In a recent otherwise excellent editorial in Thorax [1], Dr. Seersholm indicated that our previous results on FEV1 decline based on the
Copenhagen City Heart Study [2] are biased. We disagree, and rather
believe that our study of the general population is prone to less bias
than case-control or family-based studies.
Dr. Seersholm argues that because we genotyped study participants
after measuremen...
In a recent otherwise excellent editorial in Thorax [1], Dr. Seersholm indicated that our previous results on FEV1 decline based on the
Copenhagen City Heart Study [2] are biased. We disagree, and rather
believe that our study of the general population is prone to less bias
than case-control or family-based studies.
Dr. Seersholm argues that because we genotyped study participants
after measurement of FEV1 in 1976-1978, 1981-1984, and 1991-1994, our
results are biased [1]. Certainly, if conventional risk factors are
measured after development of disease, the disease might be the cause of
the risk factor, rather than vice versa. However, an alpha1-antitrypsin MZ genotype in a newborn does not change into a ZZ genotype by age.
Therefore, Pi MZ genotype preceded FEV1 outcomes in our study, even though
genotypes were determined after FEV1 measurements. Using identical logic,
genotype preceded outcomes in a similar manner in other previous studies
[3-6].
Selection bias could potentially be a reason for discrepancies
between studies on Pi MZ and COPD [1,7]. In our study where genotype
distribution was in Hardy Weinberg equilibrium, we found no evidence for
selection against any alpha1-antitrypsin genotype [2,8]. Therefore, as
also pointed out by Dr. Seersholm [1], selection bias is more likely in
case-control and family-based studies than in cohort studies of the
general population.
Morten Dahl and Børge G. Nordestgaard. Dept of Clinical
Biochemistry, Herlev University Hospital, Copenhagen, Denmark.
References
(1) Seersholm N. Pi MZ and COPD:
will we ever know? Thorax 2004;59:823-825.
(2) Dahl M, Tybjærg-Hansen A, Lange P, Vestbo J, Nordestgaard BG.Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes. A longitudinal study of
the general population. Ann Intern Med 2002;136:270-279.
(3) Juul K, Tybjærg-Hansen A, Steffensen R, Kofoed S, Jensen G,
Nordestgaard BG. Factor V leiden: The Copenhagen City Heart Study and 2
meta-analyses. Blood 2002;100:3-10.
(4) Bojesen SE, Tybjærg-Hansen A, Nordestgaard BG. Integrin beta3Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst
2003;95:1150-1157.
(5) Dahl M, Tybjærg-Hansen A, Schnohr P, Nordestgaard BG. A population
-based study of morbidity and mortality in mannose-binding lectin
deficiency. J Exp Med 2004;199:1391-1399.
(6) Wadsworth MEJ, Vinall LE, Jones AL, Hardy RJ, Whitehouse DB,
Butterworth SL, Hilder WS, Lovegrove JU, Swallow DM. Alpha-1-antitrypsin
as a risk factor for infant and adult respiratory outcomes in a national
birth cohort. Am J Respir Cell Mol Biol (in press).
(7) Hersh CP, Dahl M, Ly CS, Nordestgaard BG, Silverman EK. Chronic
obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a
meta-analysis. Thorax 2004;59:843-849.
(8) Dahl M, Tybjærg-Hansen A, Sillesen H, Jensen G, Steffensen
R, Nordestgaard BG. Blood pressure, risk of ischemic cerebrovascular and
ischemic heart disease, and longevity in alpha1-antitrypsin deficiency:
the Copenhagen City Heart Study. Circulation 2003;107:747-752.
I read with interest the paper by Meyer et al
about the increased incidence of peripheral airflow obstruction in 171
patients with PPH when compared to 64 age and sex matched controls. [1]
The authors speculate on possible explanations for this finding. They
provide three main theories, all of which are plausible. First, that
increased production of cytokines and growth mediators in...
I read with interest the paper by Meyer et al
about the increased incidence of peripheral airflow obstruction in 171
patients with PPH when compared to 64 age and sex matched controls. [1]
The authors speculate on possible explanations for this finding. They
provide three main theories, all of which are plausible. First, that
increased production of cytokines and growth mediators in the pulmonary
vasculature in PPH may also cause proliferation in adjacent small airways.
