Skeletal Muscle Weakness, Fatigue and Sarcoidosis the Levels of Muscle Enzymes Such As

EDITORIAL 1

Skeletal muscle weakness, fatigue and sarcoidosis The levels of muscle enzymes such as ...... creatine phosphokinase may be raised. Thorax: first published as 10.1136/thx.2004.027342 on 23 December 2004. Downloaded from Chronic myopathy is also rare. In a review of 800 patients with confirmed Skeletal muscle weakness, fatigue and sarcoidosis Silverstein and Siltzbach14 found that only two had severe persis- sarcoidosis tent sarcoid myopathy and, in the recent prospective ACCESS study, only one of U Costabel 215 patients had initial muscle involvement.15 The symptoms are bilateral ...... weakness and wasting of proximal muscles. Whereas corticosteroids are It is important to remember that sarcoidosis is a complex clearly indicated in these forms of multiorgan disease with multiple non-specific symptoms which go clinically apparent muscle involvement, beyond the usual experience of chest physicians diagnostic difficulty may arise when myopathy occurs in patients with sarcoidosis under treatment with cortico- arcoidosis is a multisystem granu- strength were found in this study steroids since corticosteroid myopathy lomatous disorder that may involve between patients who were taking has a similar distribution to that seen in many organs. Beside organ specific steroids and those who were not. S sarcoid myopathy. symptoms, non-specific constitutional Other factors may therefore be What are the practical issues emer- complaints such as fatigue and general involved in the development of skeletal ging from the paper by Spruit et al? For weakness are frequent. The granuloma muscle weakness. One could be reduced differential diagnostic purposes, the formation in sarcoidosis is driven by an physical activity which can induce gen- muscle force tests are not useful since array of cytokines such as tumour eral deconditioning in these patients they do not discriminate between the necrosis factor (TNF)-a, interleukin who complain of fatigue, general possible different causes of skeletal (IL)-6, interferon (INF)-c and others. malaise and depression, all of which muscle weakness in sarcoidosis. As High circulating levels of such cytokines will probably reduce the patients’ phy- previously mentioned, the causes may have been found in sarcoidosis and may sical activities. One major shortcoming be limited physical activities, sarcoidosis be responsible for provoking the consti- of the paper by Spruit et al is that they involvement of the muscles, or cortico- tutional symptoms fatigue and general did not investigate patients who did not 1–4 steroid myopathy. Ideally, we should weakness. complain of fatigue so it is difficult to have discriminating tests available Fatigue and general weakness may be generalise their findings to other pati- which would be non-invasive and not the reason why patients with sarcoidosis ents with sarcoidosis. Would reduced depend on muscle biopsy. Less invasive frequently experience exercise intoler- skeletal muscle strength also be present techniques such as electromyography 56 ance. In one study 67% of patients in sarcoidosis patients without fatigue? and nerval conductance velocity may with sarcoidosis terminated their peak We do not know since the number of differentiate between myopathy (either 7 exercise test due to ‘‘leg complaints’’. patients studied in the first paper on sarcoidosis or corticosteroid induced) Skeletal muscle weakness may therefore skeletal muscle strength8 was probably and weakness due to limited exercise. http://thorax.bmj.com/ be responsible for the limited exercise too small to exclude a type II error. Unfortunately, such neurological mea- capacity, although quadriceps muscle Another factor contributing to the surements for determining the cause of force and handgrip force were found to muscle weakness could be involvement the skeletal muscle weakness were not 10 be normal in the first study to investi- of the skeletal muscle by sarcoidosis. included in the present study. gate skeletal muscle force in patients The first published case of sarcoidosis of If we apply muscle force tests more 8 with sarcoidosis, but most of these the skeletal muscles was reported as frequently in patients with sarcoidosis patients did not complain of fatigue. early as 1908 by Licharew who pre- and find reduced muscle strength, how 9 In this issue of Thorax Spruit et al sented a girl with many palpable should we manage such patients? We

