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).
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.
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.
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.
Maguire et al.[1] estimated recently in the journal that the rate of
recent transmission of M tuberculosis in London was 14.4 % between 1995 and
1997. Estimation of this parameter is an important contribution to the
understanding of transmission dynamics of tuberculosis in the capital and
should assist policy-makers in developing responses to enhance control. We
suggest, however, that if this estim...
Maguire et al.[1] estimated recently in the journal that the rate of
recent transmission of M tuberculosis in London was 14.4 % between 1995 and
1997. Estimation of this parameter is an important contribution to the
understanding of transmission dynamics of tuberculosis in the capital and
should assist policy-makers in developing responses to enhance control. We
suggest, however, that if this estimate is adjusted for a potential bias
discussed in this letter, the resulting adjusted estimate may be closer to
estimates from other reports from Western Europe and North America.
The study did not include all cases notified during the study period,
a factor that is largely unavoidable in studies of this nature. However,
the sampling fraction in the London study was smaller than studies
reported from elsewhere. The reported study included approximately one
third (2042 cases) of notified cases during the same period in London. In
a 5-year Dutch study the sampling fraction was 52 % (4266 subjects of 8183
notifications) and in a 2-year study from San Francisco 69 % (473/688) of
notifications were studied. [2,3]
The lower the sampling fraction falls the greater the potential to
miss clusters. Some members of clusters are always likely to fall within
the unsampled population and if by chance only one or no members of a
cluster are sampled the cluster will be missed. This error will be worse
when there are few members in a cluster.
Most of the clusters in the London study were small – 65% were
clusters of two individuals only, and only 8.3 % had more than 4 members.
In comparison, the Dutch study reported 51 % of clusters had two
individuals and 22 % had more than four individuals whilst the study from
San Francisco showed 45 % of clusters contained two individuals and 16 % had
more than four persons.
Previous studies have shown that there is a linear relationship
between the sampling fraction (if random) and the proportion of two person
clusters missed through sampling error.[4] Given Maguire’s approximate
sampling fraction was one third, this would mean that the proportion of
cases in two person clusters would have been underestimated by
approximately two thirds (although we recognise that some clusters
classified as two-person may in reality have been larger). Including these
potentially missing clusters would translate into an estimate of recent
transmission of 21 % in London. Similar analyses of Dutch and San Francisco
data would increase estimates of recent transmission only marginally,
however, from 35 % to 37 % in the Netherlands and 31 % to 32 % in San
Francisco, respectively.
These estimates do not include any determination of the
underestimates regarding clusters of more than two persons. For a random
sampling fraction of 30 %, the proportion of cases in three person clusters
will be underestimated by approximately 60 % and four-person clusters by
approximately a half (if using the n-1 method to calculate the proportion
clustered, as here).[4]
As inclusion in the study was dependent on having a culture positive
isolate, it would be expected that index cases of clusters would have a
better than random chance of inclusion in the study. Others in the cluster
would be expected to have a random chance of being included. Thus the
underestimation will not be to the degree expected if chance alone
dictated whether individuals were included.
In this letter we have discussed the possible effects of only one
potential source of bias, but recognise that study duration and the
distribution of age, HIV status, and pulmonary/non-pulmonary disease are
also important potential sources of bias.[4-6]
We suspect the relatively small sample fraction of the London study
has led to a relatively large underestimation of the amount of clustering
of tuberculosis in the capital and that in reality the degree of recent
transmission of tuberculosis in London may be closer to that described
elsewhere. In devising public health approaches to control tuberculosis in
London we urge that policy-makers should continue to focus on steps that
inhibit ongoing transmission.
Stuart Paynter
ECOHOST, London School of Hygiene and Tropical Medicine
Richard Coker
ECOHOST, London School of Hygiene and Tropical Medicine
References
(1) Maguire H, Dale JW, McHugh TD, et al. Molecular epidemiology of
tuberculosis in London 1995-7 showing low rate of active transmission.
Thorax 2002;57:617-622.