Secondly that decreased endothelial synthesis of nitric oxide and
prostacyclin along with increased production of endothelin-1 might
directly affect peripheral airways function, and finally that coupling
between pulmonary blood vessels and airways may lead to a direct
mechanical effect causing an impairment of lung elastic recoil.
It should be possible to test at least two of these theories by
further analysis of the data. First, what were the results of subgroup
analyses of the 32 % of the patients taking iloprost? It is eminently
plausible that inhaled iloprost may either cause or protect against
bronchospasm, and this would test the second theory, or perhaps explain a
false positive result.
Was a vasodilator study done at enrolment or previously? Responders
by definition have a flexible circulation and it is possible that this
subgroup is more likely to demonstrate airflow obstruction than non-
responders. In a similar way, it can be argued that responders are more likely to
benefit from a protective effect of vasodilators. On the other hand it may
be that non-responders are protected from developing peripheral airflow
obstruction due to mechanical stabilisation lending credence to the third
theory. Furthermore, did those with airflow obstruction demonstrate
bronchodilator reversibility? If they did then the first and third
theories are less likely.
Reference
(1) F J Meyer, R Ewert, M M Hoeper, H Olschewski, J Behr, J Winkler, H Wilkens, C Breuer, W Kübler, and M M
Borst. Peripheral airway obstruction in primary pulmonary hypertension. Thorax 2002;57: 473-476.
Heinzer et al. report cases of severe respiratory effects
following exposure to aerosol waterproofing sprays in Switzerland [1].
They report that while there are reports from elsewhere in Europe there
are no reports yet from the UK. We report the experience of the National
Poisons Information Service (London) [NPIS(L)] with these products in
2003.
Heinzer et al. report cases of severe respiratory effects
following exposure to aerosol waterproofing sprays in Switzerland [1].
They report that while there are reports from elsewhere in Europe there
are no reports yet from the UK. We report the experience of the National
Poisons Information Service (London) [NPIS(L)] with these products in
2003.
The European Association of Poisons Centres and Clinical
Toxicologists (EAPCCT) issued a warning regarding the risk of respiratory
distress developing in people using aerosol waterproofing agents. Subsequently NPIS(L) received an enquiry concerning a patient who
had developed Adult Respiratory Distress Syndrome (ARDS) following the use of an
aerosol waterproofing product in a confined space. This patient developed
respiratory failure and despite supportive treatment died [2].
Since this date the NPIS(L) has undertaken enhanced surveillance of
enquiries regarding such products. There were 43 enquiries to the NPIS(L)
concerning 33 cases of inhalation of aerosol waterproofing agents in 2003.
Of these cases, 31 (94%) involved adults and 2 (6%) children. All cases
were accidental exposures, with 27 (82%) exposures occurring at home, 4
(12%) at work and 2 (6%) in cars. All patients were or had been
symptomatic (symptoms were scored using the IPCS/EAPCCT Poisoning Severity
Score [3] following their exposure; 22 (67%) with mild symptoms and 10
(30%) with moderate symptoms, mostly respiratory in nature. One patient
had severe symptoms leading to death [2].
Although the number of enquiries to NPIS(L), from 2000 to 2003,
regarding aerosol waterproofing agents was very small compared with total
enquiry load, the number of enquiries concerning these products has
increased each year from 18 in 2000 [0.011%] to 43 in 2003 [0.067%]. This
is despite a significant decrease in total call load and represents a
proportional increase of 5.6 fold from 2000 to 2003. 2003 saw the most
serious case reported to NPIS(L) [2].
The manufacturer of the product implicated in the death [2] informed
the NPIS of a recent change in formulation. A high-odour solvent had been
replaced by a low-odour solvent blend. This change may have allowed greater
exposure to the product than is recommended, as there would be less olfactory
warning compared with the original solvent (i.e. allowing heavier exposures to
be tolerated). This is despite the manufacturer’s instructions on the package
indicating that indoor use is not recommended. This low-odour variant has since
been withdrawn [4]. 11
further cases in 2003, many in the early part of the year (1 case in
2002), involved this particular product. The high incidence may have been
related to the new low-odour variant, however, the variant involved in
these cases was either not known or not specified by the enquirer.
