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ADAM33 and asthma statistical association is not revealed in ...... a particular population irrespective of Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from size does not necessarily mean that the in question is not contributing to Is big beautiful? The continuing story of the phenotype, but the mode of its influence may be complex involving ADAM33 and asthma gene-gene or gene-environmental inter- actions.14 However, as the number of S T Holgate, J W Holloway independent studies increases, it would be valuable to accrue the evidence ...... systematically as was reported for link- age analysis for asthma on Role of ADAM33 in the development and progression of asthma 5 (the Consortium on Asthma Genetics).15 With the recent establish- ment of the Network of Excellence for he gene encoding A And asthma in four unique asthma popula- Asthma and Allergy (GA2LEN), there is Metalloprotease (ADAM) 33 was tions comprising African American, US a unique opportunity to further develop the first asthma susceptibility gene white, US Hispanic, and Dutch white T 1 meta-analyses for candidates such as to be discovered by positional cloning. populations. Significant associations ADAM33. The study by Blakey et al is an In 460 families enriched with asthma, with at least one SNP and asthma were excellent example of the power of this linkage analysis using microsatellite found in each of the populations approach. markers spaced ,9 cM apart revealed (p = 0.0009–0.04) with multiple SNPs At present the SNPs that cause the a region on chromosome 20p13 that associating with asthma or its partial dysfunction in ADAM33 predisposing to carried one or more asthma , phenotypes in some of the populations. asthma are not yet clear, although achieving a Maximum Lod Score Further replication has been reported in several SNPs (T1, F+1 and ST+7) are (MLS) of 2.24 at 9.99 cM. The addition separate case-control and family based coming through in a number of differ- of further markers at 1.2 cM increased association studies in Germany,4 Korea,5 6 ent studies as being associated with the MLS to 2.94 at 12.1 cM which and Japan. However, there are two asthma. However, because of the very further rose to 3.93 when bronchial published studies showing no evidence 7 8 large degree of linkage disequilibrium hyperresponsiveness was included in of association or weak association. between many SNPs in ADAM33 so far the definition of asthma despite halving It is therefore timely that, in this issue identified (possibly in excess of 100), the sample size, thereby exceeding the of Thorax, Blakey and colleagues report genetics alone is unlikely to cast much threshold for genome wide significance. the result of a meta-analysis involving further light on the disease related Physical mapping, direct cDNA selec- eight separate populations totalling variants although new analytical meth- tion, and sequencing of DNA cloned into 1299 cases and 1665 controls used in odologies are being developed.16 Some bacterial artificial (BACs) case-control association analysis and clues about how ADAM33 may influ- identified 25 candidate genes. Linkage 4561 families used in transmission ence the asthma phenotype are emer- 9 http://thorax.bmj.com/ disequilibrium mapping of single disequilibrium tests (TDTs). In both ging. In 200 Dutch patients with asthma nucleotide polymorphisms (SNPs) on types of analysis several SNPs were who had regular lung function measure- 23 genes spanning the peak of linkage significantly associated with asthma. ments made over 20 years, the rare together with case-control and family The important point the authors made alleles of the SNPs S-2, T-1 and T-2 of based association analyses revealed that is that, based on allele frequencies for the ADAM33 gene were associated with a ADAM33 accounted for the linkage the ST+7 G allele of 84.9% in the significant excess decline in baseline signal. asthmatic population and 79.1% in the forced expiratory volume in 1 second Several features of this initial report controls and an asthma prevalence of 17 (FEV1) of 23.7–30 ml/year. These data raised questions regarding the generali- 8%, this SNP would potentially contri- imply a role for ADAM33 in airway wall on September 26, 2021 by guest. Protected copyright. sability of the results.2 Firstly, although bute to ,50 000 excess asthma cases in remodelling which is known to contri- significant evidence for linkage was the UK population. bute to chronic airflow obstruction in observed, this region on chromosome What is important to point out is that moderate to severe asthma.18 A second 20p had not been identified in previous most case-control and family based study conducted in infants born of genome wide screens in asthma. association studies looking for disease allergic/asthmatic parents in Northern Secondly, the initial publication did related genes in complex disorders are England (NACMAAS) has revealed posi- not have a truly independent replication statistically underpowered and that far tive associations between SNPs of sample. Thirdly, no single SNP demon- larger sample sizes are needed. Part of ADAM33 and increased airway resis- strated significant association in both the reason for this is the existence of tance measured by plethysmography at the UK and US populations that made genetic heterogeneity with any one gene age 3 and again at age 5 years, with the up the total sample when these were varying in its influence over a disease strongest effect seen in the homo- analysed separately. Finally, no func- phenotype between populations with zygotes.19 20 These data support the idea tional data regarding the role of asso- differing genetic backgrounds and dif- that alterations in the expression or ciated SNPs in alteration of gene fering environmental exposures.10 11 For function of ADAM33 is in some way expression and/or function and in the example, natural selection may have involved in impairing lung function in development of asthma phenotypes acted on a disease gene haplotype early life and, as a consequence, increas- were presented. differentially in different populations ing the risk of asthma developing. Since 2002 there have been a number as recently described for the IL-4 The initial study1 as well as others35 of separate replication studies in diverse on chromosome 5q31–34.12 Another have revealed some of the strongest ethnic populations. The first by Howard example is the NOD2/CARD 15 gene associations when bronchial hyperre- et al3 examined eight SNPs in the 39 on chromosome 16 which has been sponsiveness (BHR) is incorporated into portion of ADAM33 reported in the associated with Crohn’s disease in some the asthma phenotype. The cellular original study to be associated with but not all populations.13 Because a provenance of ADAM33 mRNA and

www.thoraxjnl.com 264 EDITORIAL protein in being restricted to mesen- future challenge. We are now entering 11 Ioannidis JP, Ntzani EE, Trikalinos TA, et al.

