The ebb and flow of asthma

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EDITORIAL                                                                                                                                  87

Changes in the prevalence of asthma                                                         symptomatic boys who used asthma
.......................................................................................     medication during this period. The
                                                                                            finding of no change in the prevalence

The ebb and flow of asthma
                                                                                            of airway hyperresponsiveness between
                                                                                            1992 and 2002 in an Australian series15
                                                                                            tends to support the view that there has
B G Toelle, G B Marks                                                                       been no real change in disease preva-
                                                                                            lence over that period and, rather, the
                                                                                            observed decreases in reports of asthma
                                                                                            reflect more specific application of the
More studies reporting international time trends will put us in a                           diagnostic label in recent times.
better position to explain the changing prevalence of asthma                                   Repeat cross sectional studies provide
                                                                                            a useful insight into changes over time.
                                                                                            Comparison of studies from different

          ithout ever fully understanding     school children.17 The studies conducted
          the reasons for the global          in 1989, 1993, 1997, and 2001 measured        countries and regions are informative,
          increase in the prevalence of       respiratory symptoms and treatment in         but these comparisons have been lim-
asthma during the later part of the 20th      8–9 year olds. The strengths of this          ited by the lack of standardised methods
century, we are now faced with the            series of consecutive studies are that        between studies. The most accurate
challenge of explaining an apparent           all the studies included well over 1000       insights into international time trends
decrease in prevalence. A challenge           children and had participation rates of       will be gleaned from repeat cross sec-
indeed! During the 1980s and early            over 95%. Identical sampling methods          tional studies conducted as part of the
1990s several repeat cross sectional          and questionnaires were used, giving us       major multicentre studies of the
studies, conducted in widely varying          confidence that the results are repre-        International Study of Asthma and
regions of the world, reported an             sentative of Dutch school children in         Allergies in Childhood (ISAAC) and
increase in the prevalence of symptoms        this region and that the differences are      the European Community Respiratory
of asthma, diagnosed asthma, and              not due to changes in measurement             Health Survey (ECRHS). Three of the
medication use for asthma.1 2 Although        instruments.                                  studies from 2004 were repeat cross
most studies relied on self-reported             Between 1989 and 2001 there was a          sectional studies from ISAAC.10 13 16
symptoms and diagnoses—and hence              downward trend in the prevalence of           When we have more studies reporting
could be subject to reporting bias—at         recent wheeze which was statistically         international time trends, we will be in
least one3 observed substantial changes       significant for boys but not for girls. The   a better position to explain the ebb and
in airway hyperresponsiveness, lending        largest reduction was over the most           flow of asthma.
credence to the view that this was not        recent period (1997–2001). Over this          Thorax 2005;60:87–88.
simply related to changes in disease          12 year period there was no statistically     doi: 10.1136/thx.2004.038331
classification and labelling. Parallel        significant trend in the prevalence of
increases in hospitalisation rates4 and       shortness of breath, coughing with            ......................
mortality rates5 also were consistent         phlegm, or chronic cough, with the            Authors’ affiliations
with a true rising tide of asthma. This       prevalence remaining fairly stable in         B G Toelle, G B Marks, Woolcock Institute of
trend led to major national and inter-        both boys and girls. However, there           Medical Research, Sydney, NSW 2050,
national initiatives to control the dis-      was a significant trend towards an            Australia
ease.6–9                                                                                    G B Marks, University of Sydney, Sydney,
                                              increased use of asthma medication by
                                                                                            NSW 2006, Australia
   There are now several reports to           boys who reported recent wheeze over
suggest that the tide has turned.             this period. Girls who reported recent
During 2004 there have been a number          wheeze also used more medication but          Correspondence to: Dr B Toelle, Woolcock
                                                                                            Institute of Medical Research, P O Box M77,
of repeat cross sectional studies from        this trend was not significant. So, in        Missenden Road Post Office, NSW 2050,
Hong Kong,10 Korea,11 Switzerland,12 the      Dutch school children between 1989            Australia;
UK,13 Scotland,14 Belmont, Australia15        and 2001 it appears as though the
and Melbourne, Australia16 that have          prevalence of asthma symptoms has
reported a levelling off in asthma pre-       remained stable or, in the case of recent
valence. In some studies there has been       wheeze, the prevalence has decreased           1 Woolcock AJ, Peat JK. Evidence for the increase
                                                                                               in asthma worldwide. Ciba Found Symp
a statistically significant decrease in the   while the use of asthma medication in            1997;206:122–34.
prevalence of asthma symptoms.                those children who have symptoms has           2 Burney P. The changing prevalence of asthma?
Although numerous environmental fac-          increased. This apparent paradox may             Thorax 2002;57(Suppl II):ii36–9.
                                                                                             3 Peat JK, van den Berg RH, Green WF, et al.
tors—including indoor and outdoor air         contain a clue to the explanation for the        Changing prevalence of asthma in Australian
quality, infections, diet, sibship, breast-   recent trends.                                   children. BMJ 1994;308:1591–6.
feeding, and pet ownership—have been             The authors suggest that increasing         4 Burney P. Asthma: evidence for a rising
linked to the aetiology of asthma in                                                           prevalence. Proc R Coll Physicians Edinb
                                              use of treatment may be responsible for          1993;23:595–600.
cross sectional studies, none of these        this trend by suppressing asthma symp-         5 Burney P. Asthma deaths in England and Wales
provides a robust explanation for the         toms in a larger proportion of the               1931–85: evidence for a true increase in asthma
previous increasing trend or the appar-       population. An alternative explanation           mortality. J Epidemiol Comm Health
ent reversal of that trend. This is           is that the diagnosis of asthma is being       6 NHLBI/WHO. Global initiatives for asthma.
particularly the case as the trends have      used more sparingly in 2001 than it was          Bethesda, MD: National Health Lung and Blood
been observed in a wide range of              in previous years. In other words,               Institute, 1995:69–117.
                                                                                             7 National Asthma Education and Prevention
countries, including those with both a        children with episodic or intermittent           Program. Expert Panel Report 2: Guidelines for
high and low baseline prevalence of           wheeze, who do not require asthma                the diagnosis and management of asthma.
asthma.                                       medication, may have been less likely to         Bethesda, MD: National Institutes of Health,
   In this issue of Thorax Mommers et al      be labelled as having asthma symptoms            National Heart, Lung, and Blood Institute, 1997.
                                                                                             8 British Thoracic Society, Research Unit of the
report the results of a series of four        in 2001. This would explain the                  Royal College of Physicians of London, King’s
repeat cross sectional studies in Dutch       observed increase in the proportion of           Fund Centre, National Asthma Campaign.

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88                                                                                                                                        EDITORIAL

   Guidelines for management of asthma. I. Chronic    12 Braun-Fahrlander C, Gassner M, Grize L,
                                                                        ¨                                  15 Toelle BG, Ng K, Belousova E, et al. Prevalence
   persistent asthma. BMJ 1990;301:651–3.                et al. No further increase in asthma, hay            of asthma and allergy in schoolchildren in
 9 Woolcock A, Rubinfeld AR, Seale JP, et al.            fever and atopic sensitisation in adolescents        Belmont, Australia: three cross sectional
   Thoracic Society of Australia and New Zealand.        living in Switzerland. Eur Respir J                  surveys over 20 years. BMJ 2004;328:
   Asthma management plan, 1989. Med J Aust              2004;23:407–13.                                      386–7.
   1989;151:650–3.                                    13 Anderson HR, Ruggles R, Strachan DP, et al.       16 Robertson CF, Roberts MF, Kappers JH.
10 Wong GWK, Leung TF, Ko FWS, et al. Declining          Trends in prevalence of symptoms of asthma, hay      Asthma prevalence in Melbourne schoolchildren:
   asthma prevalence in Hong Kong Chinese                fever, and eczema in 12–14 year olds in the          have we reached the peak? Med J Aust
   schoolchildren. Clin Exp Allergy                      British Isles, 1995–2002: questionnaire survey.      2004;180:273–6.
   2004;34:1550–5.                                       BMJ 2004;328:1052–3.                              17 Mommers M, Gielkens-Sijstermans C,
11 Hong S-J, Lee M-S, Sohn MH, et al. Self-reported   14 Devenny A, Wassall H, Ninan T, et al.                Swaen GMH, et al. Trends in the prevalence of
   prevalence and risk factors of asthma among           Respiratory symptoms and atopy in children in        respiratory symptoms and treatment in Dutch
   Korean adolescents: 5-year follow-up study,           Aberdeen: questionnaire studies of a defined         children over a 12 year period: results of the
   1995–2000. Clin Exp Allergy                           school population repeated over 35 years. BMJ        fourth consecutive survey. Thorax
   2004;34:1556–62.                                      2004;329:489–90.                                     2005;60:000–0.

