We thank Dr Agarwal for responding to our article. We agree that the
commonest cause of steroid resistant asthma is failure to take the
prescribed steroids. However, there are perhaps more diagnostic aids than
is acknoweldged. Compliance can be taken out of the equation by doing a
therapeutic trial of a single intramuscular injection of depot
triamcinolone.[1-4] If asthma persists, then it can truly be...
We thank Dr Agarwal for responding to our article. We agree that the
commonest cause of steroid resistant asthma is failure to take the
prescribed steroids. However, there are perhaps more diagnostic aids than
is acknoweldged. Compliance can be taken out of the equation by doing a
therapeutic trial of a single intramuscular injection of depot
triamcinolone.[1-4] If asthma persists, then it can truly be said to be
steroid resistant. Alternatively, measuring serum prednisolone and
cortisol levels may also be illuminating, if the child is supposedly
taking oral steroids.
References
(1) Veeraraghavan S, Sharma OP. Parenteral triamcinolone acetonide:
an alternative corticosteroid for the treatment of asthma. Curr Opin Pulm
Med 1998;4:31-5.
(2) McLeod DT, Capewell SJ, Law J, MacLaren W, Seaton A.
Intramuscular triamcinolone acetonide in chronic severe asthma. Thorax
1985;40:840-5.
(3) Willey RF, Fergusson RJ, Godden DJ, Crompton GK, Grant IW. Comparison
of oral prednisolone and intramuscular depot triamcinolone in patients
with severe chronic asthma. Thorax 1984;39:340-4.
(4) Ogirala RG, Aldrich TK, Prezant DJ, Sinnett MJ, Enden JB,
Williams MH Jr. High-dose intramuscular triamcinolone in severe, chronic,
life-threatening asthma. N Engl J Med 1991;324:585-9.
Medication compliance in asthma is disappointingly low and leads to poor asthma control in children. It is very common that parents do not supervise treatment and often report poor asthma control. Many difficult-to-manage asthmatics have ongoing exposure to allergens or other asthma
triggers. In such instances, required medication may be very high and the results may be disappointing. Only 30% of pediatric a...
Medication compliance in asthma is disappointingly low and leads to poor asthma control in children. It is very common that parents do not supervise treatment and often report poor asthma control. Many difficult-to-manage asthmatics have ongoing exposure to allergens or other asthma
triggers. In such instances, required medication may be very high and the results may be disappointing. Only 30% of pediatric asthmatics, age 7 to 15, have optimal environmental control at home. Children who are
nonadherent to both medications and environmental control measures can be challenging to manage.
Despite the fact that many immunologic abnormalities have been identified, there is no laboratory test that can be used in making the diagnosis of steroid-resistant asthma. As a result the diagnosis of steroid-resistant asthma remains a clinical one.
Experts were given no clinical details except for times of waking and
sleeping, and times of starting and leaving work. They were asked to make
judgements based on the peak expiratory flow record alone, similar to the
judgements made by the Oasys program. Oasys-2 has been shown to have a
sensitivity of around 70%, when tested against independent objective
diagnoses (mostly specific bronchial provocation t...
Experts were given no clinical details except for times of waking and
sleeping, and times of starting and leaving work. They were asked to make
judgements based on the peak expiratory flow record alone, similar to the
judgements made by the Oasys program. Oasys-2 has been shown to have a
sensitivity of around 70%, when tested against independent objective
diagnoses (mostly specific bronchial provocation testing), and a
specificity of 94%. The need is therefore to achieve increased sensitivity.
The experts underscored compared with Oasys-2, and did not appear to be
detecting work-related changes missed by Oasys-2. In practice tests are
interpreted in the light of clinical information (requiring expertise),
however in our practice occupational asthma often occurs in unlikely
places, and is frequently diagnosed when the specific exposures are
unknown.
We hope we have provided a tool for use by the non-expert inthe
initial assessment of occupational asthma. We agree that these records
need to be made as soon as the diagnosis is suspected, and before workers
are removed from their jobs. Supervising such records does however needs a
degree of expertise, with particular emphasis on recording working times,
keeping treatment constant, and recording the timings of readings. Help is
provided for this on the website occupationalasthma.com, as well as
suitable record forms with instructions which can be downloaded.
