V/I), as
WEI-PING FU*, M.S. LU-MING DAI, PH.D. First Affiliated Hospital of Kunming Medical College Kunming, China CHANG SUN, PH.D. Chinese Academy of Sciences Kunming, China YAN-QIN WANG, M.S. Yunnan University Kunming, China * These authors contributed equally to this work.
References 1. Smolonska J, Wijmenga C, Postma DS, Boezen HM. Meta-analyses on suspected chronic obstructive pulmonary disease genes: a summary of 20 years’ research. Am J Respir Crit Care Med 2009;180: 618–631. 2. Vibhuti A, Arif E, Deepak D, Singh B, Qadar Pasha MA. Genetic polymorphisms of GSTP1 and MEPHX correlate with oxidative stress markers and lung function in COPD. Biochem Biophys Res Commun 2007;359:136–142. 3. Chan-Yeung M, Ho SP, Cheung AH, So LK, Wong PC, Chan KK, Chan JW, Ip MS, Mak JC. Polymorphisms of glutathione S-transferase genes and functional activity in smokers with or without COPD. Int J Tuberc Lung Dis 2007;11:508–514.