11 on October 4, 2021 by guest. Protected copyright. report that skeletal muscle weakness is nodules in the muscle. In 1952 it was would expect that most of these patients present in patients with sarcoidosis who recognised that inactive sarcoidosis also have the subjective complaint of complain of fatigue, and that the pre- granulomas might frequently be found fatigue, so the more general question sence of skeletal muscle weakness is in clinically normal muscles.12 In 50– would be how to manage skeletal associated with reduced health status as 75% of patients with sarcoidosis a muscle weakness and fatigue in sarcoi- assessed by two questionnaires and also muscle biopsy may detect non-caseating dosis. Given the very rare clinically with reduced exercise capacity. In addi- granulomas.12 13 None of the patients in apparent skeletal muscle involvement tion, quadriceps muscle force was inver- these screening studies had symptoms by sarcoidosis granuloma and the very sely related to fatigue but not to the suggesting muscle involvement. This frequent subclinical muscle involvement circulating levels of several proinflam- symptomless involvement resolves in which most probably represents harm- matory cytokines. This would indicate the majority of cases during the natural less granuloma formation without that skeletal muscle weakness rather course of the disease. impairment or wasting of the skeletal than the circulating cytokines are Clinically symptomatic skeletal mus- muscle, one would not start prednisone responsible for the complaints of fatigue cle involvement in sarcoidosis is rare. treatment for these patients but, rather, in these patients. Interestingly, quad- There are two manifestations—acute would recommend that they undergo riceps muscle force was inversely related polymyositis and chronic myopathy. controlled physical training prog- to the daily dose of corticosteroids in Acute polymyositis has been reported rammes. As Spruit et al discuss, the patients who received such treatment. in no more than 15 cases.10 The proximal positive effect of exercise training in This would imply that steroid induced shoulder and pelvic girdle muscles are chronic pulmonary and cardiac disease myopathy may be one factor for reduced most often involved and the condition is has been shown for other conditions skeletal muscle function in sarcoidosis, often associated with fever, erythema and may reduce clinical symptoms of although no differences in muscle nodosum, myalgia, and polyarthralgia. fatigue, anxiety, and depression.

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In this regard the great merit of the REFERENCES 8 Wirnsberger M, Drent M, Hekelaar N, et al.

Relationship between respiratory muscle function Thorax: first published as 10.1136/thx.2004.027342 on 23 December 2004. Downloaded from paper by Spruit et al is to remind the 1 Asano M, Minagawa T, Ohimichi M, et al. and quality of life in sarcoidosis. Eur Respir J readers of Thorax that sarcoidosis is a Detection of endogenous cytokines in sera or in 1997;10:1450–5. complex multiorgan disease with multi- lymph nodes obtained from patients with 9 Spruit MA, Thomeer MJ, Gosselink R, et al. sarcoidosis. Clin Exp Immunol 1991;84:92–6. Skeletal muscle weakness in patients with ple non-specific symptoms which go 2 Shijubo N, Imai K, Shigehara K, et al. Soluble sarcoidosis and its relationship with exercise beyond the usual experience of chest intercellular adhesion molecule-I (ICAM-1) in intolerance and reduced health status. Thorax physicians. The study underlines the sera and bronchoalveolar lavage fluid of 2005;60:32–8. importance of taking such patient com- patients with idiopathic pulmonary fibrosis and 10 Rizzato G, Montemurro L. The locomotor system. pulmonary sarcoidosis. Clin Exp Immunol In: James DG, ed. Sarcoidosis and other plaints seriously, performing adequate 1994;95:156–61. granulomatous disorders. New York: Marcel investigations which may include mus- 3 Prior C, Knight RA, Herold M, et al. Pulmonary Dekker, 1994:349–73. cle force tests, and giving them the sarcoidosis: patterns of cytokine release in vitro. 11 Licharew W. Moskauer venerologische und Eur Respir J 1996;9:47–53. dermatologische Gesellschaft. Dermatol Zentralbl appropriate treatment which would 4 Mu¨ller-Quernheim J. The cytokine network 1908;11:235. probably include an exercise programme in sarcoidosis. Eur Cytokine Netw 12 Myers GB, Gottlieb AM, Mattman PE, et al. Joint to improve their physical activity which 1996;7:13–26. and skeletal muscle manifestations in sarcoidosis. 5 Sharma OP. Fatigue and sarcoidosis. Eur Respir J Am J Med 1952;12:161–9. would also reduce the complaint of 1999;13:713–4. 13 Wallace SL, Lattes R, Malia JP, et al. Muscle fatigue. 6 Drent M, Wirnsberger RM, de Vries J, et al. involvement in Boeck’s sarcoid. Ann Intern Med Association of fatigue with an acute phase 1958;48:497–511. Thorax 2005;60:1–2. response in sarcoidosis. Eur Respir J 14 Silverstein G, Siltzbach LE. Muscle involvement in doi: 10.1136/thx.2004.027342 1999;13:718–22. sarcoidosis. Arch Neurol 1969;21:235–41. 7 Miller A, Brown LK, Sloane MF, et al. 15 Judson MA, Baughman RP, Thompson BW, et al. Correspondence to: Dr U Costabel, Cardiorespiratory responses to incremental Two year prognosis of sarcoidosis: the ACCESS Ruhrlandklinik, Tueschener Weg 40, 45239 exercise in sarcoidosis patients with normal experience. Sarcoidosis Vasc Diffuse Lung Dis Essen, Germany; [email protected] spirometry. Chest 1995;107:323–9. 2003;20:204–11.