It seems likely that the fluorocarbon compounds in these products
cause the pulmonary problems [5,6,7] however the reason for this is not
clear. Nor is it clear why there has been an increase in cases in the UK
and elsewhere in Europe and unexpectedly severe effects. Some products
may generate smaller aerosol droplets, allowing the fluorocarbons to
penetrate deeper into the pulmonary tract [8,9,10] or that exposure is
prolonged because the products are less noxious due to different carrier
solvents. The cases reported to NPIS(L) involved at least 14 different
waterproofing brands and products and in some cases the exact product and
therefore ingredients are not known, the exact cause of the respiratory
problems is difficult to assess and is possibly due to a combination of
these factors.
References
(1) Heinzer R, Fitting JW, Ribordy V, Kuzoe B, Lazor R. Recurrence of
acute respiratory failure following use of waterproofing sprays
[Correspondence]. Thorax 2004;59:541-542
(2) Malik M. Acute respiratory syndrome associated with extreme superpruf
aerosol [Correspondance]. Anaesthesia 2003;58:1037-8.
(3) The International Program on Chemical Safety/European Association of
Poison Centres and Clinical Toxicologists Poisoning Severity Score
(http://www.intox.org/pagesource/intox%20area/other/pesticide/annex3pss.htm)
(4) Communication from Grangers International Ltd to NPIS(UK)
(5) Jinn Y, Akizuki N, Ohkouchi M, Inase N, Ichioka M, Marumo F. Acute
lung injury after inhalation of water-proofing spray while smoking a
cigarette. Respiration 1998;65:486-8.
(6) Kupfershcmidt H. Epidemy of acute respiratory illness linked to use of
waterproofing textile and leather spray [Abstract No. 59]. Clinical
Toxicology 2003;41:665.
(7) Laliberte M, Sanfacon G, Blais R. Acute pulmonary toxicity linked to
use of a leather protector. Annals of Emergency Medicine 1995;25:841-4.
(8) Yamashita M, Tanaka J. Pulmonary collapse and pneumonia due to
inhalation of a waterproofing aerosol in Female CD-1 mice. Clinical
Toxicology 1995;33(6):631-7.
(9) Yamashita M, Tanaka J, Yamashita M, Hirai H, Suzuki M, Kajigaya H.
Mist particle diameters are related to the toxicity of waterproofing
sprays: Comparison between toxic and non-toxic products. Veterinary and
Human Toxicology 1997;39(2):71-4.
(10) Yamashita M, Yamashita M, Tanaka J, Hirai H, Suzuki M, Kajigaya H.
Toxicity of waterproofing spray is influenced by the mist particle size.
Veterinary and Human Toxicology 1997;39(6):332-4.
We wholeheartedly welcome the article by Douwes et al. and it’s
accompanying editorial by O’Donnell and Frew.[1,2] The review highlights
the heterogeneity of airway inflammation in 'asthma' and especially the
potential role of the neutrophil in a substantial proportion of patients.
The authors use the term 'non-eosinophilic asthma' to categorise this
disease entity and they state that other manif...
We wholeheartedly welcome the article by Douwes et al. and it’s
accompanying editorial by O’Donnell and Frew.[1,2] The review highlights
the heterogeneity of airway inflammation in 'asthma' and especially the
potential role of the neutrophil in a substantial proportion of patients.
The authors use the term 'non-eosinophilic asthma' to categorise this
disease entity and they state that other manifestations include elevated
levels of IL-8 and a reduced prevalence of non-specific bronchial
hyperresponsiveness.
We have previously demonstrated that atopic asthmatic subjects with
persistent symptoms despite moderate doses of inhaled corticosteroids
(ICS) have significantly elevated levels of IL-8 in BAL fluid compared to
normal controls and this was not related to BAL eosinophilia.[3] In
contrast, IL-8 levels were strongly related to neutrophil-derived
myeloperoxidase (MPO) levels (r=0.9) and more weakly to BAL neutrophil
numbers (unpublished data). Additionally, there was a significant and
positive relationship between MPO levels (but not eosinophils) and
methacholine hyperresponsiveness. Although these subjects did not have an
increase in absolute airway neutrophil numbers, our findings suggest IL-8
driven neutrophil activation may also be relevant to disease activity in
'classical' eosinophilic allergic asthma. Interestingly, escalating the
dose of ICS in these recent subjects significantly elevated airway
neutrophil numbers providing evidence for a pro-neutrophilic effect of
ICS.