(2) van Soolingen D, Borgdorff MW, de Haas PEW, et al. Molecular
epidemiology of tuberculosis in The Netherlands: a nationwide study from
1993 through 1997. The Journal of Infectious Diseases 1999;180:726-36.
(3) Small PM, Hopewell PC, Singh SP, et al. The epidemiology of
tuberculosis in San Francisco - A population-based study using
conventional and molecular methods. N Eng J Med
1994;330(24):1703-1709.
(4) Glynn JR, Vynnycky E, P.E.M.F. Influence of sampling on estimates of
clustering and recent transmission of Mycobacterium tuberculosis derived
from DNA fingerprinting techniques. Am J Epidemiology
1999;149(4):366-371.
(5) Vynnycky E, Nagelkerke N, Borgdorff MW, et al. The effect of age and
study duration on the relationship between "clustering" of DNA fingerprint
patterns and the proportion of tuberculosis disease attributable to recent
transmission. Epidemiology and Infection 2001;126:43-62.
(6) Glynn JR, Bauer J, de Boer AS, et al. Interpreting DNA fingerprint
clusters of Mycobacterium tuberculosis. International Journal of
Tuberculosis and Lung Disease 1999;3(12):1055-1060.
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.
Dr Polosa and colleagues provided an informative review of the
mechanisms and clinical application of bronchial challenge with adenosine
monophosphate (AMP) in asthma and COPD.[1] I would however contest their
proposal that AMP may be the preferred challenge stimulus for monitoring
treatment efficacy, as well as disease progression and severity when
compared with direct agents such as methacholine, and a...
Dr Polosa and colleagues provided an informative review of the
mechanisms and clinical application of bronchial challenge with adenosine
monophosphate (AMP) in asthma and COPD.[1] I would however contest their
proposal that AMP may be the preferred challenge stimulus for monitoring
treatment efficacy, as well as disease progression and severity when
compared with direct agents such as methacholine, and ask that they
consider the clinical relevance of attenuating bronchial
hyperresponsiveness (BHR) to these stimuli.
AMP works primarily through degranulation of primed mast cells, so
drugs that specifically prevent this action can markedly attenuate BHR to
AMP. Nedocromil sodium is a potent mast cell stabiliser, and almost
completely attenuates AMP BHR, causing a 4.5 to 4.8 doubling dose (DD)
improvement in PC20.[2,3] However it has little or no effect as 1st line
therapy in the vast majority of adult asthmatics, nor on methacholine
challenge in over 1000 children with mild to moderate asthma .[4]
Likewise antihistamines cause an 80% attenuation of BHR to AMP [5,6] but
no effect on methacholine.[6,7] Anti-leukotrienes also have a
disproportionate effect on AMP challenge versus methacholine whilst having
no demonstrable effect on inflammatory surrogates such as exhaled NO and
serum eosinophils or ECP.[8] One might argue that measuring the anti-
asthma effect of inhaled corticosteroids by simply measuring a surrogate
for this small component of the asthma phenotype is of limited relevance.
The main effect of inhaled corticosteroids on mast cells is to
decrease their growth and development, with no direct effect on mediator
release (reviewed in [9]). They do, however, have effects at many other
levels on the asthmatic airway, from the acute inflammatory response to
tissue remodelling, and it might be that higher doses may be required to
prevent these endpoints than for mast-cell attenuation alone.
Methacholine challenge, I would propose, is a much more representative
surrogate of these processes, and a composite measure of the multiple
pathophysiological aspects of asthma, acute and chronic. If one is
reviewing the results of a study, one has to look at what the endpoints
actually measured, and if this is only the 'anti-mast-cell' properties of
a drug, then many other desirable aims of treatment may not have been
assessed.
References
(1) Polosa R, Rorke S, Holgate ST. Evolving concepts on the value of
adenosine hyperresponsiveness in asthma and chronic obstructive pulmonary
disease. Thorax 2002;57:649-54.
(2) Richards R, Phillips GD, Holgate ST. Nedocromil sodium is more potent
than sodium cromoglycate against AMP- induced bronchoconstriction in
atopic asthmatic subjects. Clin Exp Allergy1989;19:285-91.