Ideally, OASYS should be used interactively. The patient returns to
clinic with his PEF record stored in an electronic meter. The clinician
and patient review the record together. This allows the clinician to ask
those question suggested by the record such as "did you have a respiratory
infection last week" (if there was an unexpected fall in PEF crossing
work/rest interfaces), or "remind me of your work pattern on the 25th of
last month" (when a single work-day shows no deterioration when others
do). Thus the integration of clinical information and record is even
closer enhancing the diagnostic toolkit mentioned by David Fishwick and
colleagues.
We read with interest the article by Baldwin et al.[1] relating to
the level of agreement between expert clinicians and OASYS software when
making a diagnosis of occupational asthma. Our clinical unit uses OASYS
plotting regularly, and find this of great use as one element of the
diagnostic toolkit available for the confirmation of a diagnosis of
occupational asthma.
We read with interest the article by Baldwin et al.[1] relating to
the level of agreement between expert clinicians and OASYS software when
making a diagnosis of occupational asthma. Our clinical unit uses OASYS
plotting regularly, and find this of great use as one element of the
diagnostic toolkit available for the confirmation of a diagnosis of
occupational asthma.
We were interested to note that there was a low level of agreement
between experts and OASYS when asked to interpret peak expiratory flow
(PEF) records, but agreement within experts was better. We would be
interested to know whether the information provided to the experts on the
nature of work was used in determining their final outcome, i.e. if an
individual was working with a known sensitiser or was in a perceived high
risk job, did this influence the outcome more than the graphical and
mathematical data.
Practically in clinic, a decision is made to perform regular PEF
monitoring in those patients who are thought to have a reasonable chance
of having occupational asthma, as judged by the clinical information to
date. Perhaps a further study option would be to give experts clinical
data first (more like the real life situation), and ask for a likelihood
of occupational asthma based on this assessment, followed by a revision of
that likelihood after PEF data is supplied. Would then revealing the work
effect score lead to further revision of the perceived estimate?
Individual experts may be more or less swayed by the clinical data due to
variation in their own practice, types of cases seen, geographical
location and so on.
Again, experts were deemed to "under report" possible cases of
occupational asthma. Whilst this may indeed be the case, an alternative
explanation is that the experts were more realistic, taking into account
the clinical likelihood as well as the PEF pattern. OASYS systems clearly
invoke complex comparisons between known cases of occupational asthma and
the record being assessed.
Finally, the authors suggest that PEF interpretation is best left to
experts. Whilst we agree that expert centres, consistently diagnosing
occupational asthma are needed, as many as one in ten adult asthmatics are
likely to have a substantial effect from work.[2] It is therefore
important for all such patients in the UK to have access to competent
individuals trained to assess these patients. This is where OASYS (or
similar) systems are likely to be very important as an initial screen, and
could be carried out by primary care or occupational health nurses or
other competent non clinical people in the workplace. This would enable
patients currently working to undergo PEF assessment, as opposed to the
common situation of seeing patients in secondary care already following
prolonged period of sickness absence, making diagnosis even more
challenging.
At present, the consistency of diagnosis of occupational asthma
throughout the UK is likely to be highly variable. We are currently
involved in a multicentre UK based study assessing the application of the
toolkit to diagnose occupational asthma, and it is evident that practice
remains disparate between various expert centres.
We are sure that the future of occupational asthma evaluation will
and should rely on OASYS like programmes, but that the diagnosis must be
seen also in broader terms, taking into account clinical, immunological
and exposure data.
References
(1) DR Baldwin, P Gannon, P Bright, DT Newton, A Robertson, K Venables, B Graneek, RD Barker, A Cartier, J-L Malo, M Wilsher, CFA Pantin, and PS Burge. Interpretation of occupational peak flow records: level of agreement between expert clinicians and OASYS-2. Thorax 2002;57: 860-864.
(2) Blanc P, Toren K. How much adult asthma can be attributed to occupational factors? Am J Med 1999;107:580-587.