Replication validity of genetic association studies. Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from chymal cell types (fibroblasts, myofibro- the new research era of translational Nat Genet 2001;29:306–9. blasts and smooth muscle) reinforces science and the rebirth of experimental 12 Sakagami T, Witherspoon DJ, Nakajima T, et al. the view that this molecule is involved medicine as a research focus.29 Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci. Genes in the pathophysiology of BHR and Thorax 2005;60:263–264. Immun 2004;5:389–97. airway remodelling rather than the doi: 10.1136/thx.2004.031385 13 Arnott ID, Nimmo ER, Drummond HE, et al. immunological or inflammatory compo- NOD2/CARD15, TLR4 and CD14 mutations in 121 Scottish and Irish Crohn’s disease patients: nents of asthma. Expression of full ...... evidence for genetic heterogeneity within Europe? length ADAM33 in mammalian cell Authors’ affiliations Genes Immun 2004;5:417–25. lines has shown that the metallopro- S T Holgate, J W Holloway, Allergy and 14 Vercelli D. Genetics, epigenetics, and the environment: switching, buffering, releasing. tease domain of ADAM33 is func- Inflammation Research, Division of Infection, J Allergy Clin Immunol 2004;113:381–6. 22 23 tional but the biological targets of Inflammation and Repair, School of Medicine, 15 Lonjou C, Barnes K, Chen H, et al. A first trial of the metalloprotease activity are as yet Southampton General Hospital, Southampton retrospective collaboration for positional cloning unknown. In cell based sheddase assays SO16 6YD, UK in complex inheritance: assay of the cytokine J W Holloway, Division of Human Genetics, region on chromosome 5 by the Consortium on ADAM33 functioned as a negative reg- Asthma Genetics (COAG). Proc Natl Acad Sci ulator of b-amyloid precursor peptide School of Medicine, Southampton General USA 2000;97:10942–7. (APP) cleavage and mediated some Hospital, Southampton SO16 6YD, UK 16 Bureau A, Dupuis J, Falls K, et al. Identifying SNPs predictive of phenotype using random constitutive shedding of stem cell factor forests. Genet Epidemiol 2005;28:171–82. (SCF, ckit ligand); however, the kinetics Correspondence to: Professor S T Holgate, 17 Jongepier H, Boezen HM, Dijkstra A, et al. Allergy and Inflammation Research, MP810, of these cleavage reactions would indi- Polymorphisms of the ADAM33 gene are Level D, Centre Block, Southampton General associated with accelerated lung function decline cate that these two proteins are not the Hospital, Southampton SO16 6YD, UK; sth@ in asthma. Clin Exp Allergy 2004;34:757–60. natural substrates.23 soton.ac.uk 18 Bel EH. Clinical phenotypes of asthma. Curr Opin Six alternatively spliced variants of Pulm Med 2004;10:44–50. 19 John S, Jury FAC, Holloway J, et al. ADAM33 ADAM33 in airway fibroblasts have polymorphisms predict early-life lung function: a recently been described including one REFERENCES population based cohort study. Am J Hum Genet putative secreted variant.24 Ninety per- 2003;73:209. 1 Van Eerdewegh P, Little RD, Dupuis J, et al. 20 Simpson A, Jury F, Cakebread J, et al. cent of ADAM33 mRNA is retained in Association of the ADAM-33 gene with asthma Manchester Asthma and Allergy Study: the nucleus and subtle differences in the and bronchial hyper-responsiveness. Nature polymorphisms in ADAM 33 predict lung function 2002;418:426–30. composition of nuclear and cytoplasmic at age 5 years. J Allergy Clin Immunol 2 Weiss ST, Raby BA. Asthma genetics 2003. Hum 2004;113:S340. mRNA indicate important events in Mol Genet 2004;13:R83–9. 21 Umland SP, Garlisi CG, Shah H, et al. Human both splicing and selecting of ADAM33 3 Howard TD, Postma DS, Jongepier H, et al. ADAM33 messenger RNA expression profile and transcripts for processing into proteins. Association of a disintegrin and metalloprotease post-transcriptional regulation. Am J Respir Cell 33 (ADAM33) gene with asthma in ethnically Mol Biol 2003;29:571–82. What is of great interest is that none of diverse populations. J Allergy Clin Immunol 22 Garlisi CG, Zou J, Devito KE, et al. Human the six variants contain the metallopro- 2003;112:717–22. ADAM33: protein maturation and localization. tease catalytic domain, suggesting pos- 4 Werner M, Herbon N, Gohlke H, et al. Asthma Biochem Biophys Res Commun 2003;301:35–43. is associated with single-nucleotide 23 Zou J, Zhu F, Liu J, et al. Catalytic activity of sible other key functions of the polymorphisms in ADAM 33. Clin Exp Allergy human ADAM33. J Biol Chem 2004;279:9818–30. molecule—for example, in cell fusion 2004;34:26–31. http://thorax.bmj.com/ and adhesion.25 5 Lee J-H, Park H-S, Park SW, et al. ADAM33 24 Powell RM, Wicks J, Holloway JW, et al. The polymorphism: association with bronchial hyper- splicing and fate of ADAM33 transcripts in There is still much to find out about responsiveness in Korean asthmatics. Clin Exp primary human airways fibroblasts. Am J Respir this fascinating and complex molecule Allergy 2004;34:860–5. Cell Mol Biol 2004;31:13–21. in relation to the development and 6 Sakagami T, Hasegawa T, Yoshizawa H, et al. 25 Cakebread JA, Haitchi HM, Holloway JW, et al. The role of ADAM33 in the pathogenesis of progression of asthma. Added to it are ADAM 33 polymorphisms are associated with aspirin intolerant asthma in Japanese population. asthma. Springer Semin Immunopathol three further new asthma/allergy genes Am J Respir Crit Care Med 2003;167:A750. 2004;25:361–75. identified by positional cloning: PDH 7 Lind DL, Choudhry S, Ung N, et al. ADAM33 is 26 Zhang Y, Leaves NI, Anderson GG, et al. Positional cloning of a quantitative trait locus on Finger Protein II (PHF11) on chromo- not associated with asthma in Puerto Rican or Mexican populations. Am J Respir Crit Care Med chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet on September 26, 2021 by guest. Protected copyright. some 13q14 which encodes NY-REN-34, 2003;168:1312–6. 2003;34:181–6. a protein first described in patients with 8 Raby BA, Silverman EK, Kwiatkowski DJ, et al. 27 Allen M, Heinzmann A, Noguchi E, et al. 26 ADAM33 polymorphisms and phenotype renal cell carcinoma; dipeptidyl dipti- Positional cloning of a novel gene influencing 27 associations in childhood asthma. J Allergy Clin dase 10 (DDP10) on chromosome 2q14; asthma from chromosome 2q14. Nat Genet Immunol 2004;113:1071–8. and G protein-coupled receptor for 2003;35:258–63. 9 Blakey J, Halapi E, Bjornsdottir US, et al. 28 Laitinen T, Polvi A, Rydman P, et al. asthma susceptibility (GPRA) on chro- Contribution of ADAM 33 polymorphisms to the Characterization of a common susceptibility locus mosome 7p.28 For each of these genes, as population risk of asthma. Thorax for asthma-related traits. Science for ADAM 33, determining normal 2005;60:274–6. 2004;304:300–4. 10 Cookson W. A new gene for asthma: would you 29 Wills-Karp M, Ewart SL. Time to draw breath: functions and how these are disordered ADAM and Eve it? Trends Genet asthma-susceptibility genes are identified. Nat in asthma related alleles is the real 2003;19:169–72. Rev Genet 2004;5:376–87.

