Assessment of Therapeutic Benefit in Asthmatic Patients

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special report Assessment of Therapeutic Benefit in Asthmatic Patients* The lntemationul Clinical Respiratory Group (Chest 1993; 103:91416)

he International Clinical Respiratory Group proTvides a forum for a number of specialists from

Europe and North America to discuss current issues in the clinical management of asthma and COPD. The fourth meeting, held in Brussels, Belgium, examined the ways in which therapeutic benefit may be assessed in patients with asthma. The numerous mechanisms involved in the etiology of asthma may respond independently to a given treatment, thus complicating assessment of therapeutic efficacy. This may be manifested by, for example, a reduction in symptoms resulting from a selected therapy despite no obvious improvement in FEV, values. It is therefore inadvisable to measure the effectiveness of therapy by assessing the symptoms alone. Lung- function tests must also be carried out to obtain a complete picture. The ideal lung function test or battery of tests has yet to be defined for asthma. The usefulness of various pulmonary function tests in the classification of disease severity remains controversial. The Fischl index is but one example of an attempt to derive clinically useful information from an aggregate store. When first described, the index appeared to predict treatment outcome in acutely ill asthmatic patients being treated in hospital emergency rooms.' However, prospective studies using the index could not demonstrate any useful predictive v a l ~ e . ~ J Until now. maximal ex~iratorvflow/volume or vol-

ume/time measurements of lung function have been favored by clinicians and investigators. However, there may be settings in which inspiratory loop measures may be just as effective, while being more acceptable to patient^.^ There is a good correlation between expiratory and inspiratory measures of airflow, and the inspiratory measures correlate well with clinical assessments of disease severity. Peak flow values correlate well with both symptoms thereby providand bronchial hyperresponsivenes~,~.~ ing a convenient and simple method for assessing lung function and therapeutic efficacy on a long-term basis. Peak flow measurement may be a particularly useful objective assessment parameter for long-term followup, because of its convenience and ease of use as a self-monitoring method for patients.

There seems to be little useful correlation between the degree of exercise-induced bronchoconstriction and the severity of asthma. Although studies have occasionally shown statistical correlation between the degree of exercise-inducedairway narrowing and some measures of bronchial hyperreactivity,' the exercise result has little value as a global measure of disease severity in the individual asthmatic. For asthmatic patients, exercise testing is more an indication of the ~ h ~ s i c fitness al of the patient than it is a guide to disease severity. Patients with respiratory disease tend to be less physically fit than "healthy" individualss Among asthmatic subjects, the normal breathlessness following a period of exercise may be mistaken for exercise*Participants in this meeting: Roger Bone, M.D., F.C.C.l?, Dean, Rush Medical College; Vice President, Medical Affairs; Chief, induced bronchoconstriction and may lead to mistaken Section of Pulmonary Medicine, Rush-Resbyterian-St. Luke's attempts to increase antiasthma therapy. Medical Center, Chica o. &ter Calcerley, M.D., EC.C.C, Consultant Physician, Fazaferley Hospital, Liverpool. United KingIndividuals who suffer from asthma are often indom. Kenneth R. Chapman, M.D., EC.C.E, Acting Director, structed by their physicians to limit their daily exerAsthma Centre of the Toronto Hospital, Toronto, Can&. Ronald DaM, M. D., Department of Respiratory Disease, University cise, and their overall physical fitness is adversely Hospital of Aarhus, Aarhus, Denmark. Nicholas Gmss, M.D., affected as a result. Among asthmatic patients with F.C.C.L, Department of Pulmonary Diseases, Stritch School of Medicine, Loyola University, Chicago. Helgo Magnumen, M.D., mild to moderate disease, aerobic fitness, as reflected Zentrum fiir Pneumologie und Thoraxchirurgie, LVA-Freie und Hansestadt Hamburg, Grosshansdorf, Germany. Andrd h- by peak Vo,, is unrelated to methacholine responsivechoud, M. D., F.C.C.C. Division of Pulmonary Diseases, Univerness or FEV,. Instead, exercise performance is highly sittitsklinik Basel, Basel, Switzerland. correlated to the asthmatic patient's habitual level of The International Clinical Respiratory Group is supported by Boehringer Ingelheim GmbH. exercise activity, the same determinant of physical Franklin Scientific Rejects, 516 Reprint mquests: Dr. Felicity h, fitness as in healthy nonasthmatic person^.^ W h h n n t h Road, Ladon SW8 3JX, England