Angiogenesis and VEGF in COPD                                                                              and exudation and transudation of
.......................................................................................                    mediators, particularly if vascular per-
                                                                                                           meability was altered. The increased

Angiogenesis and vascular endothelial                                                                      vasculature could also contribute to
                                                                                                           airway hyperresponsiveness by support-

growth factor in COPD
                                                                                                           ing the increased airway smooth muscle
                                                                                                           mass which is a feature of both asthma
                                                                                                           and COPD.21 Interestingly, the study by
A J Knox, J Stocks, A Sutcliffe                                                                            Kranenburg et al16 showed increased
                                                                                                           staining in bronchial smooth muscle
                                                                                                           consistent with this hypothesis. An
A possible role for VEGF in the pathology of asthma and COPD                                               alternative hypothesis, however, is that
                                                                                                           the increase in the bronchial vasculature
                                                                                                           is a protective mechanism which results

  t has been recognised for several                   expression pattern of VEGF and its                   in increased clearance of proinflamma-
  hundred years that the bronchial                    receptors Flt-1 and KDR/Flk-1 by immuno-             tory mediators and cytokines from
  vasculature is an extensive one with                histochemistry in central and peripheral             inflamed airways. Studies in mouse
early descriptions by Ruysch and possi-               airways obtained from ex-smokers with                models have helped to shed light on
bly Da Vinci.1 However, its function and              or without COPD. They found that                     this issue. Lee et al22 showed that VEGF
regulation in health and in disease                   VEGF Flt-1 and KDR/Flt-1 immuno-                     was increased in the lungs in a mouse
remain poorly understood. Studies a                   staining was localised in vascular and               model of asthma and that VEGF recep-
number of years ago suggested an                      airway smooth muscle cells, epithelial cells,        tor inhibitors inhibited cellular influx as
increased number of bronchial vessels                 and macrophages. In contrast, the                    well as inhibiting airway hyperrespon-
in asthma where increased collagen IV                 endothelial cells did not express VEGF               siveness and reducing microvascular
staining, a marker of new vessels, was                but did express its receptors, consistent            leakage.
seen in bronchial biopsies of asthmatic               with them being effector cells for VEGF to              Interestingly, a number of treatments
airways compared with controls.2                      act on rather than an important autocrine            for airway diseases can modify VEGF
Subsequent studies by the same group                  source.                                              production. Glucocorticoids reduce
and by Salvato and colleagues have                       VEGF expression on bronchial tissues              VEGF secretion by structural17 and
confirmed the presence of angiogenesis                was higher in patients with COPD than                inflammatory airway cells23 in vitro
in the bronchial circulation in asthma.3 4            in those without COPD. VEGF exists as                and both glucocorticoids and long act-
There are a number of candidate angio-                at least five gene products A–E with                 ing b agonists have been shown to
genic factors for these changes, perhaps              VEGF-A being the most potent.17 VEGF-                reduce the vascularity of asthmatic air-
the most important of which are vas-                  A has several spliced variants which are             ways in vivo.2 3 The effect of these
cular endothelial growth factor (VEGF)                expressed by airway cells.17 A number of             agents on VEGF expression and angio-
and the angiopoietins which are distinct              conditions relevant to COPD have been                genesis in COPD has not yet been
molecules that act together at different              shown to increase VEGF expression and                studied but would be interesting to
stages of angiogenic processes in several             release including cigarette smoke,18                 determine. This suggests that strategies
biological systems.5–11 Other molecules               hypoxia,19 and cytokines such as IL-1b               targeting VEGF may have a beneficial
with angiogenic potential are fibroblast              and transforming growth factor (TGF)-                effect on bronchial wall inflammation
growth factor,9 angiogenin,9 and chemo-               b.20                                                 and remodelling, at least in asthma. The
kines such as interleukin (IL)-812 and                   What is the significance of VEGF                  situation may be more complex in
eotaxin.13 Interestingly, angiogenesis                expression patterns in the bronchial                 COPD, however, due to coexisting
seems to be a feature of inflammatory                 vessels in asthma and COPD and how                   emphysema and pulmonary hyperten-
diseases at a number of sites in the body             might VEGF contribute to the pathology               sion.
including the joints14 and the gut.15                 of these diseases? Increased airway wall                In addition to studying VEGF expres-
   The study published in this issue of               thickening would cause enhanced air-                 sion in bronchial and bronchiolar walls,
Thorax by Kranenburg and colleagues16                 way narrowing on stimulation with                    Kranenburg et al16 also looked at VEGF
suggests that bronchial vascular                      constrictor agents, thereby contributing             staining in the alveolar spaces and
changes may also occur in chronic                     to bronchial hyperresponsiveness. An                 pulmonary vessels. They found that the
obstructive pulmonary disease (COPD).                 increased bronchial vasculature would                epithelial and endothelial cells in the
The authors measured the cellular                     increase inflammatory cell trafficking               alveolar spaces and the distal airways
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EDITORIAL                                                                                                                                               89