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NO, hypoxia, and superoxide Interestingly, the effect of hypoxia on ...... NO levels in the airway is primarily a Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from result of airway and alveolar oxygen tension rather than vascular oxygen Nitric oxide, hypoxia, and superoxide: tension.18 19 One proposed mechan- ism(s) for oxygen regulation of NOS the good, the bad, and the ugly! activity is outlined in fig 1. NOS activity during the steady state includes an R A Dweik active cycle (A) that generates NO and an inactive cycle (B) that involves ...... formation and decay of a heme-NO complex. In the active cycle, oxygen A possible role for NO in ARDS binding to ferrous heme (Fe2+) is limit- ing for activity. In contrast, itric oxide (NO) is endogenously cytokines, endotoxin, or reactive oxygen resolution of the inactive cycle and entry synthesised by nitric oxide species, it is continuously expressed in into the active cycle is oxygen-depen- synthases (NOS) which convert normal human airway epithelium at dent due to effects on the stability of the N 816 L-arginine to L-citrulline and NO. Three basal airway conditions. heme-NO complex. This includes a NOS isoforms (types I, II and III) have Once produced, NO is freely diffusible reaction between the heme-NO complex been identified and all of them are and enters target cells activating soluble and oxygen which results in loss of the 17 expressed in the human lung.1–8 NOS I guanylate cyclase to produce guanosine heme-NO complex (fig 1). (nNOS) and III (eNOS) are constitu- 39,59-cyclic monophosphate (cGMP) The oxygen concentration in intact 41720 tively expressed in tissues and are which mediates most of the physiologi- tissues ranges from 1 to 150 mM, dependent on increases in intracellular cal effects of NO on smooth muscle with the highest levels found in the calcium for enzyme activation while including vasodilation and broncho- lung. Airway epithelial cells are unique NOS II (iNOS) is an inducible form that dilation.211 NO reaction products may in their exposure to oxygen since, above is calcium independent (table 1).9 All also mediate other physiological and a thin layer of epithelial lining fluid, the NOS isoforms require oxygen, NADPH, pathological functions in the lungs and airway cells are exposed directly to air FAD, FMN, tetrahydrobiopterin, and many other organ systems. Due to the containing 21% oxygen. Based on oxy- gen solubility and the low differential calmodulin for activity.19 NO is recog- high reactivity, NO participates in a oxygen gradient between overlying fluid nised to have a key role in virtually all wide variety of reactions at different to intracellular endoplasmic reticulum aspects of lung biology and has been sites within the cell, lung tissue, extra- (1–2 mM),4 the levels of oxygen in implicated in the pathophysiology of cellular fluids, and intravascular com- airway epithelial cells may actually lung diseases.1 4 6 10–15 It is involved in partments. Primary reactions that may approach 260 mM. Thus, the Michaelis pulmonary neurotransmission, host involve NO intracellularly and extracel- constant (K O ) determined for NOS II defence and bacteriostasis, airway and lularly include its reaction with oxygen, M 2 superoxide, haemoglobin, another (135 mM), but not NOS III (4 mM) or vascular smooth muscle relaxation, pul- http://thorax.bmj.com/ molecule of NO, containing NOS I (400 mM), is well within the monary capillary leak, inflammation, physiological range of oxygen concen- mucociliary clearance, airway mucus iron-sulfur centres, heme-containing 12 trations in lung epithelial cells. Impor- secretion, and cytotoxicity.4614 proteins, and thiol proteins. Notably, tantly, KMO2 for NO synthesis in the Cellular sources of NO in the lung NO undergoes a direct bimolecular reaction with superoxide (O 2) yielding intact human lung (190 mM) is similar include epithelial cells, endothelial cells 2 3421 peroxynitrite (ONOO2) at a rate that is to NOS II KMO2 in vitro. of pulmonary arteries and veins, inhibi- 2 even faster than the dismutation of O2 tory non-adrenergic non-cholinergic REGULATION OF NOS GENE neurones, smooth muscle cells, mast by superoxide dismutases (SOD), which

EXPRESSION BY OXYGEN on September 26, 2021 by guest. Protected copyright. cells, mesothelial cells, fibroblasts, puts NO at the epicentre of oxidative metabolism and inflammation. The immediate effects of short term neutrophils, lymphocytes, and macro- changes in oxygen concentration on the phages.4614 Specifically, NOS I is located in inhibitory non-adrenergic REGULATION OF NO SYNTHESIS Abbreviations: ARDS, acute respiratory non-cholinergic neurones in the lung BY OXYGEN distress syndrome; FAD, flavin adenine while NOS III is found in endothelial All NOS isoforms require the presence dinucleotide; FMN, flavin mononucleotide; cells and the brush border of ciliated of oxygen for activity.9 Although it is KMO2, Michaelis constant; NADPH, reduced epithelial cells.157 NOS II is found in recognised that oxygen is a substrate for nicotinamide-adenine dinucleotide phosphate; NO, nitric oxide; NOS, nitric oxide synthase; the epithelial cells of the airway. NOS, its effects on the regulation of 2 2 O2 , superoxide; ONOO , peroxynitrite; Although NOS II may be induced in NOS activity are more complex than a ROS, reactive oxygen species; SOD, several types of cells in response to simple enzyme-substrate interaction.417 superoxide dismutases

Table 1 Nitric oxide synthase enzymes

Numerical NOS isoforms designation Other designation Expression Regulation NO output Chromosome

Type I 1 nNOS Constitutive Calcium/CaM Low (picomol) 12 Type II 2 iNOS Inducible Induced by cytokines, High (nanomol) 17 endotoxin, and oxidants Type III 3 eNOS Constitutive Calcium/CaM Low (picomol) 7

NO, nitric oxide; NOS, nitric oxide synthase; nNOS, neural nitric oxide synthase; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase; CaM, calmodulin.

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measured the formation of superoxide Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from B by ferricytochrome c reduction. They also measured the expression of pro- _ teins by Western blotting and immuno- NO3 O2 cytochemistry. The absence of oxygen in the ambient air promoted the forma- _ e NO tion of superoxide in the studied NOS-Fe3+ NOS-Fe2+ NOS-Fe2+-NO tissues and cells. Various enzyme inhi- bitors were used to determine the source of superoxide production. They also Arginine pre-incubated the cells with several inflammatory mediators to determine O2 A if they could enhance the effects of hypoxia. A summary of the findings is that hypoxia upregulates NADPH oxi- dase and NOS III resulting in increased Citrulline + NO production of superoxide, NO, and peroxynitrite in their system. Figure 1 Simplified proposed mechanism of oxygen regulation of NOS enzyme kinetics. NOS A major component missing in the activity during the steady state includes an active cycle (A) that generates NO and an inactive cycle model studied by Muzaffar and collea- (B) that involves formation and decay of a heme-NO complex. In the active cycle, oxygen binding to gues is the role of NOS II. In humans ferrous heme (Fe2+) is limiting for enzyme activity. In contrast, resolution of the inactive cycle and entry into the active cycle is oxygen-dependent due to effects on the heme-NO complex stability. NOS II is continuously expressed in the This includes a reaction between the heme-NO complex and oxygen, which results in loss of the airway epithelium, is a major source of heme-NO complex. NO in the lung, and appears to be the most responsive to hypoxia in the physiological range.2321 Due to the free activity of NOS enzymes are probably expression and NOS activity in rat diffusion of NO and the close apposition due to the effects of oxygen on NOS carotid bodies.27 28 of airways to pulmonary vessels, endo- enzyme kinetics. However, prolonged In this issue of Thorax, Muzaffar et al genous NO production in the airways hypoxia can have significant effects on describe the effect of hypoxia on the can have significant effects on the the gene expression of the different NOS expression of endothelial nitric oxide pulmonary vessels. The authors com- 2321–23 phox isoforms. These transcriptional synthase (NOS III) and gp91 (the ment on both eNOS (NOS III) and iNOS effects may vary among species or active catalytic subunit of NADPH oxi- (NOS II) throughout the paper, but among organ systems in the same dase), and the formation of superoxide their system does not seem to be 2321 species. For example, while hypoxia in pig pulmonary artery segments, appropriate for the study of NOS II produces a progressive decline in con- pulmonary artery smooth muscle cells, which is mainly expressed in the airway stitutive NOS mRNA levels in bovine and pulmonary artery endothelial cells. epithelium (which the authors did not

