On observing patterns of airflow obstruction in chronic asthma

BY. J. Dis. Chest (1977),

71, 73

Point of View ON OBSERVING OBSTRUCTION

PATTERNS OF AIRFLOW IN CHRONIC ASTHMA

MARGARET Cardiothoracic

TURNER-WARWICK

Institute,

Brompton

Hospital,

London

I do not indeed swear by an opinion because it is old; but neither do I fall in love with every extravagence at first sight because it is new. I conceive that a thing may have been repeated a thousand times without being a bit more reasonable than it was the first time; and I also conceive that an argument or an observation may be very just, though it may so happen it was never stated before. William Hazlett: Table TaZk INTRODUCTION

There is now a large literature on the physiology and drug treatment of asthma and many recent symposia have been published reviewing the subject from almost every conceivable angle. In the face of this, it might seem unreasonable to attempt to write any more upon clinical aspects of asthma; nevertheless the observations recorded here are simple and give useful information. The recordings are not undertaken as a routine in many hospitals and, indeed, recent texts covering clinical and laboratory aspects of asthma in great detail make no mention of them (Stein 1976). There are a number of conventional classifications of asthma based variously on presumed causes, on the mechanisms of induction of airway narrowing and on the immunological potential of the host. One or another of these systems is often used to sort patients in formal controlled drug trials and, this having been done, it is then often assumed that the groups of patients being compared are similar. There is no right or wrong method of classification in medicine and the value of any one system depends upon the purpose for which it is to be used. I wish to discuss briefly some of the limitations of conventional classification when used in the assessment of drugs in chronic asthmatics (both in formal trials and in the management of individual patients) and to suggest a possible alternative approach using observations on the clinical patterns of varying airway obstruction. Such an approach has sharpened our appreciation of the clinical problem presented by individual patients and we think it has helped us to achieve more optimal therapy more quickly, often using fewer drugs. Whether classification by these or other clinical patterns will be a useful approach in the assessment of new drugs in groups of asthmatic patients in formal controlled trials has still to be assessed. We also need more observations to answer many questions such as the length of time over which the described patterns persist and whether individual patients exhibit different patterns at different times. We do know, however, that certain patterns in some patients show a remarkable consistency.

74

Mavgavet Turner- Warwick

This article should be regarded more as ‘table talk’ than completed scientific study; its publication is defended because the observations it contains are valid in the circumstances in which they were recorded. THE LIMITATION

OF CURRENT METHODS

OF CLASSIFICATION

Causes. Asthmatic patients have attacks precipitated by many different factors and, while allergens may be important in an atopic patient, the same patients may also have attacks provoked by non-immunological causes, such as exercise, infection, change of temperature and humidity or emotional upset. Classification of asthmatics based on single causes is thus unrealistic, particularly in patients with more chronic asthma. A classification system based on mechanisms of induction is of limited value at present because we know too little. Bronchial challenge testing has identified a number of asthmatic tissue-damaging mechanisms, classified according to the interval between challenge and response. Immediate asthma occurring within a few minutes of challenge is associated with immediate skin prick test responses to the same antigens and to specific circulating IgE levels (McAllen et al. 1970); b ecause of this these immediate asthmatic responses are interpreted as due to Type I, mast cell, vasoactive amine releasing, tissue reactions. Inhibition by cromoglycate, a drug which inhibits histamine release, supports this suggestion. The pathogenesis of the bronchial reactions occurring at longer intervals after exposure, however, is far less clear and these reactions may have more than one mechanism. In some there may be Type III immune complex mediated tissue damage, while in others tissue damage may depend upon the liberation of various pharmacological mediators from cells over prolonged periods which are no longer dependent upon the initiating immunological event. The value of a classification based on host responsiveness, separating those with a facilitated capacity to produce specific IgE antibody to small amounts of common inhaled ubiquitious antigen (i.e. atopic individuals) from those responding far less readily and hence to only very large amounts of agents after prolonged periods (i.e. non-atopic individuals) must depend upon the importance of IgE mediated tissue damage in the development and maintenance of chronic asthma. There is increasing evidence that IgE mediated asthma may be mainly limited to those having acute short lived attacks. Certainly it appears that there is a polar group (those with intrinsic asthma and who are not atopic subjects) in whom IgE-mediated mechanisms do not seem to play an important part. The nature of the asthmatic response in such cases is quite unknown. Nonimmunological triggers stimulate asthmatic attacks in intrinsic asthmatics with the same frequency as in extrinsic asthmatics (BTTA 1975), a fact which could be used equally as evidence of the importance of non-immunological factors in extrinsic asthma and of the importance of possible undetected type I mechanisms in intrinsic asthmatics. Thus conventional systems of classification are not of great practical help in the physician’s management of chronic asthma. In a new analysis of the problem of classification we have returned to the arbitrary starting point of a purely functional definition for the use of the word ‘asthma’, as indeed is common practice. This specifies a partial obstruction of the airways, reversible with time, either spontaneously or with treatment. We have then attempted to distinguish different types of variability, either spontaneous or with certain treatments.