Chemistry of exhaled nitrogen oxides see that the sum total exhalation of NO ...... plus NOx is somewhat higher in CF than in controls, while the ratios of NO to NOx between the groups differ by a Informative complexity of exhaled factor of 6. If we consider the original source of all the nitrogen oxides in the nitrogen oxide chemistry lung to be from NOS (a somewhat risky assumption), then these data suggest J F Hunt that NO production is actually enhanced in the CF airway, not decreased as has at ...... times been supposed. The fact that NO exhalation is low in CF then appears to Seeking the meaning of exhaled NO result from overactive oxidative pro- nthisissueofThorax, Ojoo et al1 aforementioned processes or, impor- cesses consuming NO. conclude their paper with a sentence tantly, from decreases in various NO A little more caution is needed here, as that is worthy of direct quotation. Their consumptive pathways that also are it is not clear how much of the gas phase http://thorax.bmj.com/ I NO available for exhaled measurements data ‘‘draw attention to the complexity of abundantly active in the airway. Such 2 also contributes to the EBC NO2 and NO [nitric oxide] metabolism, where consumptive pathways include reaction 2 multiple pathways of NO synthesis and with haemoglobin and various thiols, NO3 levels. That work has yet to be clearance are likely to have variable reduction by bacteria, and oxidation done. But, as the authors note, it seems relevance in different circumstances’’. reactions that form the higher oxides clear that NOx in EBC are not derived 2 solely from NO gas dissolving and oxidis- Exhaled NO measurement is now a clini- of nitrogen (NOx)—specifically NO2 , 2 ing in the EBC ex vivo, as there are not cally approved test and, with approxi- S-nitrosothiols, and nitrate (NO3 )—as mately 1000 articles so far published, products.5 enough available moles of NO gas in the there are sufficient data to support its Ojoo et al1 report that, while high aci- exhaled air to provide for the levels of on October 4, 2021 by guest. Protected copyright. utility as an objectively measurable bio- dity (low pH) of exhaled breath con- NOx seen in the EBC of CF patients. marker relevant to lung disease. How- densate (EBC) was identified in subjects Oxidation is one key sump for NO in ever, despite all of the publications, how with cystic fibrosis (CF), exhaled NO the airway. Many believe oxidative pro- the multiple intracorporeal biochemical levels were lower than in controls. These cesses to be a key mechanism by which pathways interact and determine NO data suggest that airway acid acting on ‘‘inflammation’’—a generic term of 2 exhalation remains unclear. NO2 is neither the sole nor the domi- uncertain meaning beyond the classical In order to avert confusion, it is nant determinant of exhaled NO in this ‘‘rubor’’, ‘‘tumor’’, ‘‘calor’’ and ‘‘dolor’’— necessary to assure that vocabulary is patient group. Additionally, their data dutifully accomplishes its various mis- shared. ‘‘Exhaled NO’’ has become the reveal that, in contrast to NO, NOx are sions. In general we consider NOS to vernacular for the fractional exhalation exhaled in greater amounts from sub- be upregulated, acidity increased, and of NO (FENO). This is not the amount of jects with CF than controls. If we oxidation enhanced in inflammatory NO produced in the lung. Indeed, only a roughly back calculate from Ojoo’s data conditions. Inflammation might lead tiny fraction of NO produced in the lung we find that, in their healthy control to higher or lower exhaled NO levels ends up being exhaled. Increased pro- subjects, mole for mole, the amount of depending on the relative effects of the duction of NO in the airway can occur NOx exhaled per hour as identified in inflammation on NOS activity and from increased nitric oxide synthase EBC (90 nmol/h) is about half the acidic and oxidative stresses. (NOS) activity, from inorganic acidifica- amount of NO exhaled when measured Ojoo et al have shown how these three 2 2–4 tion of nitrite (NO2 ), and from in gas phase (180 nmol/h). In patients chemical aspects of inflammation (NO, 5 homolytic cleavage of nitrosothiols. with CF, however, NOx are exhaled at acid, and oxidants) can be monitored Increased exhalation of NO can occur the rate of 240 nmol/h compared with and distinguished. By measuring from enhanced action of any of these only 80 nmol/h exhaled as NO. One can exhaled NO, exhaled acids, and exhaled