22–24 http://thorax.bmj.com/ pulmonary artery endothelial cells, They incubated pulmonary artery seg- study) and not in the endothelium or chronic hypoxia upregulates constitu- ments (with and without intact smooth muscle (reported here). The tive NOS expression in rabbit heart25 endothelium) and cells (endothelial cells they studied do not express and rat lung pulmonary arteries.26 and smooth muscle cells) in the absence NOS II in detectable levels at baseline Chronic hypoxia also increases NOS of ambient oxygen for 2 hours and and that does not change with hypoxia. So, the additional use of NOS II inhibi- tors does not add much. While the authors emphasise the relevance of their Tyr-NO 2 findings to acute respiratory distress NOS on September 26, 2021 by guest. Protected copyright. syndrome (ARDS), the link is rather speculative. They studied healthy piglets + - and evaluated their pulmonary artery ONOOCO2 CO rings or cells in isolation from the rest NO 2 of the lung. Although they used pre- incubation with some inflammatory markers as a suggestion as to what ONOO - - Hypoxia NO3 happens in ARDS, it would have been more appropriate to study rings from .- piglets with and without ARDS. The O 2 weak link to ARDS, however, does not + + H H diminish the relevance of the findings. ONOOH + NO-SUPEROXIDE INTERACTION Free radicals/reactive oxygen species NADPH oxidase Mitochondria (ROS) may be toxic in two ways. They Xanthine oxidase can interact with metal or organic redox centres and promote irreversible oxida- Figure 2 Simplified proposed model of NO reaction with superoxide (O2). NO undergoes a 2 2 tion reactions inactivating the target direct bimolecular reaction with O2 yielding peroxynitrite (ONOO ) at almost diffusion limited metabolic process, or they can initiate rates (k = 6.7 – 19 6 109/M/s ). The rate constant is over 3.5 times faster than the dismutation of 2 2 reactions which then become self-sus- O2 by superoxide dismutases. By rapidly consuming superoxide, NO produces ONOO / ONOOH, a far less reactive oxidant than superoxide that can be further metabolised to innocuous taining through the generation of pro- 2 products like NO3 . Tyr-NO2, nitrotyrosine. pagating radicals. In either case, this can

www.thoraxjnl.com EDITORIAL 267 result in deleterious effects on the cell. oxidative stress and/or hypoxia have a 15 Ozkan M, Dweik RA. Nitric oxide and airway

reactivity. Clin Pulmon Med 2001;8:199–206. Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from The most effective protection against role. 16 Guo FH, De Raeve HR, Rice TW, et al. Continuous oxidant mediated tissue damage is to Thorax 2005;60:265–267. nitric oxide synthesis by inducible nitric oxide scavenge the initiating radical.15 29 synthase in normal human airway epithelium in doi: 10.1136/thx.2004.038471 vivo. Proc Natl Acad Sci USA 1995;92:7809–13. Although NO is itself a radical, many 17 Abu-Soud HM, Rousseau DL, Stuehr DJ. Nitric of the same chemical and physical Correspondence to: Dr R A Dweik, Department oxide binding to the heme of neuronal nitric- properties of NO that allow it to exert of Pulmonary, Allergy, and Critical Care oxide synthase links its activity to changes in Medicine, The Cleveland Clinic Foundation, oxygen tension. J Biol Chem 1996;271:32515–8. oxidant effects can also result in anti- 9500 Euclid Avenue/A90, Cleveland, Ohio 18 Ide H, Nakano H, Ogasa T, et al. Regulation of oxidant actions. The role of NO as an 44195, USA; [email protected] pulmonary circulation by alveolar oxygen tension oxidant or an antioxidant probably via airway nitric oxide. J Appl Physiol Dr Dweik is supported by the National Institutes 1999;87:1629–36. depends on the local tissue milieu. In of Health grant NIH-HL68863. 19 Grimminger F, Spriestersbach R, Weissmann N, an environment where the oxidant load et al. Nitric oxide generation and hypoxic is low, the highly reactive properties of vasoconstriction in buffer-perfused rabbit lungs. REFERENCES J Appl Physiol 1995;78:1509–15. NO give the molecule oxidant proper- 20 Vanderkooi JM, Erecinska M, Silver IA. Oxygen ties. However, in situations where the 1 Dweik RA, Laskowski D, Ozkan M, et al. 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to 6 months. This wide range of patient

Early diagnosis of lung cancer Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from ...... delay times is likely to be a result of many factors, including socioeconomic, cultural and health care differences. The Symptoms and the early diagnosis of reasons why patients did not interpret their symptoms as serious or seek lung cancer medical attention sooner are not reported by Corner et al and need further S S Birring, M D Peake investigation. The most plausible expla- nation for this is that, while reported ...... symptoms were new, they were too non- Significant delays remain in the diagnosis of lung cancer specific—especially in the context of co- existing respiratory disease—to raise alarm. A limitation of the data reported ung cancer is the leading cause of persistent and occur in those at higher by Corner et al is that there is no cancer death in the western world, risk of lung cancer—for example, smo- objective validation of the presence and resulting in nearly 30 000 deaths in kers and ex-smokers, especially those timing of symptoms reported before the L 1 England and Wales in 2002. Advances over the age of 50 and with chronic first consultation with the GP. Patients, in the management of breast, cervical, airflow obstruction. Unfortunately, with hindsight of the diagnosis, may and prostate cancer have led to symptoms of lung cancer are largely look for explanations and re-examine improved survival rates, whereas mor- non-specific and recognition of new past events which we recognise in other tality from lung cancer has remained symptoms is more difficult in the pre- clinical situations are often false. 2 largely unchanged. Even the best sence of co-existing respiratory disease Prospective studies of the specificity reported 5 year survival rates for lung such as chronic obstructive pulmonary and predictive value of reported symp- 34 cancer are only 10–15% and, in disease. In addition, the evidence base toms for the diagnosis of lung cancer England, in patients diagnosed between for these guidelines (and the forthcom- and their prevalence in high risk indivi- 1993 and 1995 the survival rate was only ing updated NICE version) is weak and duals would be required to answer these 5 5.5% at 5 years and 22% at 1 year. contains no data on the predictive value questions, although such studies are This high mortality is very largely a of symptoms or symptom complexes for complex, expensive, and long term. consequence of patients presenting late the presence or absence of lung cancer Other factors that may contribute to when the cancer is already locally in a primary care based population. patient delays in diagnosis include advanced or has disseminated. Around In this issue of Thorax Corner and denial, fear, guilt, other psychosocial 80% of patients with lung cancer have colleagues present the findings of an issues, poor public health education, stage III or IV disease at presentation, exploratory retrospective interview and issues relating to access to health therefore excluding them from poten- study commissioned by the Depart- care. The fact that the patients in this tially curative surgical resection.6 ment of Health’s policy research pro- study did not interpret the early changes