Patterns of Airjlow

Obstruction iti Chronic Asthma

75

The practical management of chronic asthma depends upon the use of a range of drugs which in the short or long term decrease resistance to airflow in the airways. Assessment of the drug responsiveness might be more logically based on the identification of different types of airways obstruction, if patterns could be identified and defined which are consistent enough over long enough periods of time. Asthmatic patients having symptoms sufficiently troublesome and frequent to justify their assessment in hospital are now monitored routinely several times each day using simple measurements of airflow with a Wright’s peak flow meter, a dry spirometer or a portable instrument to record flow volume loops. These records have been kept in hospitals over a period of two or three weeks or at home over months or even years. A preliminary examination of these records has revealed a number of basic patterns. It is important to emphasize at the outset that these patterns of asthma may prove to be no more mutually exclusive or immutable than other classifications used to subdivide groups of asthmatic patients. Their value may, however, lie in the fact that the measurements are directly related to the objectives of drug treatment and may therefore have practical advantages in drug management and in the assessment of new drugs.

SOME PATTERNS OF ASTHMA

Some asthmatic patients may be classified according to the patterns of variation airflow obstruction:

in their

1. The ‘brittle’ asthmatic. 2. The ‘morning dipper’. 3. The ‘irreversible’ asthmatic: (a) never achieving a normal peak flow, but showing a reversible component; either a spontaneous fluctuation or after exhibition of the appropriate drug. (b) having a reversible FVC but an irreversible FEVr and peak flow. (c) the ‘drifter’, having irreversible airways obstruction gradually improving over weeks of intensive therapy. No doubt with time other useful patterns will be identified, but the present discussion will be confined to those described above. It is important to emphasize that some of the comments made about the response of the patterns of asthma to various antiasthmatic drugs should not at this stage be taken as a dogmatic statement of proven invariable behaviour. For instance, the fact that we have seen a number of patients with ‘brittle’ asthma who have failed to respond to corticosteroids does not necessarily mean that those with this pattern of asthma always fails to respond to corticosteroids.

The ‘Brittle’ Asthmatic These patients (Fig. 1) complain of intractable persisting asthma which may be resistant to all conventional therapy. They can mislead the doctor by having no wheeze at one moment and gross wheeze a short time later, with an equally rapidly resolution later still. Such patients are often accused of having ‘emotional’ asthma or of deliberately ‘putting it on’ because of their extreme variability. Regular records show a chaotic

Margaret

76

Turner- Warwick

Prednisone

3mg Solbutomol

Aerosol

3 hourly 0.2 ml Atropine

Solbutamol

Choline theophyllinate <

q.d.s.