www.thoraxjnl.com EDITORIAL 3

Thorax 2005;60:2–3. NOx all together, one can make the conscientious interpretation—of the following suppositions. If exhaled NO is chemistry of the airways helps us to doi: 10.1136/thx.2004.024364 Thorax: first published as 10.1136/thx.2004.027342 on 23 December 2004. Downloaded from high while exhaled NOx are low, then recognise how acidic and oxidative pro- Correspondence to: Dr J Hunt, Division of that particular airway inflammatory cesses, as well as NO chemistry, behave in Pediatric Respiratory Medicine, Box 800386, process has a relatively high ratio of various lung diseases. These processes are University of Virginia, Charlottesville, VA airway NO production to oxidant activ- key mechanisms of inflammatory effect 22908, USA; [email protected] ity. If exhaled NO is low while exhaled and are relatively easy therapeutic targets. Competing interest statement: (1) The University of Virginia owns intellectual property relating to NOx are high, then the inflammation is Another point is worth noting. relatively more dominated by oxidant Spirometric values in CF in this study measurement of exhaled breath condensate pH. (2) The author is a founder of Respiratory stress than by NO production. When were not significantly lower on average Research Inc, a company that builds exhaled acidification is present, then NO will be during acute respiratory exacerbations. 2 breath condensate collection equipment. (3) The both produced from NO2 and con- This statement reminds us that ‘‘no author is an inventor on US and international sumed by the higher oxidative activity statistically significant difference’’ is patents relating to measurement of exhaled that occurs in acidic conditions.3 Thus, not synonymous with ‘‘no difference’’. breath condensate nitrogen oxides, but has no EBC acidity stands by itself as an Given that EBC pH was significantly financial interest in these patents. indicator of airway acid stress but not lower in the exacerbating group relative of NO production, and exhaled NO and to the stable group, the lay reader might REFERENCES NO measured concurrently begin to x conclude that EBC pH is more useful 1 Ojoo JC, Mulrennan SA, Kastelik JA, et al. elucidate the relative—not absolute— than spirometry at identifying CF Exhaled breath condensate pH and exhaled nitric activities of the NO production path- exacerbations. A more cautious and oxide in allergic asthma and in cystic fibrosis. ways and oxidative processes. Thorax 2005;60:22–6. probably wiser interpretation might be 2 Lee KH, Rico P, Billiar TR, et al. Nitric oxide The same acidity that can convert that—together—spirometry, EBC pH, production after acute, unilateral hydrochloric 2 2 2 aqueous NO2 into NO will also enhance exhaled NO, and NO2 and NO3 assays acid-induced lung injury in a canine model. Crit oxidative activity in general, including provide a more comprehensive and true Care Med 1998;26:2042–7. 2 3 Weitzberg E, Lundberg JO. Nonenzymatic nitric the reaction of NO2 with the reduc- picture of airway disease than any single oxide production in humans. Nitric Oxide tant, glutathione. This reaction forms measurement. EBC pH informs us about 1998;2:1–7. 4 Hunt JF, Fang K, Malik R, et al. Endogenous S-nitrosoglutathione, an endogenous airway acid stress. NO and NOx, when 5 airway acidification. Implications for asthma bronchodilator. To complicate matters, measured together, inform us about pathophysiology. Am J Respir Crit Care Med glutathione stores themselves can be NO production and oxidative burden. 2000;161:694–9. depleted by excessive oxidative processes. Spirometry provides physiological data. 5 Gaston B, Drazen JM, Loscalzo J, et al. The biology of nitrogen oxides in the airways. Furthermore, the CF airway is commonly Of course, none of these tests delineates Am J Respir Crit Care Med 1994;149:538–51. colonised with bacteria capable of redu- perfectly the amount of ‘‘inflamma- 6 Gaston B, Ratjen F, Vaughan JW, et al. cing NO to ammonia, a process which tion’’. But then, in the absence of a Nitrogen redox balance in the cystic fibrosis 6 airway: effects of antipseudomonal therapy. can consume NO. Despite these com- unifying definition of inflammation, no Am J Respir Crit Care Med plexities, efforts at measurement—and one test possibly could. 2002;165:387–90.