(3) Phillips GD, Scott VL, Richards R, Holgate ST. Effect of nedocromil
sodium and sodium cromoglycate against bronchoconstriction induced by
inhaled adenosine 5'-monophosphate. Eur Respir J 1989;2:210-7.
(4) The Childhood Asthma Management Program Research Group. Long-term
effects of budesonide or nedocromil in children with asthma. N Engl J Med
2000;343:1054-63.
(5) Rafferty P, Beasley R, Holgate ST. The contribution of histamine to
immediate bronchoconstriction provoked by inhaled allergen and adenosine
5' monophosphate in atopic asthma. Am Rev Respir Dis 1987;136:369-73.
(6) Phillips GD, Rafferty P, Beasley R, Holgate ST. Effect of oral
terfenadine on the bronchoconstrictor response to inhaled histamine and
adenosine 5'-monophosphate in non-atopic asthma. Thorax1987;42:939-45.
(7) Finnerty JP, Holgate ST, Rihoux JP. The effect of 2 weeks treatment
with cetirizine on bronchial reactivity to methacholine in asthma.
Br J Clin Pharmacol 1990;29:79-84.
(8) Dempsey OJ, Kennedy G, Lipworth BJ. Comparative efficacy and anti-inflammatory profile of once-daily therapy with leukotriene antagonist or
low-dose inhaled corticosteroid in patients with mild persistent asthma.
J Allergy Clin Immunol 2002;109:68-74.
(9) Busse WW. Inflammation in asthma: the cornerstone of the disease and
target of therapy. J Allergy Clin Immunol 1998;102:S17-S22.
Such as the paper from Dales et al. concerning the influence of
family income on asthma morbidity,[1] understanding socioeconomic effects
on adolescent health is a critical and important area of research if we
are to eliminate health disparities.[2]
Moreover, traditionally used tools to evaluate socio-economic gradient are
difficult to construct within this population and new indicators must...
Such as the paper from Dales et al. concerning the influence of
family income on asthma morbidity,[1] understanding socioeconomic effects
on adolescent health is a critical and important area of research if we
are to eliminate health disparities.[2]
Moreover, traditionally used tools to evaluate socio-economic gradient are
difficult to construct within this population and new indicators must be
developed for more specific measurements of the socio-economic status of
adolescents.[3] Thus, a cross-sectional analysis of the 1998 cross-
national study "Health Behaviour of School aged Children " (HBSC) in
French-speaking Belgium was undertaken.
The survey was based on a self-
completed questionnaire concerning various aspects of physical and social
health. The health problems (asthma and any other respiratory difficulty)
were considered present when a positive reply was given to close-end
questions stating if the pupils suffered, or have suffered from these
problems during the last six months. We analysed a representative sample
of 12,012 pupils aged 11 to 19 years in fifth and sixth grades of primary
school, and in all six grades of secondary school. Socio-economic
variables where "the perceived family economic status" and a family
economic score. This score combines three variables: "has a room for
him/herself", "family has a car or a van" and "number of holidays with
parents over the last year". This score is more adapted like measures of
economic status [4] rather than traditional indicators (occupation of the
father, current work of the parents, family incomes). The overall
prevalence of self-reported asthma is 6.6 % and asthma shows significant
differences according to sex (more for girls ), age (more when 17-19 years
old), nationality (more in Belgians than among foreigners). No difference
is found for socio-economic score. However, 21.1 % of the pupils say
having had respiratory difficulties during the last 6 months and the
prevalence of this affection increases with age, is more significantly
reported by girls than boys and by pupils from vocational and technical
types of education, by those having no sibling and/or being in a single-
parent or recomposed family and by pupils reporting poorer economic
conditions.
In our study, active smoking is not a risk for self reported
asthma in adolescence but is nonetheless significantly associated with
self-reported respiratory difficulties.
Our results confirm socio-economic predictors of respiratory health
problems in adolescence. Subjective respiratory health problems present a
significant socio-economic gradient. Pupils with a lower economic score
have a higher prevalence of subjective complaints concerning their health
compared with the more favoured groups. More studies must make it possible
to understand the mechanisms that may underline symptom reports and self-
assessment of general health status.