Aerosol *

Orciprenoline

a

I

2

3

4

5

6

7

8

9

IO

II

I2

I3

I4 Days

15

I6

17

18

I9

20

21

22

23

24

25

Fig. 1. Brittle asthma. Peak flow recordings over one month showing unresponsiveness to a wide range of drugs. Not included on this record is the patient’s unresponsiveness to a trial of cromoglycate and a longer period on high dose corticosteriods pattern of peak flow recordings varying from normal to gross obstruction randomly throughout the 24 hours. The low readings are rapidly reversed by bronchodilators, usually in quite small doses (e.g. 0.2 mg of salbutamol as aerosol) but all attempts to stabilize them with regular sympathomimetics, such as slow release compounds, oral preparations or combinations with theophylline, seem to fail. Response to sympathomimetic drugs without stabilization is the salient feature of these cases. Attempts at stabilization with cromoglycate or corticosteroids also fail.These patients may be atopic or non-atopic and their attacks appear to continue irrespective of the environment and so can be identified in hospital as well as by out-patient records. Recognition of this chaotic pattern is useful because it helps the doctor understand why patients need to use their bronchodilator aerosols frequently and that this is not necessarily a question of ‘addiction’. It also demonstrates the continued responsiveness of airways to sympathomimetics over weeks and months without the development of refractoriness. Recognition of this pattern is also a challenge to better understanding of its mechanism at cell level and this may lead to better forms of therapy. This description of intractable ‘brittle’ asthma does not mean that all patients showing this pattern are resistant to full conventional therapy: the point being made here is that some patients show a persistent pattern of highly unstable airways. It is likely that some patients demonstrating a similar pattern before the administration of cromoglycate or corticosteroids will in fact stabilize once placed upon them. If this is so, then two functional groups of asthmatics may be identified where drug responsiveness has revealed subgroups and where the mechanisms of asthma in both can be compared. The ‘Morning

Dipper’

Worsening of asthma during the night time is a common and well recognized feature amongst asthmatics (Fig. 2). Although a minority may be related to close contact with the

26

77

Patterns of AiryTow Obstruction in Chronic Asthma

house dust mite resident in bedding, persistence of this pattern with change of bedding or on admission to hospital and other evidence to be reviewed, suggests that non-allergic factors are also of great importance. Some patients complain less of nocturnal asthma and more of morning tightness. My own interest in this symptom was first stimulated by Professor J. B. Howell who stressed the importance of this symptom in questionnaires designed to monitor asthma during drug trials.

I

I I

Fig. 2. ‘Morning spontaneously out the day

or

I 2

dipper’. after

Low peak bronchodilator

I 3

I

1 4

expiratory aerosol

5 Days flow rates to normal

I 6

I 7

I 8

1 9

early each morning (around 6 a.m.) rising values which are maintained through-

When peak flow measurements are recorded frequently in these patients throughout the 24 hours, several interesting facts emerge. The observations summarized here are based on a number of early studies on nocturnal asthma (Soutar et al. 1975). The subject is now being studied by Clark and Hetzel(l977). 1. The rhythmicity with well maintained readings during the day and reduction during the early hours every morning can be very persistent and we have two patients who have kept meticulous records for up to three years showing the regularity of this pattern. 2. The readings during the daytime may be completely stable and normal so that no asthma is observed during normal working hours or at the time of visits to a doctors’ surgery or to out-patients. One again, professional staff may be misled into believing that the patient’s symptoms have no real basis. 3. Measurements of airflow throughout the night hours have shown that in children they are often at their lowest around 2 a.m., occurring during the later sleeping hours (Kales et al. 1970). The nocturnal dips in adults are more variable. Some have been

78

lbfaygaret Turner- Warwick

recorded developing slowly from about midnight (Soutar et al. 1975) and others seem to develop quite rapidly (Hetzel & Clark 1976). 4. The fact of just waking patients long enough to obtain these recordings does not eliminate the pattern and, if modified, the rhythmicity is still easily recordable. Whether waking patients more thoroughly has a more substantial effect has yet to be investigated. Understanding the mechanisms and prevention of morning dips is probably very important in relation to asthmatic deaths. A recent study on asthma mortality in patients between the ages of 35 and 64 years in the greater London hospitals (Cochrane & Clark

Intensive

I I

Fig. 3. ‘Morning

I 2

dipping’

I 3

developing

treatment

I

I

4

5 Days

during

recovery

I 6

I 7

I 8

I 9

from an episode of service asthma

1975) showed that 13 of 19 occurred during the night between 1 a.m. and 8 a.m. A recent study of a group of very severe asthmatics showed that of 10 episodes of ventilatory arrest occurring over a 30-month period (7 of whom survived), 8 occurred during the early hours of the morning before 8 a.m. (Hetzel & Clark 1976) Analyses have shown also that deaths from asthma are very uncommon in patients during their stay in intensive care areas (Jones 1971) but they may occur suddenly during the night three of four days later when the daytime recordings of peak expiratory flow or other measurements are greatly improved. The records may, however, show a change from the ‘irreversible’ obstruction of very severe asthma to a fluctuating unstable morning dipping (Fig. 3). This pattern of early morning instability during recovery needs to be recognized and patients should be observed very carefully until stability is achieved and not discharged from hospital prematurely. Interesting observations have been made by Clark and Hetzel(l977) on asthmatic shift workers with morning dipping. As these patients change shift, so the pattern of asthma