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Assessment of Therapeutic Beneffl in Asthma Patients (Kerf et a/)

It is important to realize that, except for more severely ill patients, it is possible for individuals with asthma to achieve normal levels of fitness. Indeed, patients with respiratory disease of mild to moderate severity should be actively encouraged to improve their physical fitness through increased daily exercise. Most COPD patients should also be encouraged to pursue a program of exercise conditioning, although the goals of the program are necessarily more r n ~ d e s t . ~ In COPD of moderate or greater severity, exercise capacity is limited by decreased ventilatory reserve. Thus, the COPD patient's exercise tolerance may improve, but aerobic conditioning is not achieved.

Few clinical data exist to provide a convincing and clinically useful correlation between histamine or methacholine reactivity and disease severity. Many anomalies are evident in everyday practice: for example, the asymptomatic patient with trivial asthma who is highly reactive to a histamine challenge or, at the opposite extreme, the clinically brittle asthmatic whose response to inhaled histamine is minimal. The poor correlation between histamine reactivity and clinical disease renders histamine challenge testing of uncertain value to the physician, either in diagnosing respiratory disease or in estimating its severity. Methacholine challenge testing may be more valuable, but even here the interpretation of existing data is fraught with difficulty. Only 75 percent of patients with asthma respond to a methacholine challenge-a surprisingly low figure, given that 96 percent respond to hyperventilation with hyperreactivity. In contrast, a surprisingly high proportion of COPD patients react positively to a methacholine or histamine challenge. Thus, either a high proportion of COPD patients have bronchial inflammation, or the airway response to these chemical agents is a poor indicator of inflammation.1° Of course, some of the apparent responsiveness to bronchial challenge in COPD is the geometric consequence of airway narrowing at baseline. There is a significant correlation between baseline FEV, and histamine PC,.L1 Some 5 percent of the population without pulmonary disease demonstrate hyperreactivity to methacholine, further clouding the issue. In spite of these conflicting data, methacholine challenge testing may provide useful clinical information in certain circumstances, particularly when the diagnosis is difficult. A positive methacholine test result is so loosely correlated with disease severity in asthma that it would be unwise to base a diagnosis on this result alone. The interpretation of a methacholine challenge test in a given patient must be weighed against the clinical assessment that prompted testing; the significance of a test result is, in part, a product of

the prior probability that asthma is present. A negative test may have the greatest value, indicating with high probability that the patient is not asthmatic. Hence, although methacholine testing cannot substitute for clinical diagnosis, it can provide useful evidence to help complete the diagnostic picture. The test may also prove useful in monitoring asthmatic patients who do not perceive the severity of their disease: the so-called poor perceivers, who are at the greatest risk of dying of asthma. Regular selfmonitoring of peak flow, the most desirable monitoring method, may not be practical in these patients; poor perceivers may be negligent in self-monitoring and may provide only an incomplete record of their peak flow values. In these cases, a methacholine challenge test would give the physician some indication of the patient's condition using a method that can be carried out during a single visit to the clinic or office. However, the utilization of methacholine challenge to assess the poor perceiver who may not be compliant with therapy is poorly studied. The data on bronchial reactivity to histamine and methacholine are thus difficult to interpret, other than to draw the broad conclusion that any reduction in reactivity is probably to the patient's benefit. The management of the asthmatic patient may be further confounded by the patient's self-perception of symptom severity. While the majority of asthma patients are able to assess their clinical status quite acc~rately,~~ others may either overestimate or underestimate the severity of their symptoms, creating the potential for problems in their management.13 A small number of patients are oversensitive to their symptoms, reporting severe symptoms that cannot be supported by objective measurement. Such patients are clearly at risk of overmedication. In contrast, another minority of patients-the poor perceivers-are relatively insensitive to airflow obstruction and the characteristic symptoms of asthma. Indeed, patients who have near-normal peak flow rates but who complain of coughing, wheezing, and chest tightness after coughing spells are frequently undertreated. Such patients may be at increased risk of experiencing an acute, life-threatening attack.13-l4 Factors that contribute to the poor perception of symptoms may include increased bronchial hyperresponsiveness and the age of the patient, in that older asthmatic patients and those who experience longstanding airflow obstruction may be less likely to appreciate the severity of acute symptom^.'^.'^ Furthermore, psychologists have recently characterized asthma patients by personality and have described a subgroup of emotionally reserved patients whom they have termed "repressors." In one study carried out to CHEST 1 1W 1 3 1 MARCH, 1993