Furthermore, we have already previously demonstrated that neutrophil
activation as measured by luminol-dependent latex-stimulated
chemiluminescence was increased, even in mild asthma, even where
neutrophil numbers were within the normal range.[4] These observations
suggest that neutrophil activation may be important across the spectrum of
'allergic asthma' and not just a feature of acute exacerbations and severe
disease. This would be consistent with the author’s hypothesis that asthma
may be manifest by a mixed eosinophil/neutrophil response as a consequence
of combined activation of the innate and allergic immune systems.
Finally, we would agree about the difficulty of overcoming the entrenched
'dogmas' – attempts to get these data published have been met by reviewers
refusing to accept biological plausibility, rather than criticizing
methods or analysis. Fortunately, the wheel now seems to be turning to
allow a more objective and evidence-based view. Our study should be
appearing in full, in the near future, in the European Respiratory
Journal.
References
(1) O’Donnell RA, Frew AJ. Is there more than one inflammatory
phenotype in asthma? Thorax 2002; 57:566-568.
(2) Douwes J, Gibson J, Pekkanen J, Pearc N. Non-eosinophilic asthma:
importance and possible mechanisms. Thorax 2002; 57:643-648.
(3) Ward C, Li X, Wang N, et al. Salmeterol reduces IL-8 levels in
asthmatics on low dose inhaled corticosteroids [abstract]. Eur Respir J
1998; 12 (Suppl. 28):S380.
(4) Kelly C, Ward C, Stenton CS, Bird G, Hendrick DJ, Walters EH. Number and
activity of inflammatory cells in bronchoalveolar lavage fluid in asthma
and their relation to airway responsiveness. Thorax 1988;43(9):684-92.
Like Dr. Silvestri, I support a model of shared
decision making when considering chemotherapy [1]. Unfortunately, many
patients don’t realize that the advantages of chemotherapy are not shared
equally by those treated. For example, Spiro et al. show that
chemotherapy reduces the risk of death from lung cancer by 9% and 5% at
one and two years, respectively [2]. The fact that the reduction benefits
o...
Like Dr. Silvestri, I support a model of shared
decision making when considering chemotherapy [1]. Unfortunately, many
patients don’t realize that the advantages of chemotherapy are not shared
equally by those treated. For example, Spiro et al. show that
chemotherapy reduces the risk of death from lung cancer by 9% and 5% at
one and two years, respectively [2]. The fact that the reduction benefits
only a fraction of those treated is sure to be misunderstood by many. A
more straightforward (and honest) way to describe these data is the number
needed to treat (NNT)[3], which would allow patients to consider that 11
individuals would need chemotherapy for one to survive an additional year,
and 20 would need treatment for one to survive an additional two. The NNT
is a useful concept for patients to incorporate into their decisions about
whether the chemotherapy glass is half empty or half full.
References
(1) Silvestri G. Chemotherapy for advanced lung cancer: is the glass half
full or half empty? Thorax 2004; 59:821.
(2) Spiro SG, Rudd RM, Souhami RL, et al.Chemotherapy versus supportive
care in advanced non-small cell lung cancer: improved survival without
detriment to quality of life. Thorax 2004;59:828–36.
(3) Cook RJ and Sackett DL. The number needed to treat: a clinically useful
measure of treatment effect. BMJ 1995;310:452-4.
Paynter and Coker have made an important point about the extent to
which clustering depends upon sample coverage. We believe that this is
valid, but strictly correct only in the situation where a representative
(e.g. random) sample of the population have been studied. In our study we
included 2490 isolates with linked demographic information. This is 77 % of
the total of 3260 culture-confirmed cases...
Paynter and Coker have made an important point about the extent to
which clustering depends upon sample coverage. We believe that this is
valid, but strictly correct only in the situation where a representative
(e.g. random) sample of the population have been studied. In our study we
included 2490 isolates with linked demographic information. This is 77 % of
the total of 3260 culture-confirmed cases and about 44 % of the notified
cases (total: [half 1995]+1996+1997 = 5622).[1] These figures are not
unlike the Dutch study (78 % and 52 %, respectively). Thus, it is
unreasonable to suggest that our study had a “relatively small sampling
fraction”. Comparison of our findings with the Dutch study is valid,
although the Dutch study did include low-copy strains, analysed by PGRS
typing and the equivalence of these PGRS clusters to IS6110 clusters in
high copy strains remains to be confirmed.