Asthma and obesity England. Such surveys routinely include

...... height and weight, as increased body http://thorax.bmj.com/ mass index (BMI) in adults is a risk factor for a number of diseases, but the Concurrent trends in asthma and Health Survey for England has included respiratory symptoms only in selected obesity surveys. Increases in asthma and in overweight (BMI 25–,30 kg/m2)or S Chinn obesity (BMI >30 kg/m2) have been reported many times over the last

...... 20 years, but rarely in the same study. on October 4, 2021 by guest. Protected copyright. This has led to speculation that the rise Is the concurrent rise in the prevalence of asthma and obesity a in obesity might explain some of the red herring? increase in the prevalence of asthma, but there has been little direct evidence tudies that have reported an asso- to establish the lag, but frequent follow to support or refute the hypothesis.1–4 ciation between asthma and obe- up would be required. However, pure Ssity have mostly been single cross cohort studies cannot answer the ques- REPEATED CROSS SECTIONAL sectional studies, although an increased tion of how much of the increase in the STUDIES IN CHILDREN incidence of asthma in participants who prevalence of asthma in a population Some direct evidence is provided in this were overweight at baseline has been can be explained by an increase in issue by Wickens et al.5 They studied reported in several longitudinal studies. obesity, as age and period are comple- comparable groups of 11–12 year old The latter have contributed to the tely confounded. Repeated cross sec- children in New Zealand in 1989 and debate about the nature of the associa- tional studies in the same population 2000 and found an increased prevalence tion, showing that the reverse causality are needed to answer this question. of symptoms, asthma, and medication explanation—that decreased physical in 2000 compared with 1989, but little activity as a result of asthma leads to POPULATION SURVEYS difference in the corresponding odds increased weight—is not plausible. Some countries have regular cross sec- ratios unadjusted or adjusted for BMI. Cohort studies have the potential to tional population health surveys, such They also found a stronger relation bet- determine whether increased symp- as the National Health and Nutrition ween most outcomes and BMI in 2000 toms of asthma are an immediate Examination Surveys (NHANES) in the than in 1989, particularly for wheeze consequence of weight gain or, if not, United States and the Health Survey for and medication in the last 12 months,

www.thoraxjnl.com 4 EDITORIAL which remained statistically significant A rough estimate of the maximum overweight and obesity explains little or in the 2000 data after adjustment for a likely effect on the rise in asthma can be none of the trend in asthma, we can Thorax: first published as 10.1136/thx.2004.027342 on 23 December 2004. Downloaded from number of potential confounders. obtained, for a given increase in pre- conclude that controlling the weight of The results are similar to those of valence of overweight and obesity, on the population would do little to reduce Chinn and Rona from the National the assumption that the association is the prevalence of asthma as the asso- Study of Health and Growth (NSHG),6 causal. For example, a change in BMI ciated relative risks are too small. How- who found that virtually none of the distribution from 85% normal weight, ever, it may take more direct evidence to increase in wheeze or asthma in 8 and 10% overweight and 5% obese to 75% convince the whole of the scientific 9 year old children in the UK from 1982 normal, 15% overweight and 10% obese community of this and, if further data to 1994 was explained by the rise in would, at most, increase the prevalence exist to establish whether the association overweight and obesity, and also of asthma by 6.8% over baseline, given is recent or long standing in adults, this reported a stronger association between the published estimates of relative risks. would be of interest. A long standing asthma and obesity in the later than A baseline prevalence of 5% would association in adults would contrast with in the earlier year in children aged increase to 5.3%, a very modest rise that in children and would make changes 5–11 years. The UK and New Zealand compared with most of those reported. in the population in diet and physical studies were each carried out in a school So we should not expect the rise in activity less likely as an explanation. population with symptoms and medica- overweight and obesity to explain more Thorax 2005;60:3–4. tion reported by parent or caregiver. than a very small amount of the doi: 10.1136/thx.2004.031161 Height and weight were measured, increase in asthma. Correspondence to: Professor S Chinn, unlike in many adult studies from Department of Public Health Sciences, King’s which an association between asthma EVIDENCE FROM TRENDS College London, London SE1 3QD, UK; and obesity has been reported. However, Ideally, trends should be calculated from [email protected] in children BMI is a poorer measure of more than two time points. Long term fatness than skinfold thickness. In the trends in asthma and BMI can show NSHG there was a weaker association of whether the increase in asthma started REFERENCES asthma and persistent wheeze with close to, or soon after, the beginning of 1 Shaheen SO. Obesity and asthma: cause for skinfold measurements than with BMI.7 the major increase in obesity. Parallel concern? Clin Exp Allergy 1999;29:291–3. 