The recent case report from Smyth and Riley[1]
describes nicely an extremely uncommon chronic respiratory failure due to
hypoventilation secondary to brainstem stroke, and documents a new
treatment
option with medroxyprogesterone acetate.
We recently saw two patients also with central hypoventilation
resulting in chronic type II respiratory failure and treated both with,
among other things, me...
The recent case report from Smyth and Riley[1]
describes nicely an extremely uncommon chronic respiratory failure due to
hypoventilation secondary to brainstem stroke, and documents a new
treatment
option with medroxyprogesterone acetate.
We recently saw two patients also with central hypoventilation
resulting in chronic type II respiratory failure and treated both with,
among other things, medroxyprogesterone acetate (30 mg b.i.d.) with good
results.
The first patient, a 69-year-old man, with in his medical history a glomus
caroticum resection due to malignancy with postoperative radiotherapy in
1979
presented to our outpatient clinic with polyglobulia. His arterial blood
gas revealed marked hypoxemia (PaO2 4.8 kPa) and hypercapnia (PaCO2 6.9
kPa). An intensive search for the cause showed no abnormalities, his
lungfunction
showed only marginally COPD (FEV1/VC of 68 %), but his hypoxic ventilatory
response was markedly decreased and his hypercapnic ventilatory response
was absent. We treated the patient with acetazolamide, theofyllin and
medroxyprogesterone acetate and his blood gas improved within days to
normal values (PaO2 10.3 kPa, PaCO2 5.1 kPa).
The second patient, a 38-year-old female, was known from birth on with a
hypothalamic-pituitary gland deficiency and with (stable) adipositas
(quetelet index of 53). She complaint about dizziness, general malaise and
dyspnoe d’effort for several time before she was sent to our department.
Arterial blood gas analysis again revealed hypoxemia and marked
hypercapnia (PaO2 8.0 kPa, PaCO2
7.2 kPa). She probably suffers from Pickwick syndrome, formal
polysomnografic measurements will be performed shortly, but she also has
totally absent hypoxic and hypercapnic ventilatory responses. Again
treatment
with theofyllin, acetazolamide and medroxyprogesterone acetate normalised
her arterial blood gas analysis within days. She furthermore now follows
an intense weight
reduction programme and has lost within weeks more than 10 kg.
Acetazolamide has been shown to augment both the hypoxic and
hypercapnic ventilatory response and decrease PaCO2 levels significantly
in COPD patients.[2,5] The mechanism of the effect is possibly due to a
direct effect on
the peripheral chemoreceptors (carotid bodies) as well as to an effect on
the cerebral blood flow regulation.[2,3]
It has been shown that medroxyprosterone acetate also acts on the
peripheral chemoreceptors (directly) as well as on the central
chemoreceptors (indirectly) and progesterone receptors in the hypothalamus
in cats.[4] This was also found in hypercapnic COPD patients indicating
that medroxyprogesterone acetate is a central acting drug of the
respiratory centres.[5] This supports the use of medroxyprogesterone
acetate in central hypoventilation. Furthermore, the combined treatment of
acetazolamide and medroxyprogesterone acetate yields an increase in
ventilation and an improvement of the arterial blood gas values i.e a
decrease in PaCO2 to normocapnic values and an increase in PaO2 to almost
normoxic values in hypercapnic and hypoxic COPD patients.[5]
In conclusion we agree with the authors that medroxyprogesterone
acetate can be used in patients with central hypoventilation disorders.
References
(1) Smyth A and Riley M. Chronic respiratory failure: an unusual cause and treatment. Thorax 2002;57: 835-836.
(2)Vos PJ, Folgering HT, de Boo TM, Lemmens WJ, van Herwaarden CL. Effects of chlormadinone acetate, acetazolamide and oxygen on awake and asleep gas
exchange in patients with chronic obstructive pulmonary disease (COPD). Eur
Respir J. 1994;7:850-5.
(3) Wagenaar M, Teppema L, Berkenbosch A, Olievier C, Folgering H. Effect
of
low-dose acetazolamide on the ventilatory CO2 response during hypoxia in
the
anaesthetized cat. Eur Respir J 1998;12:1271-7
(4) Wagenaar M, Teppema LJ, Berkenbosch A, Olievier CN, Folgering HT.