Patterns of Airflow

Obstruction in Ch~~onicAsthma

79

changes, so that the lowest peak expiratory flow readings reassert themselves towards the end of their sleeping hours. The new pattern appears to be established quickly within 24 to 48 hours of a changed shift. This contrasts with some other circadian rhythms which can be identified in normal individuals. For instance, minor changes in the forced expiratory volume in one second (FEV 1) in a group of normal workers did not change with change of shift over a period of one week and electrolyte circadian rhythms take about four days to be re-established (Guberan et al. 1969). Causative mechanisms Several suggested mechanisms have been proposed for nocturnal attacks and these include several types of immunological response, effects of posture, circadian secretion of cortisol or catecholamines, the effect of alteration of blood gases, sleep depth, the time of drug- administration and other unknown but circadian determined factors. Allergic factors. Exposure to bedding allergens, especially the house dust mite, is an attractive and simple explanation of nocturnal asthma. Environmental control may cause dramatic improvement in a minority of cases but the pattern of severe nocturnal or morning asthma is seen sufficiently frequently in hospital where the bedding has been shown to be largely free from mite antigen (Maunsell et al. 1969) to deny this as a universal explanation. Davies et al. (1974) have shown that exposure to certain antigens during the day, especially certain occupational agents, results in late asthma occurriag several hours after antigen exposure and so, depending upon the time of the exposure, asthma may occur during the night time hours. The immunological basis for these reactions, however, has not been clarified and laboratory and in vivo tests in support of conventional immunological responses are frequently negative. An additional pattern of response after natural exposure or bronchial challenge tests has recently been described (Davies et al. 1974, 1976; Gandevia & Milne 1970). In these cases asthma not only occurs during the first night after exposure but recurs over several nights without further exposure. This cyclic pattern may depend upon persistence of allergen in the bronchi, and thus have an immunological basis, or, as perhaps seems probable, the bronchi have been rendered unstable by an immunological trigger and are then at the mercy of counterbalanced endogenous neurological and pharmacological forces which, whatever their nature, either possess or are influenced by circadian rhythms. Postuve. Patients with morning dipping have been asked to lie down or to sit up during the 24 hours and neither manoeuvre eradicates the cyclic pattern observed (Hetzel & Clark 1976). Sleep patterns. Kales et al. (1970) h ave shown in children that none of 20 episodes of nocturnal asthma occurred during deep sleep but tended to occur at the end of the second period, or during the third period of lighter sleep. A small number of highly cooperative asthmatics have volunteered to remain awake for two, or on one occasion three, nights and on such a manoeuvre morning dipping appeared to cease (Hetzel, unpublished). The manoeuvre of remaining awake for such long periods may influence so many physiological processes that it is difficult to use the evidence of this study alone to explain nocturnal asthma on the basis of simple sleep patterns. It is interesting to note that waking transiently to obtain peak flow measurement or obtain

80

Margaret

blood sample from an in-dwelling rhythms.

Turner- Warwick

catheter appears to have little influence on nocturnal

Hypoxaemia and carbon dioxide retention. From the few studies so far reported, arterial samples taken during sleep do not show marked falls of Paz of increase in PCOSbefore the peak flow drops (Hetzel & Clark 1976). Endogenous co&sol leaels. The circadian pattern of asthma has been observed to coincide with that of cortisol blood levels (Soutar et al. 1975). However, infusion of hydrocortisone sufficient to eliminate the nocturnal fall below 10 pg/dl, but without introducing therapeutic amounts, failed to modify nocturnal asthma in five of the six patients studied. 500 Prednisone

30mg

daily. Salbutomol

aerosoi

0.2 mg q d s

Salbutomol

w

spandets

16mg nocth

400 -F .E \ zL f = m P

300

2 z $ 200 .-e 2 (u Y B a 100

0’

I

I 2

Fig. 4. Elimination bed

of ‘morning

I 3

dipping’