were intensively positive for VEGF in        that strategies specifically targeting                  12 Tanner JE. Nucleosomes activate NF-kappaB in
                                                                                                        endothelial cells for induction of the
patients with COPD. They hypothesise         VEGF in COPD would have unpredict-                         proangiogenic cytokine IL-8. Int J Cancer
that VEGF secreted by these cells may        able and possibly opposing effects on                      2004;112:155–60.
be involved in the establishment and         some of the different processes.                        13 Salcedo R, Young HA, Ponce ML, et al. Eotaxin
                                                                                                        (CCL11) induces in vivo angiogenic responses by
maintenance of the function of the             Over the next few years we are likely                    human CCR3+ endothelial cells. J Immunol
blood-gas interface. Studies in animal       to find out a great deal more about the                    2001;166:7571–8.
models suggest that VEGF and its             importance of the role of angiogenic                    14 Walsh DA. Angiogenesis in osteoarthritis and
                                                                                                        spondylosis: successful repair with undesirable
receptors play a protective role in the      processes in a number of different lung                    outcomes. Curr Opin Rheumatol
development of emphysema. Kasahara           diseases and the role that VEGF, its                       2004;16:609–15.
et al24 have shown that inhibition of        receptors, and other angiogenic factors                 15 Kanazawa S, Tsunoda T, Onuma E, et al. VEGF,
                                                                                                        basic-FGF, and TGF-beta in Crohn’s disease and
VEGF receptors with the specific recep-      play in several situations.                                ulcerative colitis: a novel mechanism of chronic
tor inhibitor SU5416 can cause alveolar                                                                 intestinal inflammation. Am J Gastroenterol
cell apoptosis and the development of        ACKNOWLEDGEMENTS                                           2001;96:822–8.
                                             The authors thank Rachel Small and Heather              16 Kranenburg AR, de Boer WI, Alagappan VKT,
emphysema in rats. These findings are                                                                   et al. Enhanced bronchial expression of
of interest as they suggest that the         Hickman for secretarial support.
                                                                                                        vascular endothelial growth factor and receptors
increased VEGF expression in the distal      Thorax 2005;60:88–89.                                      (Flk-1 and Flt-1) in patients with chronic
                                             doi: 10.1136/thx.2004.030544                               obstructive pulmonary disease. Thorax
airspaces seen by Kranenburg et al16 may                                                                2005;60:106–13.
be a protective compensating mechan-                                                                 17 Knox AJ, Corbett L, Stocks J, et al. Human
                                             ......................                                     airway smooth muscle cells secrete vascular
ism. Collectively, these studies suggest a
paradoxical role for VEGF in the bronchi     Authors’ affiliations                                      endothelial growth factor: up-regulation by
                                             A J Knox, J Stocks, A Sutcliffe, Division of               bradykinin via a protein kinase C and
and air spaces in COPD—with a protec-                                                                   prostanoid-dependent mechanism. FASEB J
                                             Respiratory Medicine, Nottingham City                      2001;15:2480–8.
tive role in the alveolus but a detri-       Hospital, Nottingham NG5 1PB, UK                        18 Wright JL, Tai H, Churg A. Cigarette smoke
mental function in the bronchi and                                                                      induces persisting increases of vasoactive
bronchioles.                                                                                            mediators in pulmonary arteries. Am J Respir Cell
                                             Correspondence to: Professor A J Knox,
   The situation becomes more complex                                                                   Mol Biol, 2004 (epub ahead of print)..
                                             Division of Respiratory Medicine, Clinical              19 Nilsson I, Shibuya M, Wennstrom S. Differential
still when changes in the pulmonary          Sciences Building, Nottingham City Hospital,               activation of vascular genes by hypoxia in
circulation are taken into account.          Hucknall Road, Nottingham NG5 1PB, UK;                     primary endothelial cells. Exp Cell Res
Kranenburg et al16 showed that VEGF
                                                                                                     20 Wen FQ, Liu X, Manda W, et al. TH2 Cytokine-
expression was increased in the pul-                                                                    enhanced and TGF-beta-enhanced vascular
monary vessels in COPD, suggesting a         REFERENCES                                                 endothelial growth factor production by cultured
potential role in the development of          1 Mitzner W, Wagner E. On the purported                   human airway smooth muscle cells is attenuated
                                                discovery of the bronchial circulation by Leonardo      by IFN-gamma and corticosteroids. J Allergy Clin
pulmonary hypertension. There is an                                                                     Immunol 2003;111:1307–18.
                                                da Vinci. J Appl Physiol 1992;73:1196–201.
extensive literature going back over          2 Orsida BE, Ward C, Li X, et al. Effect of a long-    21 Jeffery PK. Remodeling in asthma and chronic
10 years looking at the role of VEGF            acting b2-agonist over three months on airway           obstructive lung disease. Am J Respir Crit Care
                                                wall vascular remodeling in asthma. Am J Respir         Med 2001;164:S28–38.
and its receptors in pulmonary hyper-                                                                22 Lee YC, Kwak YG, Song CH. Contribution of
                                                Crit Care Med 2001;164:117–21.
tension. Pulmonary hypertension is            3 Orsida BE, Li X, Hickey B, et al. Vascularity in        vascular endothelial growth factor to airway
characterised by plexiform lesions in           asthmatic airways: relation to inhaled steroid          hyperresponsiveness and inflammation in a
                                                dose. Thorax 1999;54:289–95.                            murine model of toluene diisocyanate-induced
pulmonary vessels and VEGF is                                                                           asthma. J Immunol 2002;168:3595–600.
                                              4 Salvato G. Quantitative and morphological
expressed inside the plexiform lesions          analysis of the vascular bed in bronchial biopsy     23 Horiuchi T, Weller PF. Expression of vascular
as well as in smooth muscle adjacent to         specimens from asthmatic and non-asthmatic              endothelial growth factor by human eosinophils:
                                                subjects. Thorax 2001;56:902–6.                         upregulation by granulocyte macrophage colony-
the lesions.25 Data from animal models                                                                  stimulating factor and interleukin-5. Am J Respir
suggest that VEGF may have a protec-          5 Asai K, Kanazawa H, Kamoi H, et al. Increased
                                                levels of vascular endothelial growth factor in         Cell Mol Biol 1997;17:70–7.
tive role as inhibition of the VEGF             induced sputum in asthmatic patients. Clin Exp       24 Kasahara Y, Tuder RM, Taraseviciene-Stewart L,
                                                Allergy 2003;33:595–9.                                  et al. Inhibition of VEGF receptors causes lung cell
receptor II combined with chronic                                                                       apoptosis and emphysema. J Clin Invest
hypoxia causes cell death dependent           6 Kanazawa H, Hirata K, Yoshikawa J. Involvement
                                                of vascular endothelial growth factor in exercise       2000;106:1311–9.
pulmonary endothelial cell proliferation        induced bronchoconstriction in asthmatic patients.   25 Tuder RM, Chacon M, Alger L, et al. Expression of
                                                                                                        angiogenesis-related molecules in plexiform
and severe pulmonary hypertension.26            Thorax 2002;57:885–8.
                                                                                                        lesions in severe pulmonary hypertension:
Moreover, overexpression of VEGF              7 McDonald DM. Angiogenesis and remodeling of
                                                airway vasculature in chronic inflammation.             evidence for a process of disordered
using cell based gene transfer reduced          Am J Respir Crit Care Med 2001;164:S39–45.              angiogenesis. J Pathol 2001;195:367–74.
monocrotaline       induced pulmonary         8 Hoshino M, Nakamura Y, Hamid QA. Gene                26 Taraseviciene-Stewart L, Kasahara Y, Alger L,
                                                expression of vascular endothelial growth factor        et al. Inhibition of the VEGF receptor 2 combined
hypertension in rats,27 and similar find-                                                               with chronic hypoxia causes cell death-dependent
                                                and its receptors and angiogenesis in bronchial
ings were reported with adenoviral              asthma. J Allergy Clin Immunol                          pulmonary endothelial cell proliferation and
mediated overexpression in a chronic            2001;107:1034–8.                                        severe pulmonary hypertension. FASEB J
                                              9 Hoshino M, Takahashi M, Aoike N. Expression of          2001;15:427–38.
hypoxia rat model.28                                                                                 27 Campbell AI, Zhao Y, Sandhu R, et al. Cell-based
                                                vascular endothelial growth factor, basic
   The paper by Kranenburg et al is             fibroblast growth factor, and angiogenin                gene transfer of vascular endothelial growth
therefore an important one which raises         immunoreactivity in asthmatic airways and its           factor attenuates monocrotaline-induced
                                                relationship to angiogenesis. J Allergy Clin            pulmonary hypertension. Circulation
many questions about VEGF in COPD.                                                                      2001;104:2242–8.
                                                Immunol 2001;107:295–301.
VEGF and its receptors are involved in       10 Yancopoulos GD, Davis S, Gale NW, et al.             28 Partovian C, Adnot S, Raffestin B, et al.
many processes in COPD including                Vascular-specific growth factors and blood vessel       Adenovirus-mediated lung vascular
bronchial wall remodelling, emphy-              formation. Nature 2000;407:242–8.                       endothelial growth factor overexpression
                                             11 Ribatti D, Vacca A, Presta M. The discovery of          protects against hypoxic pulmonary hypertension
sema, and pulmonary hypertension.               angiogenic factors: a historical review. Gen            in rats. Am J Respir Cell Mol Biol
The complexity of these roles suggests          Pharmacol 2000;35:227–31.                               2000;23:762–71.

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90                                                                                                                    EDITORIAL

Tuberculin testing                                                                          funding bodies and political priorities—
.......................................................................................     not the quality of the researchers—that,
                                                                                            unlike probably any other disease, the

Tuberculin testing, BCG and
                                                                                            ‘‘gold standard’’ for this study as carried
                                                                                            out in 2000 was the same as it would

tuberculosis today
                                                                                            have been had it been carried out in
                                                                                               How good is that gold standard? Not
J Moore-Gillon                                                                              that good. The value of tuberculin
                                                                                            testing as an indicator of tuberculous
                                                                                            infection is hindered by prior BCG
                                                                                            vaccination and by exposure to environ-
Little progress has been made in the last 50 years                                          mental mycobacteria, hence the com-
                                                                                            plex assumptions about the relationship

     uberculosis is not simply a problem     method which gives an estimate for             between tuberculin dose and reaction
     hanging over from the past—it is a      the annual risk of infection which             size which have to be made by these and
     growing challenge—but what are          agrees best with that which would be           all other authors. The efficacy of BCG
the risks of acquiring tuberculosis infec-   expected from the prevalence of active         vaccination varies widely in different
tion in childhood, and how should those      tuberculous disease (in contrast to tuber-     populations throughout the world, and
risks be assessed?                           culous infection) in children.                 even at its very best it does not approach
   In this issue of Thorax Leung and            If these findings are applicable to         the levels of protection achieved with
colleagues1 analyse the results of tuber-    other populations, what is their impor-        vaccines against other diseases.
culin skin testing in over 21 000 chil-      tance? This paper refers to a population          Progress is being made in finding
dren in Hong Kong aged 6–9 years             with prior (neonatal) BCG vaccination,         better ways of identifying latent tuber-
between October 1999 and February            and it is possible that the tuberculin         culous infection. The identification of
2000. 99% of the children had received       skin test is a poor indicator of infection     antigen specific T cells in individuals
BCG vaccination in the neonatal period.      in the presence of BCG. Certainly, it          infected with M tuberculosis may be
The authors used three different             makes it more difficult to interpret the       achieved by demonstrating the release
approaches to the data to estimate the       test in the clinical context. The princi-      of interferon-c when they are appro-
subsequent annual risk of tuberculous        ples by which the results have been            priately stimulated.2 3 If the antigens
infection. In broad terms, one approach      analysed appear, however, to be equally        ESAT-6 or CFP10 are used, discrimina-
used the size of the tuberculin response     applicable to a population which has not       tion is possible between individuals who
to assess whether infection had              been near universally vaccinated, and          have been infected with M tuberculosis
occurred, using a cut off point of           the results suggest that the actual risk of    and those who have received prior BCG
>10 mm induration after skin testing         tuberculous infection may be lower than        vaccination4 5—a clear advantage over
with one unit of tuberculin. They then       that implied by ‘‘conventional’’ methods       tuberculin testing.
used age (which equals the number of         of its calculation. This may influence            Turning to vaccine development,
years each child had been at risk of         decisions about the cost effectiveness of      matters are less far forward. Many
infection) to estimate the annual risk.      mass BCG vaccination programmes,               approaches have been tried in animal
This is the ‘‘classic’’ method. The second   such as that currently offered to 13–          models but few are at the stage of even
approach estimated the annual risk of        14 year olds in the UK.                        phase 1 clinical trials. Possible new
infection by comparing the rates of             But there are wider issues here. The        vaccines are usually modified forms of
tuberculin positivity in the 8–9 year old    authors have used the very best avail-         BCG, are mutant strains of M tubercu-
age group with those in the 6–7 year old     able methods of testing for tuberculous        losis, or are prepared from subunits of M
group. The third estimated the preva-        infection. These tests are part of the         tuberculosis.6 New vaccines now have to
lence of infection by locating a second-     screening programme which is carried           overcome the hurdle of being safe to use
ary peak in the tuberculin reaction          out before offering BCG vaccination—           in at least the great majority of HIV
distribution curve and assuming that,        the vaccine which is again the very best       positive individuals if their benefits are
among those with tuberculosis infec-         available. It is, however, a poor reflec-      to outweigh their risks in many popula-
tion, there would be a symmetrical           tion on the priority which has been            tions at risk of TB. A greater under-
distribution of reaction sizes around this   accorded tuberculosis that exactly the         standing of the mycobacterial genome
peak. Age can then be used to calculate      same study could have been carried out         undoubtedly helps in identifying possi-
the annual risk of infection.                decades ago, because neither the best          ble ways forward,7 but at the present
   The first and second of these methods     method of diagnosing tuberculous               rate of research progress a replacement
are conventionally used to estimate the      infection nor the best vaccine against         for BCG is some way off.
annual risk of tuberculous infection,        tuberculosis have changed at all in that          There is, then, much to learn from the
and such estimates are necessary as          time. Quite clearly, this is not a criticism   study carried out by Leung and collea-
part of the calculations made about the      of these authors: they have carried out a      gues. At the most superficial level, it
cost effectiveness of BCG programmes.        first class study with the latest fully        reminds us that tuberculosis remains a
Leung et al show, however, that in their     validated tools available. The trouble is      threat to children; it ought not to be. It
population the first and second methods      that, in this area, ‘‘latest’’ means 50 or     then suggests that the methodology
gave estimates for the annual risk of        more years old. Investigation of new           usually used for estimating the annual
infection which were some three times        diagnostic techniques for tuberculous          risk of tuberculous infection in children
higher than the estimate produced by         infection (rather than disease) and the        may be inappropriate, with conse-
the third method. It would be easy to        development of new vaccines have               quences for screening and BCG pro-
conclude that the third (‘‘secondary         indeed been going on, largely by a             grammes. Finally, the nature of the
peak’’) method is not a valid approach       limited number of research groups who          tools that were available to the authors
which underestimates the risk. It is,        have struggled to find funding for             shows that there has been a compre-
however, this third non-conventional         their programmes. It is a reflection on        hensive failure on the part of the
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EDITORIAL                                                                                                                                               91