2 Camargo CA, Weiss ST, Zhang S, et al. trends, or points of inflexion close in Prospective study of body mass index, weight time,telluslittleinthemselvesother change, and risk of adult-onset asthma in women. IS THE ASSOCIATION RECENT IN than that a direct causal role is possible. Arch Intern Med 1999;159:2513–4. ? 3 Castro-Rodriguez JA, Holberg CJ, Morgan WJ, CHILDREN The contrary—especially a reversal of one Wickens et al considered that there was et al. Increased incidence of asthmalike symptoms trend in the absence of a change in the in girls who become overweight or obese during insufficient evidence to conclude that other—is evidence against a direct causal the school years. Am J Respir Crit Care Med the association in children is of recent 2001;163:1344–9. relation provided the data are represen- origin.5 They argued that comparisons of 4 Gilliland FD, Berhane K, Islam T, et al. Obesity tative of the same populations. There is and the risk of newly diagnosed asthma in school- studies over time are hampered by now some evidence for a recent slowing age children. Am J Epidemiol 2003;158:406–15. changing definitions of asthma. Cer- 5 Wickens K, Barry D, Friezema A, et al. Obesity down or cessation of the increase in and asthma in 11–12 year old New Zealand tainly, comparison is difficult as the lack 13–16 asthma in children and in adults. children in 1989 and 2000. Thorax of definition of overweight and obesity Data on BMI were not collected in the 2005;60:7–12. http://thorax.bmj.com/ in children before 2000 led to a variation individual studies and three of the 6 Chinn S, Rona RJ. Can the increase in body mass in reporting results. However, the NSHG index explain the rising trend in asthma in studies were carried out in selected children? Thorax 2001;56:845–50. had identical symptom questions over areas.13 14 16 The fourth study used data 7 Figueroa-Mun˜oz JI, Chinn S, Rona RJ. Associa- time, and there is no doubt that the from 1990 to 1998 from the UK General tion between obesity and asthma in 4 to 11 year association of persistent wheeze with old children in the UK. Thorax 2001;56:133–7. Practice Research Database and showed a 8 Somerville SM, Rona RJ, Chinn S. Obesity and BMI was stronger in the representative levelling off of trends in managed asthma respiratory symptoms in primary school. Arch Dis 78 sample in 1993/1994 than in 1977. from about 1995.15 Recent trends in BMI Child 1984;59:940–4. 6 9 Flegal KM, Carroll MD, Kuczmarski RJ, et al. Neither the NSHG nor the New in Italy or Switzerland are not available 5 Overweight and obesity in the United States: Zealand study was able to show an but in England there is evidence from the prevalence and trends, 1960–1994. Int J Obesity on October 4, 2021 by guest. Protected copyright. interaction between year of survey and Health Survey for England for an increase 1998;22:39–47. the association of asthma and BMI, 10 Kwon HL, Belanger K, Bracken MB. Asthma pre- in obesity in adults from 1993 to 1998. valence among pregnant and childbearing women possibly due to lack of power but, taken While England is not the whole of the in the United States: estimates from national together, the evidence is strengthened UK, and neither study may be fully health surveys. Ann Epidemiol 2003;13:317–24. that the association in children is recent. 11 Seidell JC, de Groot LCPGM, van Sonsbeek JLA, representative as the General Practice et al. Associations of moderate and severe Research Database may have practice overweight with self-reported illness and medical EVIDENCE IN ADULTS participation bias and the Health Survey care in Dutch adults. Am J Public Health for England individual non-response 1986;76:264–9. No direct information on the BMI 12 Negri E, Pagano R, Decarli A, et al. Body weight adjusted trend in the prevalence of bias, taken together the results suggest and the prevalence of chronic disease. J Epidemiol asthma has been published in adults, that the trends are not parallel. Community Health 1988;42:24–9. 13 Ronchetti R, Villla M, Rota R, et al. Is the increase although data on asthma and BMI were in childhood asthma coming to an end? Findings obtained in NHANES (at least in surveys CONCURRENT TRENDS—A RED from three surveys of schoolchildren in Rome, II and III).910 There is also a lack of ? Italy. Eur Respir J 2001;17:881–6. HERRING 14 Verlato G, Corsico A, Villani S, et al. Is the information on when the association There is little doubt that there was a prevalence of adult asthma and allergic rhinitis between asthma and obesity arose in concurrent rise in the prevalence of still increasing? Results of an Italian study. adults, or whether it is long standing asthma and obesity in many developed J Allergy Clin Immunol 2003;111:1232–8. 15 Soriano JB, Kiri VA, Maier WC, et al. Increasing but only noticed once obesity became countries in the 1980s and early 1990s, prevalence of asthma in UK primary care during more prevalent. The earliest studies to and this led to the speculation that the the 1990s. Int J Tuberc Lung Dis 2003;7:415–21. report an association were carried out in increase in obesity might explain some 16 Braun-Fahrla¨nder C, Gassner M, Gize L, et al. No further increase in asthma, hay fever and the early 1980s and were studies of of the trend in asthma. Even without atopic sensitisation in adolescents living in chronic disease in general.11 12 more direct evidence that the trend in Switzerland. Eur Respir J 2004;23:407–13.