I 4

by slow

I 5 Doys

release

I 6

salbutamol

I

I

7

0

(16 mg)

taken

I 9

before

going

to

at night

Endogenous catecholamines. The circadian pattern of asthma also coincides with that of catecholamine secretion as measured by noradrenaline and adrenaline levels (Soutar et al. 1976). Infusion of physiological amounts of these agents has not, however, yet been studied in relation to morning dipping. This pattern, however, is eradicated in some patients by slow release salbutamol taken last thing at night (Fig. 4). This might support the suggestion of catecholamines as an important factor. Other patients, however, failed to respond to this regimen. These variable therapeutic results may indicate that ‘morning dipping’ is likely to be based upon more than one mechanism. The time of drug administration. Clark and Hetzel (1977) have also suggested that the unequal distribution of times of drug administration over the 24 hours might be relevant,

Pattefw

of Ai$ow

Obstruction in Chronic Asthma

81

but morning dipping often persists in patients who have been woken to take their medication at regular intervals throughout the 24 hours. The metabolism of drugs also shows a circadian cycle and this may influence their effectiveness during the night. Management Studies show that there is a group of patients exhibiting morning dipping little influenced by corticosteroid treatment. Sympathomimetics, especially taken as slow release preparations last thing at night, more often help and a few cases respond to being woken and given salbutamol by aerosol before the peak expiratory flow is due, but these manoeuvres in our own experience have usually not proved wholly satisfactory in the majority of severe cases. Other methods used to increase endogenous catecholamine production, such as a brisk walk or alcohol before going to bed, seem to be a logical approach but, although tried in occasional cases, have not proved dramatically successful. Slow release theophylline has occasionally helped when added to sympathomimetics when the latter alone have failed. Atropine has not influenced the pattern. Although circadian rhythms of asthma can persist for years the night by night severity may change so that the effects of drugs studied over relatively short periods of time can be inconclusive. It is nevertheless largely true to say that at present none of the conventional asthma drugs regularly eradicate severe morning dipping. Very recently interesting preliminary results have been obtained in the short term using bromocriptine (NewmanTaylor et al. 1976) but this again only influences some cases. Its interest lies in the fact that it also points to the probable implication of catecholamines in this fascinating and potentially dangerous common pattern of asthma.

‘Iweve~~sible’ Asthma At first sight, this terminology appears to be a negation of terms when asthma is defined essentially on the basis of reversibility of airways obstruction. Several subgroups can be identified. First, the patient with a persistently reduced peak expiratory flow rate which never approaches normal values, but which nevertheless fluctuates quite markedly throughout the day by amounts commonly accepted as ‘variable’, i.e. 25% or more of baseline values (Fig. 5). Other individuals show records of irreversible airways obstruction for long periods but show complete reversibility after introduction of corticosteroids. (Fig. 6). Yet others refractory to bronchodilators, cromoglycate and corticosteroids may show at least partial reversibility with atropine (Fig. 7). The question whether these patients should be termed ‘asthmatic’ can be debated but is irrelevant to the present discussion where observed variability of airways obstruction alone is being considered. It is, however, a fact that patients showing this pattern of irreversible airways obstruction have been seen who are young atopic individuals with a history of episodic breathlessness dating back to childhood and have multiple positive prick skin tests and a blood and sputum eosinophilia. Other non-atopic patients have an adult onset of breathlessness and many of these are left untreated because they are labelled as having chronic bronchitis and emphysema. The facts that they may not fulfil the conventional criteria for hypersecretory chronic bronchitis (MRC 196.Q that they

82

Margaret

Turner- Warwick

have few or none of the physiological or radiographic features relating to emphysema and that they may be non-smokers are commonly overlooked. The important practical issue is that hidden within the large group of cases with largely irreversible airways obstruction are some who demonstrate remarkable reversibility when Prednisone 60 mg Eeclomethosone diproplonate IOOpg Hydrocortlsone 200 mg 4-hourly Aminophylllne 500 mg 8-hourly Salbutomol IPPB 2.5 mg E-hourly ------------------------------

a 4 500r

---___

I

I

I

I

2

I

3

6-hourly

Pred,cted

I

4

__f

I

5

I

6

7

Days

Fig. 5. A chaotic

pattern by sympathomimetic

reversed

of

variable aerosol,

airways obstruction but also showing

spontaneously irreversible

Predicted values FEV, 2200 ml FVC 2900 mt FRC 2600 ml ml TLC 4500 DLCO 15 ml/min/mmHg