political and medical establishment to       REFERENCES                                               4 Lalvani A. Spotting latent infection: the path to
                                                                                                        better tuberculosis control. Thorax
invest adequately in research into one of     1 Leung CC, Yew WW, Tam CM, et al. Tuberculin             2003;58:916–8.
the leading infectious threats to global        response in BCG vaccinated schoolchildren and         5 Brock I, Weldingh K, Lillebaek T, et al.
health.                                         the estimation of annual risk of infection in Hong      Comparison of tuberculin skin test and new blood
                                                Kong. Thorax 2005;60:124–9.                             test in tuberculosis contacts. Am J Respir Crit Care
Thorax 2005;60:90–91.                         2 Mazurek GH, LoBue PA, Daley CL, et al.                  Med 2004;170:65–9.
                                                Comparison of a whole-blood interferon gamma          6 Fruth U, Young D. Prospects for new TB vaccines:
doi: 10.1136/thx.2004.028746                    assay with tuberculin skin testing for detecting        Stop TB working group on TB vaccine
                                                latent Mycobacterium tuberculosis infection.            development. Int J Tuberc Lung Dis
Correspondence to: Dr J Moore-Gillon,           JAMA 2001;286:1740–7.                                   2004;8:151–5.
Department of Respiratory Medicine, St        3 Lalvani A, Pathan AA, McShane H, et al. Rapid         7 Kana Bavesh D, Mizrahi V. Molecular genetics of
Bartholomew’s and Royal London Hospitals,       detection of Mycobacterium tuberculosis infection       Mycobacterium tuberculosis in relation to the
London EC1A 7BE, UK; john.moore-gillon@         by enumeration of antigen-specific T cells.             discovery of novel drugs and vaccines.                        Am J Respir Crit Care Med 2001;163:824–8.               Tuberculosis 2004;84:63–75.

PEF data plot                                                                                        survey of American medical journals
.......................................................................................              found that, in 74 pharmaceutical gra-
                                                                                                     phical presentations, 66% contained

The PEF data plot: planning to get the                                                               ‘‘chart junk’’, 46% had redundancy in
                                                                                                     the presentation, and over a third had

                                                                                                     numerical distortion.7
                                                                                                        PEF variability is a helpful signal in
                                                                                                     the diagnosis and management of
M R Miller                                                                                           asthma. If PEF readings are presented
                                                                                                     as just a stream of numbers on a sheet
                                                                                                     of paper, which some patients will offer
Work is needed to determine the best scaling for PEF data to                                         up in the clinic, it is a laborious process
                                                                                                     to check through these to find out what
enable patients and clinicians to get the most benefit from them                                     is going on. Graphical presentation of
                                                                                                     the data will help, but it has been shown

       large part of medical practice        and learns patterns. Facial recognition                 that subjects serially process only fixed
       involves pattern recognition. A       and the interpretation of facial expres-                amounts of data at a time and so some
       clinician may note that a few         sion are key aspects of human inter-                    types of graphical display are better than
key aspects of a patient’s history, their    action involving complex pattern recog-                 others in getting the information across
demographic data, their clinical exam-       nition. The ability of a clinician to                   quickly.8 The way data are presented on
ination, and chest radiograph fit a          interpret subtle changes in facial expres-              graphs or diagrams can therefore influ-
pattern they recognise as making a           sion of patients during a consultation is               ence our ability to spot any signal.
particular diagnosis highly probable.        important to ensure optimum commu-                      Reddel and colleagues3 point out that
This pattern involves more than one          nication has been achieved. Functional                  the abscissa scale for PEF plots has not
domain of data acquisition, and both         imaging has shown that specific areas of                been standardised. They found that each
within and between these domains our         the brain—the fusiform face area on the                 of 17 different PEF charts they obtained
ability to recognise patterns may be         inferior surface of the temporal lobe and               had slightly different scales. They have
affected by how the information is           the occipital face area—are involved in                 indicated that, if PEF data are plotted on
presented to us. If data are presented       face recognition.4 Recent functional                    a compressed time scale, then the ability
to us verbally, the ordering of this         magnetic resonance evidence indicates                   to detect a true change in PEF is
information may be crucial. For exam-        that these areas appear to be used for                  enhanced. Another example of this effect
ple, verbal instructions on how to get       expert or higher level recognition irre-                of scaling in respiratory practice is the
from ward A to ward B are easier to          spective of the type of image under                     presentation of flow-volume loops where
understand and use if they are given in      consideration.5 Research into whole                     incorrect scales will distort the data and
consecutive order starting from ward A       person recognition, which involves the                  may falsely suggest to the observer the
and ending up at ward B rather than the      assessment of the face and body habi-                   presence of upper airway obstruction.
instructions coming in random order.         tus, has found that the ability to                      The ATS document for standardising
The order in which a patient’s history is    recognise people was not impaired by                    spirometry indicates the optimum scal-
presented to a colleague is an example       showing the subjects in different pos-                  ing for presenting flow-volume loops
of this. The graphical presentation of       tures whereas changes in the subjects’                  (2 l/s of flow against 1 litre of volume)
tables of numbers may improve the            clothing did impair it.6 This indicates                 to avoid this sort of error.9
usefulness of the data,1 especially if       that related visual effects can be dis-                    Computers can be used to help
there is a shape in the data that conveys    tracting and alter our ability to recognise             identify patterns in data by the training
the signal and the time required to          patterns in complex visual data. So,                    of neural networks and this approach
search the data for any signal is thereby    when constructing charts or graphs to                   has been successfully applied to the
reduced.2 In this issue of Thorax Reddel     display data, we must be careful that all               recognition of upper airway obstruction
and colleagues3 question whether we are      non-essential items (‘‘chart junk’’) are                from flow-volume curves.10 For PEF
doing enough to present our patients’        left out. The trend to use three dimens-                data,     discriminant      analysis   was
peak expiratory flow (PEF) data in a         tional graphics where two dimensional                   employed by Gannon et al11 to facilitate
manner that is likely to facilitate both     would suffice is an example of unne-                    the recognition of work related changes
clinicians and patients distinguishing       cessary distracting information; the                    in PEF and their computer program has
the signal or message in the data from       exact projection of the top of a three                  led to improved sensitivity and specifi-
all the noise.                               dimensional bar or column onto the                      city when diagnosing occupational
   Research continues to add to our          relevant axis is often distorted by                     asthma. Statistical process control
understanding of how the brain detects       the three dimensional effect. A recent                  (SPC) techniques12 have been applied