Medroxyprogesterone acetate with acetazolamide stimulates breathing in
cats.
Respir Physiol 2000;119:19-29
(5)Wagenaar M, Vos PJ, Heijdra YF, Teppema LJ, Folgering HTM. Combined
treatment with acetazolamide and medroxyprogesterone acetate in COPD
patients. Eur Respir J 2002, in press (November)
Dr GP Bootsma, MD PhD
Dr Y Heydra, MD PhD
Dr M Wagenaar, MD
Department of Pulmonary Diseases
University Medical Centre, St Radboud, Nijmegen
PO Box 9101
6500 HB Nijmegen
The Netherlands
Dr GP (Gerben) Bootsma, MD, PhD
University Medical Centre Nijmegen
Dept. of Pulmonary Diseases, 549
P.O. Box 9101
6500 HB Nijmegen
The Netherlands
Tel: ++31-24-3614579
Fax: ++31-24 3610324
Email: :G.Bootsma@long.azn.nl
Endotoxin: it’s activity in atopy and asthma is not the only
controversial issue – does it play a role in prevention of lung cancer in
some occupational populations
The paper Does environmental endotoxin exposure prevent asthma? by Douwes et al. provides an interesting overview of how endotoxin may interact in
atopy and asthma. This paper discusses issues as to whether endotoxin
pl...
Endotoxin: it’s activity in atopy and asthma is not the only
controversial issue – does it play a role in prevention of lung cancer in
some occupational populations
The paper Does environmental endotoxin exposure prevent asthma? by Douwes et al. provides an interesting overview of how endotoxin may interact in
atopy and asthma. This paper discusses issues as to whether endotoxin
plays a role in prevention of atopy and asthma or may in fact be a
contributor to these respiratory diseases. However, readers should be
aware that there is another important issue, although controversial,
related to endotoxin and the lung. That is - does endotoxin exposure in
some occupational groups’ result in reduced lung cancer rates?
There have been a number of reports [1-7] suggesting that endotoxin
exposure, mostly in organic dusts, results in reduced lung cancer rates.
This reduced lung cancer rate was first identified in textile workers[1,2] and later in agricultural[3,4] and other groups[5,6] exposed to
endotoxin. Experimental studies[8,9] have supported epidemiological
findings and clinical trials[10,11] have been undertaken to evaluate this
agent and it’s immuno-mediators effectiveness in cancer treatments.
Although the concept of a beneficial effect from occupational exposure is
novel,[4] it has been reported in at least one other occupational
epidemiological investigation of reduced lung cancer rates for a
potentially better-recognized anticancer agent (selenium) .[12,13] Most
investigators disagree with any benefit from occupational exposure and
attribute these findings to various forms of selection bias (e.g. healthy
worker effect) and lower rates of smokers in study populations (as
compared to controls).[3,4,6]
Certainly exposure to organic dusts and endotoxin does not occur with
out risk. There are numerous reports of the detrimental outcomes
associated with such exposures.[13] However, when various forms of bias
are evaluated, there appears to be in some studies an inability to explain
the reduced lung cancer rates.[1,3,6]
It is encouraged that scientists accept the concept that there is an
alternative view for lower lung cancer rates in some study populations.
Even though this challenges prevailing thought and conventional thinking,
we must remember that tradition dies hard and the birth of a new idea
requires a creative and innovative sprit.[14]
References
(1) Enterline PE, Sykora JL, Keleti G, and Lange JH. Endotoxin, cotton
dust and cancer. Lancet 1985;2:934-935.
(2) Rylander R. Environmental exposures with decreased risks for lung
cancer. Int J Epidemiol 1990;19: 567-572
(3) Mastrangelo G, Marzia V, and Marcer G. Reduced lung cancer
mortality in diary farmers: is endotoxin exposure the key factor? Am J
Ind Med 1996;30:601-609.