FEV, 770 ml FVC 2360ml FRC 5190ml TLC 6848 ml DLCO 19 ml/min/mmHg

al

occurring a persistent

FEVt FVC FRC TLC DLCO

I

I

Fig. 6. Long-standing sible

after

introduction

I

2

I

3

I

4

I

5

airways obstruction of corticosteroids

I

6

partially

ml ml ml ml ml/min/mmHg

2250 3700 4015 5965 22

t

-Prednisone ------------------------------------------~predic+ed

-;: a”

and component

I

7

I

9 8 Days

irreversible

I

I

IO

I

II

to bronchodilators

I

I2

I

I

I3

I4

but

completely

rever-

Patterns of Ai$ow

0.3ml I% Atropine -

aJ

;; 2

I I 012345678

Bg. 7. Irreversible responding partially

I

I

I

I

airways obstruction to atropine aerosol

83

Obstruction in Chronic Asthma

I

I

I 9

I IO

I II Doys

to bronchodilators, (0.3 ml of 1%

‘Brontina‘ q d.s.

Atropine -f--f

I I2

Ill 13

I4

I5

III 16

cromoglycate times daily)

three

17

and

I8

II 19

I 21

20

corticosteroids

I 22

but

the right drug is used ; the problem of how to identify this subgroup is an old and much studied one: the use of day-by-day records of air flow to monitor drug responses is not used widely enough by those responsible for prescriptions. Improvement

of FVC without improvement of FEVl

Some patients report a marked subjective improvement on therapy (often corticosteroids) without any change in recorded peak expiratory flow rate. Simultaneous recording of forced expiratory volumes may show a marked improvement of the forced vital capacity with little or no change in the FEVl (Fig. 8). More detailed studies may also show that such improvement has been accompanied by a reduction of hyperinflation as indicated by a return towards normal of the total lung capacity (TLC). This irreversibility of peak flow measurement can be misleading to the physician and may result in useful drugs being discontinued. The explanation for the fixed FEVr is still debated but it -c

‘2 3000\ E 2000.-z i IOOO-

i

I

O-

u,x

I I

FVC FEV, f----Salbutamol

Prednisone 40mg h IPPB 5mg G-hourly+

0

;5 .L 0. I 8

9

IO

II

12

I3

Days Fig. 8. A record change

in FEVl

showing or PEFR

a marked

improvement

in forced

vital

capacity

(FVC)

but

little

or no

84

Margaret

Turner- Warwick

may be related to persistent obstruction due to inspissated plugs or permanent intrinsic damage to the airways so that there is delayed emptying from alveoli through collateral channels. Slow airflow through permanently damaged and narrowed smaller airways is another possible mechanism and this may be complicated by an associated secondary compression of the larger airways on the forced manoeuvre arising from a lowered intraluminal pressure due to peripheral airways obstruction. The ‘drifter’ These patients show little day-to-day reversibility and no marked change in FVC but when the records are continued for several weeks the peak flow improves very slowly (Fig. 9). This partial improvement is seen particularly with corticosteroids and can be of great value to the patient. It takes a long time to achieve and careful recording to identify.

Prednisone

LIII I

2

3

4

lIIlIIIIIIIIIJ

5

6

7

8

9 IO Days

II

12

13

14

I5

16

17

Fig. 9. The ‘drifter’. A slowly improving PEFR during treatment with corticosteroids over several weeks. Even modest improvement may be accompanied by substantial subjective improvement of breathlessness and exercise tolerance This improvement may also be associated with some deflation of the lungs and reduction of the total lung capacity which in itself may contribute towards the patients’ greater comfort. Its recognition has a major influence on the later adjustment of corticosteroid dosage. COMMENTS An attempt has been made to show how recognition of patterns of asthma can sharpen our approach to therapy and can help us discard drugs which are clearly ineffective and persist usefully with others which might otherwise be abandoned. It also may give us a clearer idea of the optimal improvement to be expected in an individual patient so that drugs having only a partial effect can be adjusted to their lowest effective dose.