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92                                                                                                                                        EDITORIAL

          1000                                           1000                                            stable monitoring, 4 times a day moni-
                                                          900                                            toring of recovery from an acute exacer-
           900                                            800                                            bation, or 2 hourly or more frequent
           800                                            600                                            readings for occupational settings and
           700                                            500                                            severe attacks. The respiratory commu-
                                                                                                         nity should now work to determine the
 PEF (l/min)


                                                 PEF (l/min)
                                                          400                                            best scaling for these various purposes
           500                                                 300                                       together with the best algorithms for
           400                                                                                 =20%      detecting true changes in the PEF data.
           300                                                 200                              change   Only then will patients and clinicians
                                                                                                         get the most benefit from these data.
           200                                                                                           Thorax 2005;60:91–92.
           100                                                                                           doi: 10.1136/thx.2004.035782
             0                                                 100
                 Day 1 Day 2 Day 3 Day 4 Day 5                       Day 1 Day 2 Day 3 Day 4 Day 5       Correspondence to: Dr M R Miller, Department
                                                                                                         of Medicine, University Hospitals Trust,
                                                                                                         Birmingham B29 6JD, UK; martin.miller@uhb.
Figure 1 PEF data for three patients on a          Figure 2 The same PEF data as in fig 1 on a 
linear ordinate scale.                             log ordinate scale.

to PEF data as a means for improving                                                                     REFERENCES
the detection of true signals in the data.         ensure control of their asthma is rapidly
                                                                                                          1 Jarvenpaa SL, Dickson GW. Graphics and
This technique assumes that the data               regained. The optimum abscissa scale                     managerial decision making: research based
should vary randomly following a                   for PEF charting will therefore need to                  guidelines. Communications of the ACM
                                                   vary according to purpose. For assessing                 1988;31:764–74.
Gaussian distribution and so newly                                                                        2 Larkin JH, Simon HA. Why a diagram is
acquired data points are compared with             stable asthmatics with a control chart, a                (sometimes) worth 10,000 words. Cognitive
an estimate of the usual level of varia-           once a day reading is needed and a                       Science 1987;11:65–100.
                                                   compressed time scale is ideal. Reddel                 3 Reddel HK, Vincent SD, Civitico J. The need for
tion about the mean, which is the                                                                           standardisation of peak flow charts. Thorax
standard deviation (SD) of the data. A             and colleagues have previously proposed                  2005;60:164–7.
significant deviation from the baseline            an alternative method using the lowest                 4 Sergent J, Ohta S, MacDonald B. Functional
                                                   morning pre-bronchodilator PEF in the                    neuroanatomy of face and object processing: a
state is judged to have occurred if a                                                                       positron emission tomography study. Brain
single data point is more than 3 SD from           week expressed as a percentage of                        1992;115:15–36.
the mean, or two of three sequential               recent best or predicted as the preferred              5 Gauthier I, Skudlarski P, Gore JC, et al. Expertise
                                                   indicator of control.14 However, in occu-                for cars and birds recruits brain areas involved in
data are between 2 and 3 SD from the                                                                        face recognition. Nat Neurosci 2000;3:191–7.
mean, or four of five sequential data are          pational asthma readings of up to every
                                                                                                          6 Seitz K. The effect of changes in posture and
between 1 and 2 SD, or eight successive            2 hours may be needed to detect a work                   clothing on the development of unfamiliar person
data are between 0 and 1 SD from the               related change in lung function,15 and                   recognition. Appl Cognitive Psychol
                                                   this frequency may initially be the                      2003;17:819–32.
mean.12 The assumption of a Gaussian                                                                      7 Cooper RJ, Schriger DL, Wallace RC, et al. The
distribution may be true for once a day            minimum required to monitor recovery                     quantity and quality of scientific graphs in
morning pre-bronchodilator PEF values              from a severe asthma attack.                             pharmaceutical advertisements. J Gen Intern Med
                                                      The choice of abscissa scale may not                  2003;18:294–7.
and this technique has been successfully                                                                  8 Legge GE, Gu YC, Luebker A. Efficiency of
applied for the detection of changes               be the only issue. An abstract some                      graphical perception. Percept Psychophys
from baseline in otherwise stable                  years ago at a British Thoracic Society                  1989;46:365–74.
                                                   meeting suggested that a log ordinate                  9 American Thoracic Society. Standardization of
patients.13 If several data points a day                                                                    spirometry 1994 update. Official statement of the
are used for asthmatics who have a large           scale for PEF might be an improvement.                   American Thoracic Society. Am J Respir Crit Care
morning dip in PEF, then this assump-              The degree of variation in PEF is the                    Med 1995;152:1107–36.
                                                   main point of interest for helping with               10 Bright P, Miller MR, Franklyn JA, et al. The use of
tion may no longer be correct as there                                                                      a neural network to detect upper airway
are, in fact, two populations of results           the diagnosis of asthma, and a 20%                       obstruction caused by goiter. Am J Respir Crit
being lumped together. The application             change from best value has been found                    Care Med 1998;157:1885–91.
                                                   to be associated with asthma.16 17 Using              11 Gannon PF, Newton DT, Belcher J, et al.
of SPC may not therefore be so helpful                                                                      Development of OASYS-2: a system for the
for other applications of PEF data, such           a log scale for PEF might facilitate                     analysis of serial measurement of peak expiratory
as the diagnosis or monitoring of                  recognising this from the data. For                      flow in workers with suspected occupational
recovery from an acute attack.                     example, in fig 1 there are three sets of                asthma. Thorax 1996;51:484–9.
                                                                                                         12 Boggs PB. Peak expiratory flow rate control chart:
   The above control charting method               identically patterned data each with                     a breakthrough in asthma care. Ann Allergy
requires an estimate of the baseline               different mean PEF. Plotting these data                  Asthma Immunol 1996;77:429–32.
mean value and its variance which are              with PEF on a log scale as in fig 2 makes             13 Boggs PB, Wheeler D, Washburne WF. Peak
                                                                                                            expiratory flow rate control chart in asthma care:
hard to obtain from hand recorded data.            it more obvious that these all have                      chart construction and use in asthma care. Ann
The use of data logging meters facil-              identical percentage variation.                          Allergy Asthma Immunol 1998;81:552–62.
itates this approach and they are now                 We must therefore be sure that we are              14 Reddel HK, Salome CM, Peat JK, et al. Which
                                                                                                            index of peak expiratory flow is most useful in the
available for under £10 (15 euros), with           always presenting PEF data (or any                       management of stable asthma? Am J Respir Crit
associated PC software about twice                 other data) to best advantage. As                        Care Med 1995;151:1320–5.
this cost. The micro chips in these                Reddel and colleagues argue,3 if we do                15 D’Alonzo GE, Steinijans VW, Keller A.
                                                                                                            Measurements of morning and evening airflow
devices usually have spare capacity, so            not do this for our asthma patients then                 grossly underestimate the circadian variability of
interactive meters that are tailored to            we let them down and undermine their                     FEV1 and peak expiratory flow rate in asthma.
the subject and their requirements are             efforts to help in the monitoring of their               Am J Respir Crit Care Med 1995;152:1097–9.
                                                                                                         16 Higgins BG, Britton JR, ChinnS, et al. The
entirely feasible. The use of SPC on daily         condition. In future, cheap electronic                   distribution of peak flow variability in a
PEF values could easily be implemented             peak flow meters with data logging                       population sample. Am Rev Respir Dis
and, if threshold criteria as above are            capability will increasingly be used and                 1989;140:1368–72.
                                                                                                         17 Thiadens HA, De Bock GH, Dekker FW, et al.
breeched, then patients could be                   the graphical presentation of the data                   Value of measuring diurnal peak flow variability
prompted to change their treatment                 can be flexible and optimised for the                    in the recognition of asthma: a study in general
and timing of PEF measurements to                  purpose, be it once a day readings for                   practice. Eur Respir J 1998;12:842–7.
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EDITORIAL                                                                                                                             93

Starting dose of ICS in adult asthma                                                         were noted in the magnitude of change
.......................................................................................      in morning peak flow in patients receiv-
                                                                                             ing high (500 or 1000 mg per day) or low