(4) Lange JH. Reduced cancer rates in agricultural workers: a benefit
of environmental and occupational endotoxin exposure. Med Hypotheses 2000;55: 383-385
(5) Schroeder JC, Tolbert PE, Eisen EA, Monson RR, Hallock MF, Smith
TJ, Woskie SR, Hammond SK, and Milton DK. Mortality studies of machining
fluid exposure in the automile industry IV: a case-control study of lung
cancer. Am J Ind Med 1997; 31: 525-533.
(6) Rapiti E, Sperati A, Fano V, Dell’Orco V, Forastiere F. Mortality
among workers at municipal waste incinerators in Rome: a retrospective
cohort study. Am J Ind Med 1997; 31: 659-661
(7) Hodgson JT and Jones RD. Mortality of workers in the British
cotton industry in 1968-1984. Scan J Work Environ Health 1990;16:113-
120.
(8) Lange, JH (1992) Anti-cancer properties if inhaled cotton dust: a
pilot experimental investigation. J Environ Sci and Health 1992;27A:
505-514.
(9) Lange JH. An experimental study of anti-cancer properties of
aerosolized endotoxin: application to human epidemiological studies. J
Occup Med And Toxicology1:377-382.
(10) Engelhardt R, Mackensen A and Galanos C. Phase 1 trial of
intravenously administered endotoxin (Salmonella abortus equi) in cancer
patients. Cancer Research 1991;51:2524-2530.
(11) Otto F, Schmid P, Mackensen A, Wehr U, Siez A, Braun M, Galanos
C, Mertelsmann R, and Engelhardt R. Phase II trail if intravenous
endotoxin in patients with colorectal and non-small cell lung cancer.
European J Cancer 1996;32A:1712-1718.
(12) Gerhardsson L, Brune D, Norberg IFG, and Webster PO. Protective
effect of selenium on lung cancer in smelter workers. Br J Ind Med 1985;42:617-626.
(13) Lange JH, Talbott EO, Baffone KM, Weyel DA, Soboslay EG, Koros
AMC, and Sykora JL. Anti-cancer activities of selenium. Med
Hypotheses 1987;23:443-447.
(14) Paydarfar D and Schwartz WJ. Editorial, An algorithm for
discovery. Science 2001;292: 13.
Price and colleages conclude that adding formoterol confers a
therapeutic advantage to inhaled steroid in patients with mild to moderate
asthma. For the 6 month follow up in part 2 of the study, for the secondary
outcome of mild asthma exacerbations,the frequency differed by 2.5 per
patient per 6 months ,while for poorly controlled asthma days the
difference was 4.2 days per patient per 6 months.
Price and colleages conclude that adding formoterol confers a
therapeutic advantage to inhaled steroid in patients with mild to moderate
asthma. For the 6 month follow up in part 2 of the study, for the secondary
outcome of mild asthma exacerbations,the frequency differed by 2.5 per
patient per 6 months ,while for poorly controlled asthma days the
difference was 4.2 days per patient per 6 months.
These differences while
statistically significant are unlikely to be of real clinical
relevance. Indeed during the same period, the difference in quality of life
was neither significant nor clinically relevant. The main differences which
were significant, were in bronchodilator sensitive outcomes such as peak
flow and reliever use,which are to be expected when patients are taking a
24/7 bronchodilator. These data are little different from that in steroid
naive patients in the OPTIMA trial over 12 months, where adding formoterol
to low dose budesonide improved lung function but not exacerbations, while
in the same trial for prior corticosteroid treated patients,adding
formoterol conferred only a small but significant reduction in
exacerbations.[1]
Pointedly neither of these studies evaluated any
inflammatory surrogates.
We would therefore suggest that these trials indicate that most patients
with mild to moderate asthma can be adequately controlled on low to medium
doses of inhaled budesonide alone and that there is only a marginal
advantage conferred by adding in formoterol. Morevoer combination inhalers
are considerably more expensive than inhlaed steroid alone and their
routine use is not warranted in primary care.
Reference
(1) O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled
budesonide and formoterol in mild persistent asthma: the OPTIMA randomized
trial. Am J Respir Crit Care Med 2001;164:1392-7.
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.
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Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Lancet 2001;357(9273):2017-21.
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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
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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.
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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...
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