Dear Editor

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 A high-odour solvent had been replaced by a low-odour solvent blend.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.

Dear Editor

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.

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. 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.

*   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.

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 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).