Optimal starting dose of inhaled
                                                                                             ((200 mg per day) doses of FP.11 The
                                                                                             time taken to reach either 50% or 100%

corticosteroids in adult asthma: why
                                                                                             of the best observed effect was no longer
                                                                                             in the low dose group, once again
                                                                                             demonstrating no reduction in different
has it taken so long?                                                                        parameters of efficacy.
                                                                                                The major limitation of these meta-
M Masoli, M Weatherall, R Beasley                                                            analyses was the small number of
                                                                                             studies that included FP doses of
...................................................................................          1000 mg per day or more, due to the
                                                                                             requirement for the studies to be pla-
Start at a dose considered to be appropriate for the severity of the                         cebo controlled. This led to a subsequent
disease, usually 400 mg BDP or equivalent                                                    meta-analysis which specifically focused
                                                                                             on comparisons between a dose of
                                                                                             200 mg per day and higher doses to

   t is disturbing to realise that, although   approach demonstrated in this meta-
   inhaled corticosteroids have been pre-      analysis of initiating treatment with         determine whether the 200 mg per day
   scribed for over three decades in the       moderate doses of inhaled corticoster-        dose regime provided most of the
treatment of asthma, there are still           oids has advantages in terms of a better      therapeutic benefit as suggested in the
major therapeutic issues associated with       risk/benefit ratio and reduced economic       original study.8 It was confirmed that
their use that have yet to be clearly          cost. As discussed by the authors, the        most of the therapeutic effect was
determined. One of these issues is the         main limitations of their meta-analysis       achieved with a dose of 200 mg per
optimal starting dose. This uncertainty        were the small number of studies which        day, and that an increase in dose to
is illustrated by the different approaches     could be included in the subgroup             >500 mg per day resulted in minimal
that have been proposed for starting           analyses and the inability to examine         additional benefit.
inhaled corticosteroids in patients with       severe exacerbations as an outcome               Another meta-analysis with inhaled
asthma ranging from ‘‘start with a high        measure as it was not reported in most        budesonide has shown that most of the
dose then step down once control has           of the included studies. However,             clinical efficacy for the same outcome
been achieved’’,1 2 ‘‘start with a dose of     despite these limitations, the findings       measures is achieved with a dose of
400 mg3 or 200–500 mg per day beclo-           from this meta-analysis represent the         around 400 mg per day.9 Likewise, a
methasone dipropionate (BDP) or                best integration of current scientific        large dose-response study of BDP
equivalent and then step up if                 evidence and can be incorporated in           showed a plateau in response between
required’’,4 or ‘‘start at the dose con-       consensus guidelines. In this regard, the     400 and 800 mg per day, depending on
sidered to be appropriate for the severity     current British guidelines represent the      the clinical outcome variable.12 These
of disease, usually 400 mg of BDP or           ideal recommendation—to start at a            findings are comparable with those of
equivalent’’.5                                 dose considered to be appropriate for         FP when their relative potencies are
   To address this uncertainty and deter-      the severity of disease, usually 400 mg       considered (FP v budesonide or BDP
mine the optimal starting dose of              BDP or equivalent.5                           around 2:1).
inhaled corticosteroids in adults with            The findings are also consistent with         Another consideration is whether a
asthma, Powell and Gibson have under-          recent meta-analyses of the dose-             different dose-response relationship
taken a systematic review and meta-            response relationship of inhaled corti-       exists for inhaled corticosteroids in
analysis of randomised controlled trials       costeroids in adult asthma.7–11 The initial   terms of modifying the underlying air-
that have investigated this issue. Their       meta-analysis showed that, for different      ways inflammation. Only a few studies
findings were reported in a recent issue       outcome measures including lung func-         have addressed this issue because of the
of Thorax6 and indicate that, for patients     tion, symptoms, b agonist use and             requirement for repeated bronchoscopic
with asthma who require inhaled corti-         exacerbations, at least 90% of the max-       examinations to obtain bronchial biopsy
costeroids, there is no evidence of a          imum efficacy can be achieved with a          and lavage samples. These studies have
difference in efficacy between commen-         dose of fluticasone propionate (FP) of        reported no additional effect on either
cing with a moderate dose (400 mg per          around 200 mg per day.7 In the moderate       the nature or magnitude of the airways
day BDP or equivalent) compared with a         to severe adult asthmatic patients            inflammation with increasing the dose
high dose (>800 mg per day) and step-          included in the studies of the meta-          of FP from 400–500 mg per day to 1000–
ping down. An initial moderate dose of         analysis, the maximum therapeutic             2000 mg per day.13 14 As a result, the
inhaled corticosteroids was more effec-        effect was achieved with a dose of FP         dose-response relationship of inhaled
tive than an initial low dose (200 mg per      of around 500 mg per day. This meta-          corticosteroids for anti-inflammatory
day).                                          analysis challenged the dogma that            effects in the airways appears to be
   These findings are reassuring in that       existed at the time—that higher doses         similar to that for the clinical outcome
they do not support the ‘‘start high, step     were required to achieve the maximal          measures.
down’’ approach which has the poten-           obtainable effect and that there were            The major clinical outcome measure
tial to lead to inappropriately high doses     marked differences in the dose-response       which could not be assessed in dose-
of inhaled corticosteroids being used          relationship for different clinical out-      response studies is mortality because of
long term. This may occur if the patient       come measures. In particular, the dose        its rare occurrence even in patients with
does not attend for regular review so the      of FP required to reduce exacerbations        severe asthma. However, it is possible to
initial dose becomes the long term             was similar to that required to reduce        obtain an indication of the dose-
maintenance dose, or if on medical             symptoms and improve lung function.           response effect of inhaled corticoster-
review there is a reluctance to reduce            Similarly, in another meta-analysis of     oids for reducing the risk of mortality
the high dose in case it leads to wor-         placebo controlled dose-response stu-         from the epidemiological study reported
sening asthma control. The preferred           dies of FP, no significant differences        by Suissa et al.15 In this study there was a

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94                                                                                                                                    EDITORIAL

progressive reduction in risk of mortal-      add a LABA over a fivefold inhaled                         WHO Workshop Report. Bethesda, MD: National
                                                                                                         Institutes of Health, National Heart, Lung and
ity with increasing use of inhaled            corticosteroid dose range (200–1000 mg                     Blood Institute, 2002.
corticosteroids. Consistent with the          per day BDP or equivalent).2–5                         5   British Thoracic Society/Scottish Intercollegiate
major clinical outcome measures, at           Determination of the dose of inhaled                       Guidelines Network. British guideline on asthma
                                                                                                         management: a national clinical guideline.
least 80% of the maximum obtainable           corticosteroids at which to add a LABA                     Thorax 2003;58(Suppl I):i1–94.
benefit (reduction in mortality) was          as first line add-on therapy at step 3 of              6   Powell H, Gibson PG. Initial starting dose of
achieved at around 200 mg BDP per             the guidelines will probably also require                  inhaled corticosteroids in asthma for adults: a
                                                                                                         systematic review. Thorax 2004;59:1041–5.
day (adjusted odds ratio 0.15). As a          a meta-analytical approach. Elucidation                7   Holt S, Suder A, Weatherall M, et al. Dose-
result, available evidence suggests that      of the optimal starting dose and the                       response relation of inhaled fluticasone
low doses of inhaled corticosteroids are      therapeutic dose range of inhaled corti-                   propionate in adolescents and adults with asthma:
                                                                                                         meta-analysis. BMJ 2001;323:253–6.
effective in reducing the risk of death       costeroids has provided important infor-               8   Masoli M, Weatherall M, Holt S, et al. Clinical
from asthma, with a dose response             mation for the planning of such a meta-                    dose-response relationship of fluticasone
similar to that of other major outcome        analysis.                                                  propionate in adults with asthma. Thorax
variables such as symptoms, lung func-        Thorax 2005;60:93–94.                                  9   Masoli M, Holt S, Weatherall M, et al. Dose-
tion, and severe exacerbations.               doi: 10.1136/thx.2004.031179                               response relationship of inhaled budesonide in
   Based on these studies, it can be                                                                     adult asthma: a meta-analysis. Eur Respir J
recommended that the standard dose            ......................                                10   Bousquet J, Ben-Joseph R, Messonnier M, et al. A
of inhaled corticosteroid for routine         Authors’ affiliations                                      meta-analysis of the dose-response relationship of
prescribing in adult asthma is around         M Masoli, R Beasley, Medical Research                      inhaled corticosteroids in adolescents and adults
                                              Institute of New Zealand, Wellington, New                  with mild to moderate persistent asthma. Clin Ther
400 mg per day BDP or budesonide, or                                                                     2002;24:1–20.
200 mg per day FP. This recommenda-           Zealand                                               11   Szefler SJ, Bousher HA, Pearlman DS, et al. Time
                                              M Weatherall, Wellington School of Medicine                to onset of effect of fluticasone propionate in
tion should be qualified by the recogni-
                                              & Health Sciences, Wellington, New Zealand                 patients with asthma. J Allergy Clin Immunol
tion that there is considerable variability   R Beasley, University of Southampton,                      1999;103:780–8.
between individuals in their response         Southampton, UK                                       12   Busse WW, Brazinsky S, Jacobson K, et al. Effi-
to inhaled corticosteroids in asthma,                                                                    cacy response of inhaled beclomethasone dipro-
                                                                                                         pionate in asthma is proportional to dose and is
which means that some patients may            Correspondence to: Professor R Beasley,                    improved by formulation with a new propellant.
obtain a greater clinical benefit at higher   Medical Research Institute of New Zealand,                 J Allergy Clin Immunol 1999;104:1215–22.
doses, just as some patients may obtain       P O Box 10055, Wellington, New Zealand;               13   Wallin A, Sue-Chu M, Bjermer L, et al. Effect of
                                                                    inhaled fluticasone with and without salmeterol on
the maximum efficacy at lower doses.16                                                                   airway inflammation in asthma. J Allergy Clin
   So what is the priority now in terms                                                                  Immunol 2003;112:72–8.
of research into the use of inhaled                                                                 14   O’Sullivan S, Cormican L, Murphy M, et al.
                                              REFERENCES                                                 Effects of varying doses of fluticasone propionate
corticosteroid therapy in asthma?             1 Barnes PJ, Pedersen, Busse W. Efficacy and safety        on the physiology and bronchial wall
Currently, the major dilemma for clin-          of ICS: new developments. Am J Respir Crit Care          immunopathology in mild-to-moderate asthma.
icians is to know at what dose of               Med 1998;157(3 Pt 2):S1–39.                              Chest 2002;122:1966–72.
                                              2 National Asthma Council. Asthma management          15   Suissa S, Ernst P, Benayoun S, et al. Low-dose
inhaled corticosteroids to start conco-         handbook, National Asthma Council, 2002.                 inhaled corticosteroids and the prevention of
mitant long acting b agonist (LABA)           3 New Zealand Guidelines Group. Best practice              death from asthma. N Engl J Med
therapy in a patient inadequately con-          evidence-based guideline: the diagnosis and              2000;343:332–6.
trolled on inhaled corticosteroids alone.       treatment of adult asthma, New Zealand              16   Szefler SJ, Martin RJ, King TS, et al. Significant
                                                Guidelines Group, 2002:101.                              variability in response to inhaled corticosteroids
This uncertainty is reflected by the          4 Global Initiative for Asthma. Global strategy for        for persistent asthma. J Allergy Clin Immunol
different guideline recommendations to          asthma management and prevention, NHLBI/                 2002;109:410–8.