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Clinical remission of asthma In a recent issue of Thorax Vonk et al3 ...... reported evidence from such a cohort of Thorax: first published as 10.1136/thx.2004.027342 on 23 December 2004. Downloaded from 119 allergic asthmatic children (age 5–14 years) enrolled in an outpatient Clinical remission of asthma: what lies clinic in the late 1960s and re-evaluated in a follow up visit approximately beyond? 30 years later (age 32–42 years). Although the relatively small sample S Guerra size suggests caution in interpreting these data, this study provides cogent ...... findings that are consistent with those from previous longitudinal studies and Further evidence suggests that ‘‘complete’’ remission of childhood may have important implications for the asthma may be the exception rather than the rule search of optimal management strategies in asthma. sthma can be a debilitating dis- against onset of new asthma. Taken Firstly, childhood asthma appeared ease with a major impact on together, these observations strongly to remit clinically (no reported Aquality of life and an increased suggest that factors that determine the active symptoms and no use of inhaled risk of developing severe airway re- inception of asthma may differ from corticosteroids) in adult age ‘‘only’’ modelling and non-fully reversible those that affect its progression, and in approximately 50% of the cases. In airflow obstruction. In the last decades, reinforce the unique importance of interpreting these results, the selective effective pharmacological treatments studies that follow subjects with asthma nature of this cohort of outpatients and management strategies have been over time. Observational and interven- should be kept in mind. It is known developed for this disease. Yet, at the tion studies on selected cohorts of that children with asthma selected in present time, asthma remains a treat- asthmatics have indeed provided critical the clinical setting are likely to differ able but not a curable disease. contributions to our understanding of from population based samples of asth- It is not therefore surprising that the factors influencing the clinical matics in many respects, particularly in much effort is being put into studying course of the disease, and this evidence terms of increased severity of the dis- the risk factors associated with the has affected to a large extent the way we ease—a known risk factor for persis- inception and progression of asthma, currently treat and manage asthma. tence of symptoms into adulthood. since understanding these factors repre- Studies on asthmatic cohorts can also Rates of asthma persistence are there- sents the first necessary step for devel- help to elucidate the natural history and fore expected to be higher in clinic based oping effective prevention strategies. In long term outcomes of the disease. From than in population based cohorts. this respect, the increase in the inci- a clinical standpoint, this is not an issue Consistently, findings from several dence and prevalence of asthma over of secondary importance. Asthma is a long term longitudinal cohorts4–7 indi- the last decades has not only produced a variable disease that can persist, remit cate that, in the general population, general awareness of the public health conclusively, or present any possible among subjects who had episodes of burden associated with the disease, but combination of remissions and relapses wheezing in childhood, approximately it has also provided the scientific ratio- over time. Clearly, the long term seque- one third report active asthma symp- http://thorax.bmj.com/ nale for expecting a major role of lae of the disease on lung health are toms when surveyed in their young to environmental factors in its develop- likely to be quite different across these mid adult life. However, this proportion ment. However, the epidemiological different patterns. In this framework, is remarkably higher, even in population identification of these disease determi- longitudinal studies assessing the out- based studies, among subjects whose nants has not proved to be an easy task. come of childhood asthma into adult life childhood asthma was severe or char- While profiles of risk factors for asthma hold particular interest for two main acterised by frequent wheezing epi- have been identified, the exact mechan- reasons. Firstly, in the vast majority of sodes. This concept is best illustrated isms by which they operate are far from cases asthma has its onset in childhood. by data from the Melbourne Asthma being fully understood for many (or Therefore, even though adult onset Study8 in which several groups of school on October 4, 2021 by guest. Protected copyright. most) of them. In addition, many of asthma is frequently associated with age children were enrolled based on these factors are likely to be involved in severe and difficult to treat forms of their wheezing/asthma history and fol- complex gene-by-environment interac- the disease, asthma initiated in child- lowed over time into their adulthood. At tions and to be differentially linked to hood continues to have a greater public age 42, 15% of controls reported wheez- different asthma phenotypes. This com- health impact at the population level. ing episodes in the last 3 years complexity has