In the San Francisco study, the proportion of notified cases included
as culture-confirmed cases was higher (85 %) and 69 % of the notified cases
were included in their cluster analysis. However, these figures may
reflect the methods and completeness of notification; if microbiological
information forms a major source of notifications, then a higher
proportion of all notifications will be culture-confirmed. Certainly the
cases included in these studies cannot be assumed to be a random sample of
all notifications. For instance, they will probably include less non-
pulmonary TB and more “open” TB.
Any estimate of clustering, which by a molecular definition has to be
based on cultured isolates, is likely to be an overestimate. Paynter and
Coker make this point but do not elaborate upon it. Given a possible
overestimation on this account, and a possible underestimation from
incomplete case-ascertainment through culture-confirmed isolates, our
estimate of the clustering rate is unlikely to be grossly misleading and
remains “low”, even after the revisions suggested by the Paynter and
Coker. The general conclusion regarding case-to-case transmission is
valid.
We would agree that policy makers and health professionals in London
should continue to focus on steps to inhibit ongoing transmission and
believe that our study supports this by identifying groups in whom recent
transmission is a higher risk. These are the particular groups for whom
deployment of additional resources is important not only to enhance case
ascertainment but ensure treatment and monitoring of outcome.
Supervised drug-taking is frequently seen as the answer to rising levels of tuberculosis. Djuretic et al. advocate directly
observed therapy (DOT) for all patients with smear-positive pulmonary tuberculosis in London.[1] At first sight, the experience of instituting DOT in New York City appears especially impressive, with a 21 % reduction in case rates 2 and 39 % decrease in drug-resistant isolates....
Supervised drug-taking is frequently seen as the answer to rising levels of tuberculosis. Djuretic et al. advocate directly
observed therapy (DOT) for all patients with smear-positive pulmonary tuberculosis in London.[1] At first sight, the experience of instituting DOT in New York City appears especially impressive, with a 21 % reduction in case rates 2 and 39 % decrease in drug-resistant isolates. However, these reductions occurred at the same time as close attention was paid to drug regimens, the use of drug combinations, increased staffing levels and the payment of incentives combined with the threat of imprisonment for
persistent defaulters. The cost was phenomenal.[2]
The proportion of cases of tuberculosis in London that have been recently transmitted has been estimated at 14.4 %.[3] This is very low when compared to 48 % in New York City.[4] The decreased incidence of tuberculosis in New York City was
achieved entirely within groups where recent transmission was suspected. Over the same time period there was a 22 %
increased incidence among foreign-born persons. Such people have contributed most to the recent increase incidence of tuberculosis in London.[5]
Randomised controlled trials have shown that direct observation by either a health care worker or family member does not
improve treatment completion rates when compared with self-administered treatment.[6-8] Furthermore, even with supervised
drug-taking, patients can still fail to complete treatment. In one study in Denver, 18 % missed two consecutive weeks of
treatment, continued treatment for more than 30 days beyond the expected date of completion because of defaulting or were
imprisoned as a threat to public health.[9] In a review of randomised controlled trials to promote adherence, monetary
incentives, home visits and attentive staff were important elements of successful programmes.[10,11]
The situation in London clearly requires action. The data, however, suggest different approaches to those taken in New York City (see table). New entrant screening deserves greater attention and a heightened awareness of tuberculosis in primary care could complement the current system.[12] The tuberculin skin test has a poor specificity and sensitivity and we should investigate newer methods of diagnosing those patients with latent tuberculosis who have a high probability of progressing to disease.[13] We should maintain our vigilance to prevent active transmission by treating those with infectious, smear-positive
pulmonary tuberculosis rapidly and effectively. This can be complemented with well targetted contact tracing. Selective DOT
is a part of this programme, but we would emphasise that each patient should be treated as an individual and treatment tailored
to his or her needs.