Detection of the tumour at an earlier gramme investigating patient delays in http://thorax.bmj.com/ as potentially serious may also mean stage leads to an improved prognosis, cancer diagnosis.12 Detailed interviews that they were reluctant to bother their patients presenting with stage IA non- were carried out in 22 patients after GPs with what they considered ‘‘trivial’’ small cell lung cancer and undergoing diagnosis but before treatment to obtain complaints. Bowen et al14 studied factors surgical resection having a 5 year survi- a pre-diagnosis symptom history. This influencing patient delays and found val of around 60%.7 history was compared with primary care that male patients had longer delays, Patients can (and usually do) live and hospital records. Cough and dys- over half of all patients needed encour- with lung cancer for many years before pnoea were found to be the most it becomes apparent. Early lung cancer common symptoms among a wide range agement from family or friends to see is largely asymptomatic and internalisa- reported. All patients experienced at their GP, and 75% were not aware of the on September 26, 2021 by guest. Protected copyright. tion of tumours means patients are not least one new symptom before diagno- significance of their symptoms and had alerted by obvious physical changes. It sis. Although the symptoms were not received any advice about them. takes around 8 years for a squamous cell reported as a persistent change in health Future studies also need to explore how carcinoma, for example, to reach a size status, they were not interpreted as patients respond to changes in health of 30 mm when it is most commonly being serious at their onset. The median status, why patients with lung cancer diagnosed so, by the time symptoms interval from the initial change in appear to have such relatively little arise, the risk of metastasis is consider- health status and the symptom prompt- contact with their GP, and whether able.89 Once symptoms appear they are ing the first visit to the general practi- improved public awareness of lung often ignored by patients, delaying the tioner was found to be 7 months, with a cancer symptoms and easier access to a diagnosis and treatment even further. further average delay of 5 months to wider variety of sources of healthcare The reasons for patient delay in diag- diagnosis. Interestingly, there were no advice could contribute to achieving nosis are poorly understood. significant differences in delays to diag- earlier diagnosis with a consequent Lung cancer can present with a wide nosis according to operability of the improvement in survival. range of symptoms, the most common tumour. Attempts should be made to develop being cough, haemoptysis, chest and The findings of the study by Corner et public health education programmes shoulder pain, dyspnoea, hoarseness, al, although preliminary, are of interest promoting awareness of lung cancer, a weight loss, anorexia, fever, weakness, and confirm that there are significant process which needs to be accompanied and bone pain.10 Guidelines based on patient related delays for the diagnosis by the presentation of a more positive this pattern of symptoms have been of lung cancer, longer than those pre- image of lung cancer, stressing the fact developed11 and stress that the physician viously reported. Jensen et al13 reviewed that early diagnosis saves lives rather needs to be alert to the possibility of the time elapsed from symptoms to than perpetuating the negative image lung cancer in patients with such medical attention reported in 16 studies that the current prognosis for the symptoms, particularly if they are and found a wide variation from 7 days majority of patients is so poor.

www.thoraxjnl.com EDITORIAL 269

Early symptom recognition in lung reported and issues such as lead time by cause, sex and age, in England and Wales,

2002, Series DH2. London: Office for National Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from cancer will only be worthwhile if it and over-diagnosis bias add to the Statistics, 2003:29. 22 improves outcomes for patients, espe- complexity of interpretation. The nat- 2 Fry WA, Phillips JL, Menck HR. Ten year survey of cially survival. Christensen et al15 found ural history of malignant nodules as lung cancer treatment and survival in hospitals in the United States: a national cancer database that, for patients with operable lung small as 5 mm detected on CT scans is report. Cancer 1999;86:1867–76. cancer (stage I/II), the interval between not well described and even nodules 3 SEER. www.seer.gov. the trigger symptom initiating contact only 10 mm in size containing 109 cells 4 Janssen-Heijnen MLG, Gatta G, Forman D, et al. represent a fairly late stage in the Variation in survival of patients with lung cancer with the healthcare system and the time in Europe, 1985–1989. Eur J Cancer of operation was significantly shorter disease process, considering that at 1998;34:2191–6. than the time between the trigger death lung cancer tumours typically 5 Office for National Statistics. England: Cancer have 1012 cells.9 The survival benefit of survival, 1993–2000. London: Office for National symptom and the decision not to oper- Statistics, 2001. ate for patients with stage III/IV disease. any screening programme must also 6 Pearson FG. Current status of surgical resection In contrast, Mydral et al16 found the time outweigh the risks related to managing for lung cancer. Chest 1994;106:337S. false positive nodules. The optimum 7 Mountain CF. Revisions in the International from onset of symptoms to treatment System for Staging Lung Cancer. Chest was shorter in patients with stage IV strategy for the management of small 1997;111:1710–7. lung cancer (median 3.4 months) than lesions identified on screening has not 8 Geddes DM. The natural history of lung cancer: a been determined. review based on tumour growth. Br J Dis Chest in those with stage I/II disease (median 1979;73:1–17. 5.5 months). This is likely to result from Another potential screening tool is 9 Weiss ST. Passive smoking and lung cancer. the fact that patients with advanced advanced sputum cytology, enhanced by What is the risk? Am Rev Respir Dis disease had more severe symptoms and molecular genetics, immunohistochem- 1986;133:1–3. 10 Hyde L, Hyde CL. Clinical manifestations of lung signs and received more rapid treat- istry, including the monoclonal anti- cancer. Chest 1974;65:298–307. ment. The current study by Corner et al12 body staining of antigens expressed by 11 Department of Health. Referral guidelines for 23 24 did not find differences in patient delay lung cancer cells. Autofluorescence suspected cancer. London: Department of Health, bronchoscopy may complement cytology 2000. times according to the stage of lung 12 Corner J, Hopkinson J, Fitzsimmons D, et al. Is cancer, but the numbers studied were with the potential for the detection of late diagnosis of lung cancer inevitable? insufficient to answer this question. metaplasia and carcinoma in situ in Interview study of patients’ recollections of bronchial mucosa.25 A multimodality symptoms before diagnosis. Thorax Studies investigating the effect of hos- 2005;60:314–9. pital delays in diagnosis and treatment approach may be required to optimise 13 Jensen AR, Mainz J, Overgaard J. Impact of on prognosis similarly report conflicting early detection and management of lung delay on diagnosis and treatment of primary lung cancer from screening programmes and cancer. Acta Oncol 2002;41:147–52. results. Comparison of the data in these 14 Bowen EF, Rayner CF. Patient and GP led delays studies is, however, made difficult by early attempts at this approach look in the recognition of symptoms suggestive of lung 26 the differing definitions of patient promising. cancer. Lung Cancer 2002;37:227–8. While efforts consequent upon the 15 Christensen ED, Harvald T, Jendresen M, et al. delays and clinical differences of patient 27 The impact of delayed diagnosis of lung cancer groups studied.17–19 National Cancer Plan and the Cancer on the stage at the time of operation. Because of the non-specific nature of Services Collaborative have helped to Eur J Cardiothorac Surg 1997;12:880–4. reduce hospital delays, the study by 16 Myrdal G, Lambe M, Hillerdal G, et al. Effect of the symptoms in question and the fact delays on prognosis in patients with non-small cell Corner et al reminds us that significant lung cancer. Thorax 2004;59:45–9. that a paradigm shift in the behaviour of http://thorax.bmj.com/ delays remain in the diagnosis of lung the population at most risk of develop- 17 O’Rourke N, Edwards R. Lung cancer treatment cancer before the patient ever gets into waiting times and tumour growth. Clin Oncol ing lung cancer is highly unlikely, secondary care. While this is clearly an 2000;12:141–4. attempts at making major progress on 18 Aragoneses FG, Moreno N, Leon P, et al. important area for future research, it is early referral at a population level based Influence of delays on survival in the surgical probable that—in the absence of a treatment of bronchogenic carcinoma. Lung on symptoms alone seem very unlikely major advance in treatment or a sig- Cancer 2002;36:59–63. to be successful. Other methods of early 19 Billing JS, Wells FC. Delays in the diagnosis and nificant further reduction of cigarette detection therefore need to be energeti- surgical treatment of lung cancer. Thorax consumption—some form of screening 1996;51:903–6. cally explored to lower the stage at is the intervention most likely to have a 20 Flehinger BJ, Melamed MR, Zaman MB, et al. presentation in lung cancer. Screening Early lung cancer detection: results of the initial on September 26, 2021 by guest. Protected copyright. major impact on the current poor is an attractive option because there is a (prevalence) radiologic and cytologic screening in survival statistics, and it is vital that the Memorial Sloan-Kettering study. Am Rev relatively well defined high risk popula- the major funders of national research Respir Dis 1984;130:555–60. tion and the potential for curative programmes grasp this difficult nettle as 21 Henschke CI, McCauley DI, Yankelevitz DF, et al. surgery in early disease. Radiological Early Lung Cancer Action Project: overall design soon as possible. and findings from baseline screening. Lancet screening has been the most studied. 1999;354:99–105. The screening trials of the 1970/80s with Thorax 2005;60:268–269. 22 Mulshine JL, Smith RA. Lung cancer. 2: Screening chest radiography were deemed nega- doi: 10.1136/thx.2004.032698 and early diagnosis of lung cancer, Thorax 20 2002;57:1071–8. tive, but the advent of faster spiral and ...... 23 Mao L, Hurban RH, Boyle JO, et al. Detection of multiple slice CT scanners have led to a oncogene mutations in sputum precedes Authors’ affiliations renewed interest. Preliminary studies of diagnosis of lung cancer. Cancer Res S S Birring, M D Peake, Thoracic Oncology 1994;54:1634–7. low dose CT screening show promise Unit, Department of Respiratory Medicine, 24 Tockman MS, Gupta PK, Myers JD, et al. Sensitive 21 and formal trials are underway. The Glenfield Hospital, Leicester, UK and specific monoclonal antibody recognition of demonstration of benefits of screening human lung cancer antigen on preserved sputum cells: a new approach to early lung cancer programmes on the overall survival Correspondence to: Dr M D Peake, Thoracic detection. J Clin Oncol 1988;6:1685–93. statistics of the studied population is Oncology Unit and Institute for Lung Health, 25 Lam S, MacAulay C, LeRiche JC, et al. Detection essential before widespread use of this Department of Respiratory Medicine, Glenfield and localization of early lung cancer by method is adopted. Currently, the Hospital, Leicester LE3 9QP, UK; mick.peake@ fluorescence bronchoscopy. Cancer uhl-tr.nhs.uk 2000;89(Suppl):2468–73. improved survival benefits of screening 26 Loewen G, Reid M, Tan DF, et al. Bimodality lung are not known and interpretation of REFERENCES cancer screening in high-risk patients. Chest 2004;125:163–4S. published studies is made difficult since 1 Office for National Statistics. Mortality statistics 27 Department of Health. The NHS National Cancer no randomised trial has yet been cause. Review of the Registrar General on deaths Plan. London: Department of Health, 2001.