References
(1) Dales RE, , Choi B, Chen Y and Tang M. Influence of family income
on hospital visits for asthma among Canadian school children. Thorax
2002;57:513-7.
(2) Goodman E. The role of socioeconomics status gradients in explaining
differences in US adolescents'health. Am J Public Health 1999;89:1522-
28.
(3) Coppieters Y, Piette D, Kohn L, De Smet P. Health inequalities: self-
reported complaints and their predictors in pupils from Belgium. Revue
d'Epidémiologie et de Sante Publique 2002 ;50(2):135-46.
(4) Currie CE, Elton RA, Todd J, Platt S. Indicators of socioeconomics
status for adolescents : the WHO Health Behaviour in School-aged Children
Survey. Health Educ Research 1997;12:385-97.
The relationship between HIV and tuberculosis are probably
predictable. Both are lentiform diseases and immuno suppressive. Primary
tuberculous lesions may be re-activated in an immuno suppressive state and
new infections are more easily established. The real danger is that one
partner (tuberculosis) of this vicious circle is transferable by droplet
infection and in its presence the precaution required o...
The relationship between HIV and tuberculosis are probably
predictable. Both are lentiform diseases and immuno suppressive. Primary
tuberculous lesions may be re-activated in an immuno suppressive state and
new infections are more easily established. The real danger is that one
partner (tuberculosis) of this vicious circle is transferable by droplet
infection and in its presence the precaution required of the medical
personnel and caregiver alters. Given that caregivers in diseases of
similar socio-economic impact show increased stress response markers and
have less fit than normal immune defense,[1] the risk of tuberculous
infection in caregivers is probably multiplied. The viciousness of this
double-edged sword is the socio-therapeutic advice that HIV/AIDS patients
need to be integrated in the society with emphasis that HIV is not
transferable by routine social contacts. The opposite is true for
tuberculosis, which is alarmingly present in significant proportion of HIV
/AIDS patients.[2] Should we still hold on to and promote the policy of
social integration of HIV/AIDS patients? This question is especially valid
for developing countries where diagnostic facilities are barely available
but it is probably still relevant in the developed economies where the
increasing prevalence of tuberculosis is real and present evidence that we
are doing something wrong.
References
(1) Glaser R, Rabin B, Chesney M et al. Stress-induced immunomodulation.
implications for infectious diseases? JAMA 1999;281:2268-70.
(2) Rose A M C, Sinka K, Watson J M, et al An estimate of the
contribution of HIV infection to the recent rise in tuberculosis in
England and Wales. Thorax 2002;57:442-5.
I read with interest the paper by Papadopoulos et al. describing the balance between type 1 and type 2 responses by CD4 and CD8 T lymphocytes in atopic asthmatics and normal subjects stimulated by rhinovirus. They state that their data is consistent with ‘reciprocal regulation of type 1 and type 2 responses’. Their figure demonstrates that in both normals and atopic asthmatics interferon gamma and in...
I read with interest the paper by Papadopoulos et al. describing the balance between type 1 and type 2 responses by CD4 and CD8 T lymphocytes in atopic asthmatics and normal subjects stimulated by rhinovirus. They state that their data is consistent with ‘reciprocal regulation of type 1 and type 2 responses’. Their figure demonstrates that in both normals and atopic asthmatics interferon gamma and interleukin 4 levels went up following rhinovirus stimulation relative to the normal controls. While I accept that there was a difference in the ratio between interferon gamma and interleukin 4 between the 2 groups of subjects, both groups had simultaneous rises in both type 1 and type 2 responses. These responses are not therefore reciprocal.