London (current)
New York (1992-4)
Incidence of TB
35 per 100,000
(Newham 110 per 100,000)
46 per 100,000
(Central Harlem 222/100.000)
Cost of TB services
£8 million [14]
(£34.2 million)[15]*
>$400 million [2]
DOT strategy
Selective
Universal †
Completed treatment
87% ‡
<_50 _2="_2" font="font"/>
Relapsed TB
6-8% ‡
51% [2]
HIV co-infection
14% [16]
38% [2] §
Multidrug resistant TB
1.7% [1]
19% [17]
Recent transmission (estimate from
molecular epidemiology)
14.4% [3]
48% [4]
Cause of increase in TB
New entrants (Foreign-born)
Elderly women
HIV (11%) [16]
HIV [2]
Nosocomial
Homeless
Foreign-born
* estimated as £6k per TB patient and £60k per MDRTB treated
† actually around 30% were receiving DOT
‡ unpublished data, North East London TB Network office, London TB Group and King’s College Hospital, South East
London
§ 38% of all, 72% of those tested
References
(1) Djuretic T, Herbert J, Drobniewski F, Yates M, Smith EG, Magee JG, et al. Antibiotic resistant tuberculosis in the United Kingdom: 1993-1999.
Thorax 2002;57(6):477-82.
(2) Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City: turning the tide. N Engl J Med 1995;333(4):229-33.
(3) Maguire H, Dale JW, McHugh TD, Butcher PD, Gillespie SH, Costetsos A, et al. Molecular epidemiology of tuberculosis in London 1995-7
showing low rate of active transmission. Thorax 2002;57(7):617-622.
(4) Geng E, Kreiswirth B, Driver C, Li J, Burzynski J, DellaLatta P, et al. Changes in the transmission of tuberculosis in New York City from 1990 to
1999. N Engl J Med 2002;346(19):1453-8.
(5) Rose AM, Watson JM, Graham C, Nunn AJ, Drobniewski F, Ormerod LP, et al. Tuberculosis at the end of the 20th century in England and
Wales: results of a national survey in 1998. Thorax 2001;56(3):173-9.
(6) Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M. Randomised controlled trial of self-supervised and directly observed
treatment of tuberculosis. Lancet 1998;352(9137):1340-3.
(7) Walley JD, Khan MA, Newell JN, Khan MH. Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised
controlled trial in Pakistan. Lancet 2001;357(9257):664-9.
(8) Kamolratanakul P, Sawert H, Lertmaharit S, Kasetjaroen Y, Akksilp S, Tulaporn C, et al. Randomized controlled trial of directly observed
treatment (DOT) for patients with pulmonary tuberculosis in Thailand. Trans R Soc Trop Med Hyg 1999;93(5):552-7.
(9) Burman WJ, Cohn DL, Rietmeijer CA, Judson FN, Sbarbaro JA, Reves RR. Noncompliance with directly observed therapy for tuberculosis.
Epidemiology and effect on the outcome of treatment. Chest 1997;111(5):1168-73.
(10) Volmink J, Garner P. Systematic review of randomised controlled trials of strategies to promote adherence to tuberculosis treatment. Bmj 1997;315(7120):1403-6.
(11) Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet 2000;355(9212):1345-50.
(12) Bothamley GH, Rowan JP, Griffiths CJ, Beeks M, McDonald M, Beasley E, et al. Screening for tuberculosis: the port of arrival scheme
compared with screening in general practice and the homeless. Thorax 2002;57(1):45-9.
(13) Lalvani A, Pathan AA, Durkan H, Wilkinson KA, Whelan A, Deeks JJ, et al. Enhanced contact tracing and spatial tracking of
Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Lancet 2001;357(9273):2017-21.
(14) NHS_Executive. Tuberculosis Control in London - the need for change. A report for the Thames Regional Directors of Public Health.
London. 1998.
(15) White VL, Moore-Gillon J. Resource implications of patients with multidrug resistant tuberculosis. Thorax 2000;55(11):962-3.
(16) Rose AM, Sinka K, Watson JM, Mortimer JY, Charlett A. An estimate of the contribution of HIV infection to the recent rise in tuberculosis
in England and Wales. Thorax 2002;57(5):442-5.
(17) Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW. The emergence of drug-resistant tuberculosis in New York
City. N Engl J Med 1993;328(8):521-6.
Morten Dahl and Børge G. Nordestgaard argue against selection bias,
if genotyping is performed after lung function tests because a newborn
with PiMZ genotype does not change to PiZZ later in life. The latter is
obviously true and not the issue. The reason for possible selection bias
is that some persons may fail to have genotype performed due to a
characteristic of the lung function tests under stud...
Morten Dahl and Børge G. Nordestgaard argue against selection bias,
if genotyping is performed after lung function tests because a newborn
with PiMZ genotype does not change to PiZZ later in life. The latter is
obviously true and not the issue. The reason for possible selection bias
is that some persons may fail to have genotype performed due to a
characteristic of the lung function tests under study and this may affect
the result of a longitudinal study.