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Lung function estimates in IPF specifically in the context of UIP and ...... NSIP, allowing a consistent theme to Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from emerge (table 1). A PubMed literature search was performed to identify peer Lung function estimates in idiopathic reviewed manuscripts relating to lung function testing in IPF published in pulmonary fibrosis: the potential for a 1998–2004. This period was chosen because it reflects the clinical impact of simple classification the characterisation of patients based on histological subsets as described by J J Egan, F J Martinez, A U Wells, T Williams Katzenstein et al in 1998.14

...... LUNG FUNCTION AND DISEASE Application of a classification based on simple lung function SEVERITY A global view of historical lung function testing in IPF data emphasises that a poor outcome is associated with ‘‘low’’ lung function. or many years the idiopathic pul- testing, it is reproducible and has Schwartz et al12 highlighted the fact that monary fibrosis (IPF) community facilitated the identification of patients reduced lung function was associated Fhas debated the merits of the with COPD. Furthermore, it has enabled with limited survival. In a study of 74 histopathological classification of idio- worldwide harmonisation of clinical and individuals who had undergone lung pathic interstitial pneumonia (IIP).1 The experimental research studies in COPD.7 biopsy, univariate analysis showed that ATS/ERS consensus statement identifies Recent publications relating to lung there was a greater hazard of death with the importance of histological categories function, focusing specifically on IPF, lower % predicted FVC and lower % of usual interstitial pneumonia (UIP) provide a similar opportunity. The his- predicted TLCO. However, clinicians and non-specific interstitial pneumonia tological classification proposed by require a specific threshold in the (NSIP). Furthermore, it emphasises that Katzenstein and endorsed by the ATS/ context of disease severity.16 The study IPF is the clinical correlate of UIP. ERS consensus statement potentially by Gay et al17 emerged as a key publica- Despite the recognition of the impor- allows for the development of a staging tion in the context of the methodology tance of histological characterisation, system based on simple and widely used for appraising the influence of lung surgical biopsy rates vary considerably.2 available evaluation techniques. The function. In contrast to historical stu- Most clinicians do not subject their aim of such a classification would not dies which reported group differences in patients to surgical biopsy, despite the be to supersede the histological classifi- survival and hazard ratios, they applied potential prognostic benefit of detailed cation but rather to build upon it. for the first time receiver operator histological evaluation, because many The aim of this review is therefore to characteristic (ROC) curve estimates. patients are elderly and have signifi- discuss the potential of a grading system ROC state the probability that a diag- nostic criterion selects a disease subject cantly impaired lung function and other for IPF based solely on simple static http://thorax.bmj.com/ medical co-morbidities resulting in a lung function studies. For judging dis- correctly rather than a non-disease potentially high mortality rate.3 In addi- ease severity we sought a parameter that subject.18 In the context of lung func- tion, HRCT scanning provides diagnostic identified patients with impaired survi- tion, ROC curves express the ability of a data of high sensitivity and specificity val, defined as less than 2 years. For variable to discriminate between death for the diagnosis of IPF with acceptable judging disease progression we sought and/or survival. However, despite the interobserver variability.45 lung function changes which identified application of ROC analysis by Gay et al, Meanwhile, the chronic obstructive patients at increased risk of mortality. no lung function variable identified risk pulmonary disease (COPD) and lung of death (table 1). This is likely to reflect transplantation communities have HISTOLOGICAL CLASSIFICATION the efforts to study well characterised on September 26, 2021 by guest. Protected copyright. applied simple but pragmatically useful AND LUNG FUNCTION patients, resulting in a relatively small classifications. Bronchiolitis obliterans The absence of broad agreement on the number of subjects in the study. syndrome (BOS), for example, has been interpretation of lung function testing subject to a clinical grading system in IPF reflects the variability in pub- DISEASE SEVERITY: ADVANCED reflecting the degree of impairment of lished data on the subject (table 1).8 AND LIMITED DISEASE lung function following lung transplan- Impaired survival has been associated Acknowledging the need for a specific tation. The emergence of a classification with a variety of findings including no threshold value for estimating disease based on simple lung function testing relationship with lung function,9 severity, recent data suggest that sever- occurred because of the difficulties in increased ratio of forced expiratory ity of disease can be categorised as obtaining adequate tissue for the diag- volume in 1 second to forced vital advanced or limited disease on the basis 10 nosis of obliterative bronchiolitis. This is capacity (FEV1/FVC ratio), reduced of lung function. Extending the study by comparable to the situation in IPF total lung capacity (TLC),11 12 and Gay et al by using ROC analysis, where tissue is also difficult to obtain. change in FVC/carbon monoxide trans- Mogulkoc et al19 focused on lung func- The success of the classification of BOS fer factor (TLCO) after 1 year (table 1).13 tion in the context of transplant referral. is reflected by the publication of an Formerly a critical confounding factor This study targeted a well characterised updated version.6 influencing the interpretation of lung group of 115 patients with IPF aged The global initiative for COPD function was the failure to distinguish 45–65 years. A total of 12 variables influ- (GOLD) is another example of a con- between histological subsets in IIP.14 15 encing survival were significant on uni- sensus classification based on simple Consequently, early published data on variate regression analysis. A mul- lung function testing. GOLD provides a lung function have been limited by the tivariate stepwise regression analysis staging system ranging from an ‘‘at absence of focus on specific histological identified only % predicted TLCO and risk’’ category to a severe disease cate- subgroups. Recent publications have HRCT fibrosis as independent predictors gory.7 Based on simple lung function therefore focused on lung function data of 2 year survival. ROC analysis of %