Guidelines on management of pleural infection in children                                           chair of the guideline committee and
.......................................................................................             may not represent those of the other
                                                                                                    members of the committee (listed in the

Some consensus but little evidence:

guidelines on management of pleural                                                                 WHY DID WE WRITE THEM?
                                                                                                    We are not paediatricians for nothing—
infection in children                                                                               we understand sibling rivalry—so when
                                                                                                    the adult respiratory physicians got an
                                                                                                    empyema guideline,2 we wanted one.
I M Balfour-Lynn                                                                                    However, it was more than just that.
...................................................................................                 There are major differences between
                                                                                                    adult and paediatric pleural infections.
A review of the newly published guidelines on the management of                                     The principal one is that most children
                                                                                                    are fit and well before they contract
pleural infection in children                                                                       pneumonia and develop an empyema,
                                                                                                    so the outcome is almost always excel-

      ommissioned by the British              Committee (QPC) of the Royal College                  lent. This is in contrast to the disease in
      Thoracic Society (BTS) Standards        of Paediatrics and Child Health                       adults where empyema is a cause of
      of Care Committee, the BTS guide-       (RCPCH) using the AGREE appraisal                     significant morbidity and mortality
lines for the management of pleural           instrument, and consequently have                     (recent data has revealed a 12% mortal-
infection in children are published as a      been endorsed by the RCPCH. So why                    ity rate even in those without cancer3).
supplement to this month’s issue of           did we write them and was it worth it?                Nevertheless, management of childhood
Thorax.1 They have also been subject to       More importantly—should you read                      empyema can still be a therapeutic
scrutiny by the Quality of Practice           them? What follows are my views as                    challenge. Unfortunately, in the UK
                         Downloaded from on December 12, 2011 - Published by
EDITORIAL                                                                                                                             95

there is little consensus over best prac-     tifiable from previous pro/con debates).        trial provided three of the four SIGN
tice, both among respiratory paediatri-       With the use of email, only one meeting         grade B recommendations in the guide-
cians and also thoracic surgeons. It was      was required with the whole group.              lines. The only other grade B recom-
therefore considered important to             Where there was no evidence we relied           mendation was related to using
synthesise the available evidence and         on ‘‘expert opinion’’ and, while we did         microbiology results to guide antibiotic
write guidelines, even though they may        not use a formal consensus technique,           choice (grade taken from adult guide-
only point people in the right direction      the guidelines are a fair reflection of the     lines), but even then the RCPCH QPC
and highlight the unresolved issues. It is    opinions of the whole committee as well         downgraded that to a D. There was not a
hoped that the guidelines will facilitate     as the specialist reviewers. It was             single grade A recommendation, seven
dissemination of evidence and standar-        pointed out by the RCPCH that we did            grade Cs, and 46 grade Ds (fig 1). This
disation of patient care. While they are      not have ‘‘consumer input’’. While I            means that 80% of our recommenda-
principally aimed at the UK, they are         would agree that guidelines on chronic          tions were based on evidence taken
applicable to children worldwide. The         diseases such as asthma or cystic fibro-        from case reports, case series, and expert
principal differences in management           sis benefit from patient/parent input, I        opinion. This should not be used as a
from the UK will concern predominant          do not believe this to be case with a one-      criticism of the guidelines; it is simply a
local pathogens, availability of antibio-     off acute condition such as an empyema          reflection of the available evidence. In
tics and fibrinolytics, and availability of   where parents will not have gained a            addition, many of the grade D recom-
trained personnel.                            particular expertise. The guidelines went       mendations are based on safe current
                                              through several review stages including         practice and common sense. No one can
HOW DID WE WRITE THEM?                        the BTS Standards of Care Committee,            deny that ‘‘analgesia is important to
For anyone unfamiliar with the process        specialist reviewers (listed below), and        keep the child comfortable, particularly
of writing a guideline, the website of        the RCPCH QPC. Our thanks are due to            in the presence of a chest drain’’, a grade
the Scottish Intercollegiate Guideline        them all for their valuable contributions.      D recommendation that never has been
Network (SIGN) is invaluable (www.                                                            (nor ever should be) subjected to a and we followed their pro-                                                        randomised controlled trial. Perhaps
                                              WHAT PROBLEMS DID WE
cess for producing levels of evidence and                                                     SIGN should come up with an extra
grades of recommendations. Literature                                                         grade (E)—no evidence but blindingly
                                              Guidelines need to be evidence-based,
searching was extensive and profes-                                                           obvious. Our grade D recommendation
                                              so this immediately presented a problem
sional (library of National Heart Lung                                                        that ‘‘all children with parapneumonic
                                              as there is a lack of evidence from
Institute) and the search strategy is                                                         effusion or empyema should be
                                              randomised controlled trials for almost
included as an appendix to the guide-                                                         admitted to hospital’’ would fit that
                                              all the relevant issues in childhood
lines. It was kept up to date and                                                             category. Evidence from randomised
                                              empyema. In addition, it is inappropri-
rechecked by individual members res-                                                          controlled trials should not be the only
                                              ate simply to extrapolate adult data to
ponsible for a particular topic. We                                                           resource that informs guidelines, and
                                              children, particularly when the condi-
ensured the make-up of the guideline                                                          clinical experience should not be
                                              tion behaves so differently in the two
committee included all the relevant                                                           excluded.
                                              populations. Why so few trials?
disciplines: a general/emergency pae-
                                              Empyema has until recently been rela-
diatrician, respiratory paediatricians
                                              tively rare in developed countries. Over        WHAT DID WE RECOMMEND?
(including a trainee), a paediatric and
                                              the last decade there has been a notice-        There are 57 bulleted recommendations
thoracic surgeon, a microbiologist and
                                              able increase both in the UK and the            with accompanying explanatory text
a radiologist. We also ensured that
                                              USA;1 in our own institution 20 cases           and one algorithm summarising man-
representatives of the different major
                                              were reported during the 5 year period          agement. The guidelines need reading in
viewpoints were included (readily iden-
                                              from 1990 to 1994 inclusive,4 whereas           full, but there are a few points worth
                                              we now see that many cases each year.           highlighting. There is no role for routine
                                              While this may reflect a change in              lateral chest radiographs or CT scans;
                                              referral patterns, undoubtedly there            plain chest radiographs and ultrasound
                                              has been a genuine increase in inci-            are sufficient and will reduce the radia-
                                              dence. In the UK the predominant                tion burden. Pleural fluid must be sent
 60                                           pathogen is penicillin-sensitive pneumo-        for cell differential counting (or cytol-
                                              coccus, while in developing countries it        ogy) as well as microbiological analysis,
                    22                23      is still Staphylococcus aureus.1 It is possi-   but there is nothing to gain from
                                              ble that the increased incidence in the         biochemical analysis (such as pH, glu-
   0                                          UK coincides with a reduction in anti-          cose, protein, lactate dehydrogenase). If
         I          II        III     IV
                                              biotic prescribing in primary care.5            there is any suspicion of malignancy, a
                 Levels of evidence
                                              Although it is good that less amoxicillin       small volume diagnostic tap for cytolo-
                                              is given to ‘‘chesty’’ children with viral      gical testing is needed, where possible
 50                                   46
                                              upper respiratory tract infections, the         avoiding general anaesthesia/sedation to
                                              cost may be a missed opportunity for            prevent potentially disastrous superior
                                              early treatment of the few children             mediastinal obstruction. Significant
                                              with genuine pneumonia.                         effusions should be drained from the
                                                 As management of empyema became              outset; repeated taps are not recom-
                                              more of an issue, the British Paediatric        mended.
                                              Respiratory Society Empyema Study                  We recommend that a respiratory
         0                                    Group (led by Anne Thomson in                   paediatrician should be involved early
         A          B         C       D       Oxford) performed the only major pla-           in the care of all patients requiring chest
             Grades of recommendations        cebo controlled randomised trial in             tube drainage for an empyema. We feel
                                              childhood empyema—a multicentre                 strongly that this condition should be
Figure 1 Levels of evidence and grades of     trial of intrapleural urokinase that still      looked after in tertiary centres, not least
recommendation using SIGN ratings.1           took two winters to enrol 60 cases.6 This       because of the nursing expertise