Type 1 and type 2 T helper cell responses have often been considered to be reciprocal. This has lead to the suggestion that the current high levels of allergic disease are a result of an adult type 2 dominated immune systems.[1] This fails to take account of the fact that type 2 mediated diseases are associated with type 1 mediated diseases such as psoriasis, coeliac disease and type I diabetes in organs, in individuals and in populations.[2-5] There is also a parallel rise in the prevalence of type I diabetes and type 1 and type 2 mediated diseases share risk factors.[7-9] It therefore seems likely that while some factors may skew T cell development to either type 1 or type 2 some of the dominant influences may up regulate or down regulate both types of response.
References
(1) Holt PG, Macaubas PA, Stumbles PA, Sly PD. The role of allergy in the development of asthma. Nature 1999;402(Supp):B12-17.
(2) Stene L, Magnus P, Lie R, Sovik O, Joner G, Group. tNCDS. Maternal and paternal age at delivery, birth order, and risk of childhood onset type I diabetes: population based cohort study. BMJ 2001;323:369-72.
(3) Simpson C, Anderson W, Helms P, Taylor M, Watson L, Prescott G, et al. Coincidence of immune-mediated diseases driven by Th1 and Th2 subsets suggests a common aetiology. Clin Exp Allergy 2002;2:37-42.
(4) Kero J, Gissler M, Hemminki E, Isolauri E. Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease type I diabetes, or rheumatoid arthritis: A register study. J Allergy Clin Immunol108(5):781-783.
(5) Olesen AB, Juul S, Birkebaek N, Thestrup-Pedersen K. Association between atopic dermatitis and insulin-dependent diabetes mellitus: a case-control study. Lancet 2001; 357:1749-52.
(6) Stene L, Nafstad P. Relation between the occurence of type I diabetes and asthma. Lancet 2001;357:607-8.
(7) Green A, Gale E, Patterson C. Incidence of childhood-onset insulin dependent diabetes mellitus: the EURODIAB ACE study. Lancet 1992;339:905-909.
(8) Gardner SG, Bingley PJ, Sawtell PA, Weeks S, Gale EA. Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis. The Bart's-Oxford Study Group. BMJ 1997;315(7110):713-7.
(9) Patterson CC, Carson DJ, Hadden DR. Epidemiology of childhood IDDM in Northern Ireland 1989-1994: low incidence in areas with highest population density and most household crowding. Northern Ireland Diabetes Study Group. Diabetologia 1996;39(9):1063-9.
Dear Editor
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...
Dear Editor
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....
Dear Editor
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...
Dear Editor
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...
Dear Editor
Maguire et al.[1] estimated recently in the journal that the rate of recent transmission of M tuberculosis in London was 14.4 % between 1995 and 1997. Estimation of this parameter is an important contribution to the understanding of transmission dynamics of tuberculosis in the capital and should assist policy-makers in developing responses to enhance control. We suggest, however, that if this estim...
Dear Editor
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...
Dear Editor
Dr Polosa and colleagues provided an informative review of the mechanisms and clinical application of bronchial challenge with adenosine monophosphate (AMP) in asthma and COPD.[1] I would however contest their proposal that AMP may be the preferred challenge stimulus for monitoring treatment efficacy, as well as disease progression and severity when compared with direct agents such as methacholine, and a...
Dear Editor
Such as the paper from Dales et al. concerning the influence of family income on asthma morbidity,[1] understanding socioeconomic effects on adolescent health is a critical and important area of research if we are to eliminate health disparities.[2] Moreover, traditionally used tools to evaluate socio-economic gradient are difficult to construct within this population and new indicators must...
Dear Editor
The relationship between HIV and tuberculosis are probably predictable. Both are lentiform diseases and immuno suppressive. Primary tuberculous lesions may be re-activated in an immuno suppressive state and new infections are more easily established. The real danger is that one partner (tuberculosis) of this vicious circle is transferable by droplet infection and in its presence the precaution required o...
Dear Editor
I read with interest the paper by Papadopoulos et al. describing the balance between type 1 and type 2 responses by CD4 and CD8 T lymphocytes in atopic asthmatics and normal subjects stimulated by rhinovirus. They state that their data is consistent with ‘reciprocal regulation of type 1 and type 2 responses’. Their figure demonstrates that in both normals and atopic asthmatics interferon gamma and in...
Pages