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Table 1 Summary of lung function studies in IPF Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from

Author Subset N Age (years) FVC TLCO (Survival months) Result

12 Schwartz No 38 62 67% 46% NA Decreased TLC/TLCO associated with dyspnoea 12 Schwartz No 74 67 62% 44% 60 Increased FEV1/FVC ratio 13 Hanson No 58 59 61% 42% 88 1 year: 10% drop FVC, 20% drop TLCO: increased mortality Erbes11 No 99 53 89% 46% 41 Reduced TLC Hubbard9 No 244 69 78% 49% 34 No LF variable associated with mortality Gay17 Yes 38 54 UIP 69% UIP 50% 26 No LF variable associated with mortality 19 Mogulkoc Yes 115 55 UIP 72% UIP 49% 50 TLCO 39% predicted: 80% sensitivity/ specificity 2 year survival 27 Wells Yes 197 62 UIP 68% 36% 22 Mortality associated with reduced TLCO, FVC, TLC 20 Latsi Yes 104 55 UIP 72% UIP 46% UIP 33 TLCO 35% predicted: early mortality NSIP 73% NSIP 41% NSIP 56 Collard22 Yes 81 61 UIP 67% UIP 52% 51 Reduced survival: 10% drop in FVC 6 months Flaherty21 Yes 80 62 UIP 67% UIP 50% 69 (total group) Reduced survival: 10% drop in FVC/ NSIP 71% NSIP 48% 6 months

Subset refers to whether the authors specified the histological subset studied. Age and FVC/TLCO are median values; survivals are mean values. LF, lung function; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; TLC, total lung capacity; TLCO, carbon monoxide transfer factor; UIP, usual interstitial pneumonia; NSIP; non-specific interstitial pneumonia.

predicted TLCO gave an area of 0.8 (CI survival. A key observation in this study is required accurately to reflect a change 0.7 to 0.9) and HRCT fibrosis score gave is that a subgroup of patients with in vital capacity. Using TLCO requires a an area of 0.86 (CI 0.77 to 0.95). It was severely reduced TLCO, defined as change of 15% or more. Consequently, shown that a gas transfer factor of ,35% of predicted, had a survival time the baseline from which change occurs ,39% of predicted combined with of less than 2 years irrespective of is vital to observe. Because many HRCT scores had an 80% sensitivity whether they had UIP or NSIP. Those patients with IPF present with a TLCO and specificity for predicting death with a TLCO of .35% of predicted had a of ,39% of predicted, a further 15% fall within 2 years. This allowed the obser- 65% survival at 3 years. This emphasises from baseline is difficult to document. vation of a simple measure of TLCO to be that, once a certain threshold of phy- Individuals require adequate pulmonary associated with a specific limited time siological impairment is reached, mor- reserve to exhibit a change in that frame of survival. Identification of tality is increased. parameter. Inadequate reserve may a threshold value associated with As lung function is the primary explain why a significant proportion of increased mortality serves as the basis investigation performed by pulmonolo- patients fail to show evidence of lung http://thorax.bmj.com/ for a distinction between advanced and gists, patients may therefore be defined function progression. Patients with lim- limited disease (fig 1). as having advanced disease (TLCO ,39% ited disease or adequate pulmonary The concept of advanced IPF was of predicted), allowing the potential reserve therefore lend themselves to corroborated by the work of Latsi et identification of patients with poor early evaluation of disease progression. 20 al. In a retrospective study of 104 survival. Although FVC is predictive of The time required to observe a change patients with a histologically confirmed survival in univariate modelling, it does in lung function is also critical. As the diagnosis, determinants of early mortal- not maintain its effect in multivariate mean survival of some groups of ity at presentation and mortality after analysis.21 The severity of IPF is there- patients may be as low as 2.5 years, a on September 26, 2021 by guest. Protected copyright. 6 months of follow up were studied. In fore best graded by TLCO estimation. For prolonged period of observation of, for patients dying within 2 years of presen- patients with limited disease (TLCO example, 1 year biases a study towards tation, the median TLCO was 39% of the .40% of predicted), longer survival is patients with favourable survival and predicted value. These authors present more likely. It is in this latter group that limited disease. Hanson et al13 were the patients with advanced disease as an serial lung function studies have parti- first to study the change in lung func- ‘‘early mortality’’ group in whom phy- cular prognostic value. tion over 1 year. They studied 58 siology was the best determinant of patients and evaluated the influence of LUNG FUNCTION AND DISEASE a 10% change in FVC and a 20% change in TLCO. This cohort had favourable ADVANCED DISEASE LIMITED DISEASE PROGRESSION ROC curve analysis highlights the fact characteristics including a mean age TLCO <39% TLCO >40% that TLCO is superior to FVC for evaluat- of 55 years and a mean survival predicted ing disease severity.19 In contrast, a of 88 months. The mean survival of change in FVC may be the most reliable patients exhibiting a change (24% of simple lung function variable to high- the total) in FVC was 2.5 years. The PROGRESSIVE light disease progression. When apprais- mean survival of patients exhibiting a Refer for transplant DISEASE ing lung function studies of disease change was also 2.5 years in TLCO (22% if appropriate progression in IPF, three points deserve of the total.) candidate FVC fall >10% consideration: the coefficient of varia- Acknowledging this, two recent pub- tion of the test, the baseline from which lications progress the strategy described the change occurs, and the time scale by Hanson et al.13 Firstly, Collard et al,22 Figure 1 A classification of IPF based on used to determine change. in a study of 81 patients with UIP, simple lung function criteria. TLCO, carbon monoxide transfer factor; FVC, forced vital The intertest variation has been evaluated change in lung function over capacity. widely studied. A 10% change in FVC both 6 and 12 months. The median