Patterns of Ai$ow

Obstruction in Chronic Asthma

85

Clearly the suggestions set out here concerning the differential effect of drugs in patients demonstrating these patterns is, so far, only a clinical impression and much further work must be done comparing carefully defined groups of patients. However, in clinical management of individuals with severe chronic and persisting asthma, this approach to therapy is certainly useful in individual patients and is likely to reduce empirical polypharmacy. It must be emphasized that the patterns described here have been identified in patients with refractory chronic asthma studied in a specialist hospital to which patients with particularly severe problems tend to be referred. How far these patterns will be observed amongst the asthmatic population as a whole needs further study. The many patients with only occasional attacks are unlikely to show persisting abnormality in day-by-day records; however, several studies have shown that residual airways obstruction can be detected in asthmatics while they are symptom-free and between attacks, but the patterns of such obstruction has not been studied at all. Identification of these patterns of asthma certainly poses interesting questions regarding pathogenesis of airways narrowing and these now need to be tackled. It may be that in future where drugs are to be assessed in the management of chronic asthma in formal controlled trials, patients should be grouped or at least stratified according to some of these clinical patterns rather than by the more traditional classifications. ACKNOWLEDGEMENTS

I am particularly grateful to the nursing staff on the medical wards, the physiotherapists and to a succession of house officers who have meticulously collected these records. Many of the ideas summarized here have been developed in discussion and I would like to acknowledge the special contribution made by Colin Soutar, John Costello, Richard Dent and Martin Hetzel, who have been personally involved in particular aspects of this subject. T. J. H. Clark has also had a major interest in early morning asthma for many years and continues to study many aspects of this important problem in detail. I am grateful to him and Dr Hetzel for permission to quote some of their unpublished views, REFERENCES BTTA

(1975) Report of the Research Committee: Immunological features of asthma (Part I). BY. J. Dis. Chest 69, 125. COCHRANE, G. M. & CLARK, T. J. H. (1975) A survey of asthma mortality patients between 35 and 64 years in the Greater London hospitals. Thorax 30, 300. CLARKE, T. J. H. & HETZELL, M. R. (1977) Diurnal variation of asthma. BY. J. Dis. Chest 71, 87. DAVIES, R. J., GREEN, M. & SCHOFIELD, N. McC. (1976) Recurrent nocturnal asthma after exposure to grain dust. Am. Rev. vesp. Dis. 114, 1011. DAVIES, R. J., HENDRICK, D. J. & PEPYS, J. (1974) Asthma due to inhaled chemical agents: ampicillin, benzyl penicillin, 6 amino penicillanic acid and related substances. C&z. Allergy 4, 227. GAJXDEVIA, B. & MILNE, J. (1970) Occupational asthma and rhinitis due to Western Red Cedar. Br. J. indust. Med. 27, 235. GUBERAN, E., WILIAMS, M. & WALFORD, J. (1969) Circadian variation of FEV in shift workers. Br. J. indust. Med. 26, 121. HETZEL, M. R. & CLARK, T. J. H. (1976) Personal communication. JONES, E. S. (1971) The intensive care of asthma. Proc. R. Sot. Med. 64, 1151.

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A., KALES, J., SLY, R. M., SCHARF, M. B., TAN, T. L. & PRESTON, T. A. (1970) Sleep patterns of asthmatic children. J. Allergy 46, 300. MCALLEN, M. K., ASSEM, E. S. K. & MAUNSELL, K. (1970) House dust mite asthma. Results of challenge tests on five criteria with D. pteronyssinus. Br. med. J. 2, 501. MAUNSELL, K., WRAITH, D. G. & CUNNINGHAM, A. M. (1968) Mites and house dust allergy in bronchial asthma. Lancet 2, 1267. MRC (1965) Report of the MRC committee on the aetiology of chronic bronchitis. Lancet 2, 775. NEWMAN-TAYLOR, A. J., SOUTAR, C. A., SCHNEERSON, J. & TURNER-WARICK, M. (1976) Bromocriptine in the treatment of intractable asthma (abstract). Thorax 32,488. SOUTAR, C. A., CARRUTHERS, M. E. & TURNER-WARWICK, M. (1976) Unpublished. SOUTAR, C. A., COSTELLO, J., IJADUOLA, 0. & TURNER-WARWICK, M. (1975) Nocturnal and morning asthma: relationship to plasma corticosteroid and response to cortisol infusion. KALES,

STEIN,

Thorax M.

30,436. (1975) New

Directions

in Asthma.

Illinois:

American

College of Chest Physicians.