If we assume that PiMZ persons have a very fast FEV1 decline with
premature death, a number of PiMZ persons may have attended the first
examinations, but did not live long enough to show up to the last visit
with genotyping. These persons would not be included in the analysis of
FEV1 decline and the result would be an underestimate of FEV1 decline with
the possible conclusion that PiMZ is not a risk factor for lung disease.
This is usually called a survivor effect.
The opposite may also be true. Suppose a reverse relationship between
pulmonary function and compliance to study visits, that is persons with
normal FEV1, normal FEV1 decline, and no lung symptoms may not show up to
the last visit because they feel well. This would tend to exaggerate any
increased decline in FEV1 and the conclusion could be that PiMZ is an
important risk factor for lung disease.
These are just two of many examples of possible biases. They show
that even if the risk factor (PiMZ) is present from birth, it is vital to
postpone the collection of tests for analysis after genotyping has been
performed.
We thank Dr Fowler for allowing us to expand further on the subject
matter of AMP provocation clinical relevance. Could AMP be the preferred
challenge stimulus for monitoring treatment requirements in asthma and to
establish the appropriate dose of inhaled GCS needed to control airway
inflammation? Although the available evidence clearly indicates that AMP
challenge has a selective ability to probe cha...
We thank Dr Fowler for allowing us to expand further on the subject
matter of AMP provocation clinical relevance. Could AMP be the preferred
challenge stimulus for monitoring treatment requirements in asthma and to
establish the appropriate dose of inhaled GCS needed to control airway
inflammation? Although the available evidence clearly indicates that AMP
challenge has a selective ability to probe changes in allergic airway
inflammation,[1] a short but frank answer to this question is that we do
not know yet. Currently, individual adjustment of anti-asthma medications
is mainly based on measurements of symptoms and airflow limitations, but
since the association between inflammation on the one hand and airflow
limitation or symptoms on the other hand is usually either very weak or
absent, this approach may not be adequate. The clinical significance of
the reported variations in surrogate markers of airway inflammation
(including methacholine provocation) in the course of treatment with
inhaled GCS in asthma is not firmly established, but it might be
speculated that these markers may be useful in the individual adjustment
of long-term asthma management. In their 2-year parallel follow-up study
of asthmatic patients, Sont et al.[2] have demonstrated that a strategy
including monitoring of methacholine responsiveness as a guide for therapy
adjustment led to a substantial reduction in cumulative exacerbation
incidence. Whether introducing cellular or molecular markers of
inflammation for disease monitoring would improve long-term asthma
management is far from certain. However, adenosine provocation seem to
offer substantial advantages over other noninvasive surrogate markers of
airway inflammation [1,3] and might be more clinically relevant than
methacholine as it explores different components of BHR simultaneously.[4] It would be therefore desirable to evaluate a treatment algorithm
incorporating AMP responsiveness in a controlled prospective trial
involving a large number of patients.
Dr Fowler appropriately draws attention to the fact that when using AMP
provocation to evaluate asthma medications it would be difficult to
discriminate whether improvement in BHR to AMP reflects improvement in
inflammation or a specific inhibitory effect of certain asthma medication
(e.g. anti-histamines, theophylline, leukotriene antagonists, cromones,
etc – reviewed in [5,6]). However, this should not be perceived as a true
problem; good laboratory practice emphasizes that all these drugs should
be withheld for a few days prior to AMP provocation so that the measured
PC20 AMP value would genuinely reflect the true status of BHR to inhaled
AMP.
Inhaled GCS may have a number of different effects on the various
pathogenetic components of nonspecific BHR. In addition to affecting
smooth muscle responsiveness, inhaled GCS may inhibit the airway response
to inhaled AMP either at a cellular level by reducing the number and
function of airway mast cells or at molecular level by downregulating the
activity of specific adenosine receptors.[4] Marked reductions in the
number of mast cells have been observed in the bronchial mucosa of
patients with asthma after regular treatment with a number of inhaled GCS.[7,8] Whatever the mechanism accounting for the greater protective effect
of inhaled GCS on adenosine over methacholine, it is apparent that BHR to
inhaled AMP is a sensitive indicator of underlying airway inflammation.