www.thoraxjnl.com 272 EDITORIAL survival of the patients subject to classification based on lung function for function schema provides a trigger for 6 month evaluation was 4.8 years a condition in which it is difficult to discussion and a framework from which Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from and 6.2 years for those studied at acquire tissue. It would standardise additional simple and pragmatic mar- 12 months. The mean TLCO of the group nomenclature and facilitate entry into kers of progressive disease can be was 52% of predicted. Changes in TLC % emerging treatment studies. It may also identified. predicted, FVC % predicted, and TLCO % optimise referral for lung transplanta- predicted over 6 months predicted sur- tion. A limited window of opportunity ACKNOWLEDGEMENTS vival. Of these, the change in FVC % exists to refer IPF patients for lung The authors acknowledge the Irish Lung predicted was the best predictor. transplantation. The short transplant Fibrosis Association, the University of Flaherty et al21 studied 109 patients, 80 window is reflected by the high mortal- Michigan Fibrotic Lung Disease Network, of whom had UIP and 29 had NSIP. The ity rate in patients with IPF awaiting and the Brompton Interstitial Lung Disease Group. mean TLCO of the group was 50% of lung transplantation.24 The proposed predicted. 32% of patients had a fall of classification, particularly based on the Thorax 2005;60:270–273. .10% in FVC and 49% of patients concept of advanced disease, may facil- doi: 10.1136/thx.2004.035436 remained within 10% of baseline. On itate more accurate referral, the time of ...... multivariate analysis, controlling for listing being determined by local organ histological subgroups and baseline availability. Authors’ affiliations J J Egan, The Mater Misericordiae Hospital lung function, a change in FVC over Although a tentative and provocative 6 months was an independent risk and St Vincent’s University Hospital, The first step, there are potential limitations Conway Institute, Dublin Molecular Medicine factor for mortality. Both studies to the proposed classification. It must be Center, University College Dublin, Ireland included patients with preserved TLCO acknowledged that the data presented F J Martinez, Taubman Center 3916, 1500 E 21 22 in the region of 50% of predicted. by Mogulkoc and Latsi are retrospective Medical Center Dr, Ann Arbor, MI 48109- Changes in TLCO are an alternative and should ideally be validated by a 0360, USA measure of disease progression. Latsi prospective evaluation. Furthermore, A U Wells, Interstitial Lung Disease Unit, et al20 observed a higher mortality in Thabut and Fournier25 emphasise weak- Emmanuel Kaye Building, Manresa Road, patients with a decline in TLCO at 6 and nesses with reference to the definition London SW6 LR6, UK 12 months, whether trends were quan- T Williams, Alfred Hospital, Monash of disease progression based on a 10% University, Melbourne, Australia tified numerically or categorically. change in FVC. For instance, a change in However, repeat TLCO measurements FVC from 90% predicted to 80% pre- can be difficult to standardise, explain- Correspondence to: Dr J Egan, Advanced Lung dicted is not clinically comparable to a Disease and Irish National Lung Transplant ing the need for a greater change in TLCO change from 60% to 50%. There is also Program, The Mater Misericordiae Hospital than in FVC in order to categorise an inherent difference between group and St Vincent’s University Hospital, The deterioration. In the study by Latsi data and the individual patient. Conway Institute, Dublin Molecular Medicine et al, serial TLCO trends had only a Center, University College Dublin, Ireland; Although group data show that 46% of [email protected] minimal prognostic advantage over patients who exhibit a 10% fall may serial FVC trends and the analysis survive 5 years, this does not equate Conflict of interest: none included a significant subset of patients with an individual patient having a 46% http://thorax.bmj.com/ with advanced disease. In the recently chance of surviving 5 years. REFERENCES published interferon gamma-1b treat- It must also be recognised while 1 American Thoracic Society/European ment study only 14% of 300 patients monitoring disease progression that Respiratory Society. 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HRCT Re-evaluation at 12 months may be analysis suggests that such scoring diagnosis of diffuse parenchymal lung disease; inter-observer variability. Thorax particularly important in the context of systems may be more accurate prognos- a ‘‘marginal’’ decline in FVC of 5–10%, 2004;59:506–11. tically than individual lung function 6 Estenne M, Maurer JR, Boehler A, et al. which may reflect either measurement variables. However, these scoring sys- Bronchiolitis obliterans syndrome 2001: an variation or genuine disease progres- tems may not be easily applicable to the update of diagnostic criteria. J Heart Lung sion. Thus, the definition of disease Transplant 2002;21:297–310. broader community of non-specialist progression using change over 6 months 7 Vestbo J, Lange P. Can GOLD stage 0 provide centres, especially when exercise testing information of prognostic value in chronic should not obscure the need to refine and radiographic profusion scores are obstructive pulmonary disease. Am J Respir Crit prognostic evaluation at 1 year and at Care Med 2002;166:329–32. included. The focus should therefore be least 6 monthly intervals thereafter. 8 Alhamad EH, Lynch JP, Martinez FJ. Pulmonary firstly to emphasise the need for staging function in interstitial lung disease: what role do based on lung function tests. Although a they have? Clin Chest Med 2001:715–50. 9 Hubbard R, Johnston I, Britton J. Survival in BENEFITS AND DISADVANTAGES lung function classification is a first patients with cryptogenic fibrosing alveolitis. OF A CLASSIFICATION step, in the future HRCT data and Chest 1998;113:396–400. The potential benefits of a classifica- simple field exercise tests such as the 10 Schwartz DA, Helmers RA, Galvin JR, et al. Determinants of survival in idiopathic pulmonary tion based on lung function are sub- 6 minute walk test may provide com- fibrosis. Am J Respir Crit Care Med stantial. There is a critical need for a plementary data.28 29 The proposed lung 1994;149:450–4.

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Online First number. All versions of the paper will be ...... linked online and will be available to readers. We hope that the introduction of Online First in Thorax Thorax Online First will be welcomed by researchers, clinicians, and readers. We J A Wedzicha, S L Johnston, D M Mitchell encourage you all to log on frequently and to visit the new site to view the ...... recently accepted papers in the journal. Articles can be accessed using the Thorax Online First icon on the Thorax home e are pleased to announce that between acceptance of an article and page. With progress in electronic pub- http://thorax.bmj.com/ Thorax is about to start posting its appearance in the print version of the lishing, important advances in respira- Wall original articles on its web- journal. Online First in Thorax will allow tory medicine can now be implemented site in an Online First section (http:// research work to be available much much more quickly to the benefit of www.thoraxjnl.com) shortly after faster to the research community; patients all over the world. acceptance and before the papers are manuscripts that have not yet been Thorax 2005;60:273. published in the print version of the finally edited by our technical editor doi: 10.1136/thx.2005.043190 journal. Although the time from accep- will be posted on the website. tance to publication in Thorax is rela- With the introduction of Online First, ...... tively short, this initiative is a welcome authors will be asked to check their Authors’ affiliations on September 26, 2021 by guest. Protected copyright. contribution. An Online First programme papers carefully after acceptance and J A Wedzicha, S L Johnston, D M Mitchell, was introduced by the British Medical then the unedited pdf proof of the Thorax Editorial Office, BMA House, Tavistock Journal in December 2003,1 followed by manuscript will be posted. The paper Square, London WC1H 9JR, UK other specialist journals from the BMJ will be identified by its unique num- Publishing Group.2 All original articles ber—the digital object identifier Correspondence to: Professor J A Wedzicha, Thorax Editorial Office, BMA House, Tavistock have also been posted early after accep- (DOI)—which will appear at the top of Square, London WC1H 9JR, UK; tance by the American Journal of the pdf and will be used to cite the [email protected] Respiratory and Critical Care Medicine for article. Articles published Online First 3 some time. will also be indexed by PubMed early REFERENCES Authors want their research studies to after online publication and will be 1 Smith J. Online firsts. BMJ 2003;327:1302. be published as soon as possible after available when searching for papers 2 van de Putte L. ARD launches an advanced online acceptance so that their important using search engines such as PubMed publication programme. Ann Rheum Dis scientific and clinical findings can be and Google. The final version of the 2004;63:221. 3 Tobin MJ. The official copy of AJRCCM is posted cited and incorporated into practice. article will be edited by the technical but not printed. Am J Respir Crit Care Med, However, there are inevitable delays editor and then printed with its DOI 166:905–6.

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