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assess the ability of patients to estimate peak expiratory flow, repressors performed significantly worse than their "normal" counterparts.17 Hence, psychological factors may also influence a patient's ability to perceive asthma severity. When treating the patient with asthma, it is recommended that physicians first venfy reported symptoms objectively, using a series of tests or checks that facilitate identification of "insensitive" and "oversensitive" patient types. Following the verification procedure, a period of active treatment is recommended, particularly for poor perceivers. The relief of persistent airflow obstruction through effective treatment may enable these patients to become better perceivers of their symptoms. For most patients, who perceive disease severity accurately, a symptom-driven treatmentlaction plan should be formulated, based on the reported symptoms and objective findings. In the remaining subgroup of poor perceivers, an objectively monitored treatment plan is preferred, peak flow monitoring being the most readily available measurement. Treatment goals, too, should be defined on an individual basis, each patient being asked to identlfy those symptoms most disruptive to his quality of life. Those symptoms may then be used as treatment end points for that individual. This type of individualized approach minimizes the risks associated with distorted symptom perception and encourages patients to become better partners in their ongoing care. 1 Fischl MA, Pitchenik A, Gardner LB. An index predicting relapse and need for hospitalization in patients with acute bronchial asthma. N Engl J Med 1981;305:783-89 2 Rose CC. Murphy JG, Schwartz JS. Performance of an index

predicting the respnnse of patients with acute bronchial asthma to intensive emergency department treatment. N Engl J Med

1984;310673-77 3 Centor RM, Yarbrough B, Wood JP Inability to predict relapse in acute asthma. N Engl J Med 1984;310:577-80 4 Bollinger CI: Fourie PR, Joubert JR. The flow/volume loop in severe acute asthma. Eur Respir J 1991;4:230-31 5 Haahtela T, JWunen M, Kava T, Kiviranta K, Koskinen S,

Lehtonen K, et al. Comparison of a be&-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991;325:388-92 6 Ryan G, Latimer KM, Dolovich J, Hargreave FE. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway caliber. Thorax 1982;37:423-29 7 Anderton RC, Cuff MT, Frith PA, Cockcroft DW, Morse JL, Jones NL, et al. Bronchial responsiveness to inhaled histamine and exercise. J Allergy Clin Immunol 1979;63315-20 8 Garfinkle S, Kesten S, Rebuck AS, Chapman KR. Physiologic and nonphysiologic determinants of aerobic fitness in mild to moderate asthma. Am Rev Respir Dis (in press) 9 Chapman KR. Therapeutic algorithm for chronic obstructive pulmonary disease. Am J Med 1991;91:17S-23s 10 Ingram RH Jr. Physiological assessment of inflammation in the peripheral lung of asthmatic patients Lung 1991; 169(suppl): S29-39 11 Yan K, Salome CM, Woolcock AJ. Prevalence and nature of bronchial hyperresponsiveness in subjects with chronic obstruc tive pulmonary disease. Am Rev Respir Dis 1985;132:25-9 12 Shim CS, Williams MH Jr. Evaluation of the severity of asthma: patients versus physicians. Am J Med 1980;68:ll-3 13 Rubinfeld AR, Pain MC. Perception of asthma. Lancet 1976;

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14 Zach MS. Karner U. Sudden death in asthma. Arch Dis Child

1989;64:1446-50 15 Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Compbell

EJ. The perception of breathlessness in asthma. Am Rev Respir Dis 1982;126:825-28 16 Quirk FH, Jones PW. Patients' perception of distress due to symptoms and effects of asthma on daily living and an investigation of possible influential factors. Clin Sci 1990;79:17-21 17 Steiner H, Higgs CM, Fritz GK, Laszlo G, Harvey JE. Defense style and the perception of asthma. Psychosom Med 1987;49: 35-44

Assessment of Therapeutic Benefit in Asthma Patients (Kerr et e/)