That airways responsiveness to inhaled AMP may create new possibilities to
evaluate airway inflammation is also supported by the observation that in
asthmatic children allergen avoidance at high altitude resulted in a
pronounced improvement in BHR to AMP but not to methacholine .[9]
Conversely, in individuals with allergic rhinitis, deteriorations in non-
specific BHR during the onset of the pollen season were consistently
detected by AMP but not methacholine.[10] As it provides different
information compared to methacholine challenge, we strongly believe that
airways responsiveness to inhaled AMP deserves further assessment.
References
(1) Polosa R, Rorke S, Holgate ST. Evolving concepts on the value of
adenosine hyperresponsiveness in asthma and COPD. Thorax 2002; 57: 649-54.
(2) Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk
PJ. Clinical control and histopathologic outcome of asthma when using
airway hyperresponsiveness as an additional guide to long-term treatment.
The AMPUL Study Group. Am J Respir Crit Care Med 1999; 159(4 Pt 1): 1043-51.
(3) Polosa R. Adenosine receptor subtypes: their relevance to adenosine-
mediated responses in asthma and COPD. Eur Respir J 2002;20: 488-96.
(4) Prosperini G, Rajakulasingam K, Cacciola RR, Spicuzza L, Rorke S,
Holgate ST, Di Maria GU, Polosa R. Changes in sputum counts and airway
hyperresponsiveness after budesonide: monitoring anti-inflammatory
response by surrogate markers of airway inflammation. J Allergy Clin
Immunol 2002 (in press).
(5) Polosa R, Holgate ST. Adenosine bronchoprovocation: a promising marker
of allergic inflammation in asthma? Thorax 1997; 52: 919-23.
(6) Feoktistov I, Polosa R, Holgate ST, Biaggioni. Adenosine A2B
receptors: a novel therapeutic target in asthma? Trends Pharmacol Sci 1998; 19: 148-153.
(7) Djukanovic R, Wilson JW, Britten KM, Wilson SJ, Walls AF, Roche WR,
Howarth PH, Holgate ST. Effect of an inhaled corticosteroid on airway
inflammation and symptoms in asthma. Am Rev Respir Dis 1992; 145(3): 669-74.
(8) Burke CM, Sreenan S, Pathmakanthan S, Patterson J, Schmekel B, Poulter
LW. Relative effects of inhaled corticosteroids on immunopathology and
physiology in asthma: a controlled study. Thorax 1996 ; 51(10): 993-9.
(9) van Velzen E, van den Bos JW, Benckhuijsen JA, et al. Effect of
allergen avoidance at high altitude on direct and indirect bronchial
hyperresponsiveness and markers of inflammation in children with allergic
asthma. Thorax 1996;51(6):582-4.
(10) Polosa R, Li Gotti F, Mangano G, Mastruzzo C, Pistorio MP, Crimi N.
Monitoring of seasonal variability in BHR and sputum cells count in
nonasthmatic subjects with rhinitis and effect of specific immunotherapy.
Am J Respir Crit Care Med (submitted for publication).
Anti TNF treatment should be given after screening for latent
tuberculosis as this may result active tuberculosis in these cases [1]. The
World Health Organization estimates that at least one-third of the world’s
population are infected with TB [2], [3]. 95% of tuberculosis cases and
98% tuberculosis deaths are in the developing countries [2], [3]. It is
difficult to rule out latent tuberculosis infection...
Anti TNF treatment should be given after screening for latent
tuberculosis as this may result active tuberculosis in these cases [1]. The
World Health Organization estimates that at least one-third of the world’s
population are infected with TB [2], [3]. 95% of tuberculosis cases and
98% tuberculosis deaths are in the developing countries [2], [3]. It is
difficult to rule out latent tuberculosis infection in developing
countries like India, as positive tuberculin reaction is very common in
person needing health care. So use of anti TNF treatment should be
restricted as this may be a high-risk gamble with health system of this
region.
References
(1) Keane J, Gershon S, Wise R P et al.Tuberculosis associated with
infliximab, a tumor necrosis factor á-neutralizing agent. N Eng J Med
2001;345:1098-1104.
(2) Raviglione MC, Snider DE, Kochi A. Global epidemiology of
tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 1995;
273:220-226
(3) Dolin PJ, Raviglione MC, Kochi A.Global tuberculosis incidence and
mortality during 1900-2000. Bull. World Health Organ. 1994; 72(2): 213-220
Dear Editor
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