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96                                                                                                                          EDITORIAL

required to safely manage chest drains.           For those having the medical option       and discomfort must be taken into
Empyema is still relatively uncommon           (see algorithm of guideline), based on       account, not just days in hospital, as
and, given the uncertainties over man-         a randomised controlled trial,6 use of       most children would prefer an extra day
agement, we feel it is not ideal for           intrapleural urokinase is recommended        or so in hospital if it meant significantly
patients to be treated in a general            when there is thick fluid with locula-       less pain. It is likely that large multi-
paediatric unit that might only treat          tions or overt pus. The biggest issue is     centre trials will be necessary to make
one or two cases a year. To an extent          the role of surgery as primary treatment.    any serious progress, although there is
this recommendation for referral is            There is little dispute that failure of      an ongoing study at Great Ormond
happening anyway, partly because con-          chest tube drainage, antibiotics, and        Street Hospital for Children comparing
straints imposed by junior doctor work-        fibrinolytic agents should prompt dis-       intrapleural urokinase with early VATS
ing hours and the European Working             cussion with a thoracic surgeon, and         in a randomised non-blinded trial.
Time Directive mean that many paedia-          that patients should be considered for
tric specialist registrars are no longer       surgical treatment if they have persist-     CONCLUSIONS
experienced at chest drain insertion. We       ing sepsis in association with a persis-     I will conclude by quoting a statement
also find that many anaesthetists in           tent pleural collection. The issue where     from the RCPCH guideline appraisal:
district general hospitals are now             consensus cannot be reached in the UK        ‘‘Guidelines are not intended to restrict
unwilling to anaesthetise children with        is the role of medical versus early          clinical freedom, but practitioners are
respiratory compromise. Interestingly,         surgery and, if surgery is chosen,           expected to use the recommendations as
this recommendation—which I believe            whether a mini-thoracotomy or video          a basis for their practice. Local resources
to be one of the most important in the         assisted thoracoscopic surgery (VATS) is     and the circumstances and preferences
whole guideline—was the only one that          superior. There are no trial data to         of individual patients will need to be
the RCPCH QPC was not keen on                  inform the decision; however, there are      taken into account’’. This is certainly
                                               many case series, mostly written by          true of childhood empyema and, yes,
publishing in the version due to be sent
                                               enthusiasts of their own technique,          these BTS guidelines should be read.
to all UK paediatricians. Clearly, there
                                               using historical ‘‘controls’’. For this
will be circumstances when it is unne-
cessary or not in the child’s best interest
                                               reason our guideline gives medical and       ACKNOWLEDGEMENTS
                                               surgical options in the management           Paediatric Pleural Diseases Subcommittee of
to move large distances, but there is a                                                     the BTS Standards of Care Committee: Dr I M
                                               algorithm. For now, units should con-
concern that medicolegal consequences                                                       Balfour-Lynn (Chair), Dr E Abrahamson, Mr
                                               tinue to manage their cases using their
may follow if management goes wrong                                                         G Cohen, Dr J Hartley, Dr S King, Mr D
                                               own established and familiar practices,
outside a tertiary centre.                                                                  Parikh, Dr D Spencer, Dr A H Thomson, Dr D
                                               in whatever way they feel is best from       Urquhart. Also Dr B G Higgins (past Chair),
   We have suggested some antibiotic           their own experiences. Available
regimens but local antibiotic policies                                                      Dr D Boldy (present Chair) and the other
                                               resources may also affect local policy,      members of the BTS Standards of Care
and likely pathogens should also be            especially in health services with finan-    Committee.
taken into account. There is no evidence       cial constraints. Parents and children       Specialist reviewers: Dr R Dinwiddie, Dr I
that large bore drains confer any advan-       need to be fully informed of the options     Doull, Mr P Goldstraw, Dr R A Primhak, Dr P
tage over small ones, but they certainly       (good patient information sheets are         Seddon. Also Dr H Baumer (Chair) and other
cause more pain and reduce mobility, so                                                     members of RCPCH Quality of Practice
                                               essential), but ultimately they are likely   Committee.
small ones (8–12 FG) should be used            to be swayed by the opinion of the
where possible. They should be placed at       treating doctors and nurses. In the case     Thorax 2005;60:94–96.
the optimum site suggested by ultra-           series of 20 patients treated at the Royal   doi: 10.1136/thx.2004.038406
sound, but not too far posteriorly as they     Brompton Hospital during 1990–4, 65%         Correspondence to: Dr I M Balfour-Lynn,
are uncomfortable to lie on and there is       had immediate surgery but 90% even-          Department of Paediatric Respiratory Medicine,
a greater risk of traumatic bleeding from      tually required surgery;4 currently, with    Royal Brompton Hospital, Sydney Street,
the posterior intercostal spaces. One of       the use of small drains and urokinase,       London SW3 6NP, UK; i.balfourlynn@imperial.
the more contentious issues was                only 5–10% require surgery in our
whether drains should be inserted              centre. What is needed is an under-
under general anaesthesia or sedation          standing of the factors that predict         REFERENCES
with local anaesthesia. Most anaesthe-         failure of medical management, as these       1 Balfour-Lynn IM, Abrahamson A, Cohen G, et al.
                                                                                               BTS guidelines for the management of pleural
tists would not endorse intravenous            children could then be selected for             infection in children. Thorax 2005;60(Suppl
sedation (especially in a child with           immediate surgery while the rest could          I):i1–21.
respiratory compromise), but a defini-         have simple medical management.               2 Davies CH, Gleeson FV, Davies RJO. BTS
                                                                                               guidelines on the management of pleural
tive anaesthetic guideline does not exist                                                      infection. Thorax 2003;58(Suppl II):ii18–28.
to clarify this issue. Personally, I believe   FUTURE RESEARCH                               3 Maskell NA, Davies CWH, Ghabe R, et al.
a general anaesthetic is kinder for the                                                        Predictors of survival in patients with pleural
                                               The guidelines offer a list of potential        infection but without cancer: results from the
child (especially younger ones); it also       areas for future clinical research. In          MRC/BTS MIST Trial, ICTN 39138989. Thorax
makes the procedure easier and allows          terms of management, the issue of               2004;59(Suppl II):ii40.
time for a long line to be inserted. The                                                     4 Khakoo GA, Goldstraw P, Hansell DM, et al.
                                               drain/fibrinolytics versus early mini-          Surgical treatment of parapneumonic empyema.
compromise for the guidelines was our          thoracotomy versus VATS is the out-             Pediatr Pulmonol 1996;22:348–56.
recommendation that intravenous seda-          standing one. Since the outcome is            5 Ashworth M, Latinovic R, Charlton J, et al. Why
tion should only be given by those                                                             has antibiotic prescribing for respiratory illness
                                               generally so good in terms of clinical          declined in primary care? A longitudinal study
trained in the use of conscious sedation,      recovery, lung function and chest radio-        using the General Practice Research Database.
airway management and resuscitation            graphic appearance (whatever the treat-         J Public Health (Oxford) 2004;26:268–74.
of children, using full monitoring equip-      ment), it will be difficult to prove one      6 Thomson AH, Hull J, Kumar MR, et al.
                                                                                               Randomised trial of intrapleural urokinase in the
ment—something which I suspect will            better than another, and most treatment         treatment of childhood empyema. Thorax
rule out many paediatricians anyway.           regimens will show equivalence. Pain            2002;57:343–7.
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                                  The ebb and flow of asthma
                                  B G Toelle and G B Marks

                                  Thorax 2005 60: 87-88
                                  doi: 10.1136/thx.2004.038331

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