limited the implementation Secondly, asthma may lead in the long pared with 40% of the subjects who, of effective interventions to reduce the term to severe airway remodelling and, during childhood, had wheezing asso- incidence of asthma and, to date, there possibly, to the development of chronic ciated with bronchitis or respiratory is no conclusive programme of primary airflow obstruction. These observations tract infection. However, wheezing epi- prevention for this disease. raise critical questions on whether this sodes were reported by up to 70% and To complicate things even more, course is more likely to occur in the 90% of subjects who during childhood remarkable paradoxes have emerged persistent forms of asthma, whether had fulfilled the criteria for asthma and from recent research. Factors that are subjects predisposed to this progression severe asthma, respectively. known to exacerbate or trigger asthma, can be identified at early stages of their All evidence considered, it appears such as exposure to endotoxin1 or pets,2 disease, and whether optimal asthma plausible to conclude that most children appear to be somewhat protective if they management can be beneficial against with moderate to severe forms of occur early in life. Similarly, while aller- disease progression. Longitudinal stu- asthma will experience clinically active gen avoidance is undoubtedly a bene- dies following cohorts of participants disease at least in some periods of their ficial and essential part of management over a wide age span between childhood adult life. This important conclusion strategies in atopic asthma, it does not and adulthood represent our best tool to becomes even more striking when we appear to be as effective in protecting answer these questions. consider a second finding from the

www.thoraxjnl.com 6 EDITORIAL study by Vonk et al3: most cases of asthma may be related to several fac- Correspondence to: Dr S Guerra, Arizona asthma in clinical remission (in that tors, including early airway remodelling Respiratory Center, University of Arizona, Thorax: first published as 10.1136/thx.2004.027342 on 23 December 2004. Downloaded from 1501 N. Campbell Ave, P O Box 245030, study, up to 57%) still show bronchial or impaired lung growth. Regardless of Tucson, AZ 85724-5030, USA; sguerra@ hyperresponsiveness and/or reduced the nature of these factors, the fact that arc.arizona.edu lung function. This finding supports a these deficits track over time implies Dr Guerra is supported in part by a Grant clear distinction between clinical remis- that children with persistent asthma Award from the American Thoracic Society/ sion of asthma (that is, absence of will be most often destined to have Alpha One Foundation. symptoms and medication use) and lower lung function than their peers in complete remission of asthma. The adult life. In addition, among subjects implications of this distinction are quite with long term asthma, these deficits in REFERENCES relevant, given that the simple absence lung function may eventually lead to a 1 Liu AH. Endotoxin exposure in allergy and of symptoms is the most commonly non-fully reversible airflow obstruc- asthma: reconciling a paradox. J Allergy Clin used criterion for defining asthma tion—a key functional feature for the Immunol 2002;109:379–92. 2 Simpson A, Custovic A. Early pet exposure: friend remission in epidemiology and it is also definition of chronic obstructive pulmo- or foe? Curr Opin Allergy Clin Immunol used to a large extent in clinical algo- nary disease (COPD).12 The co-existence 2003;3:7–14. rithms for managing the disease. of asthma and COPD diagnoses in the 3 Vonk JM, Postma DS, Boezen HM, et al. Childhood factors associated with asthma Does the presence of bronchial hyper- same subject appears quite frequently in remission after 30 year follow up. Thorax 13 responsiveness and reduced lung func- adults and appears to be associated 2004;59:925–9. tion among these apparently remitting with increased mortality.14 It is debata- 4 Horak E, Lanigan A, Roberts M, et al. Longitudinal study of childhood wheezy bronchitis asthma cases represent structural seque- ble whether subjects with asthma are at and asthma: outcome at age 42. BMJ lae of the disease? 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Global sistently higher in subjects with tion over time shown by subjects who strategy for the diagnosis, management, and remitting asthma than in controls.9–11 had severe childhood asthma may also prevention of chronic obstructive pulmonary play an important role in increasing the disease. NHLBI/WHO Global Initiative for This evidence raises the question Chronic Obstructive Lung Disease (GOLD) whether a long term anti-inflammatory susceptibility of these subjects in adult Workshop summary. Am J Respir Crit Care Med treatment should be considered in these life to noxious agents including cigarette 2001;163:1256–76. cases of subclinical asthma. At the pre- smoking, and in lowering their thresh- 13 Soriano JB, Davis KJ, Coleman B, et al. The proportional Venn diagram of obstructive lung on October 4, 2021 by guest. Protected copyright. sent time we do not have a conclusive old for a clinically relevant lung damage disease: two approximations from the United answer to this question. 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