- Email: [email protected]
Bronchial hyperresponsiveness in patients recovering from acute severe asthma
Respiratory Medicine (1993) 87, 29-35
Bronchial hyperresponsiveness in patients recovering from acute severe asthma M. K. B. WHYTE, N. B. CHOUDRY AND P. W. IND*
Department of Medicine (Respiratory Division), Royal Postgraduate Medical School, Hammersmith Hospital, London W12 OHS, U.K.
Bronchial hyperresponsiveness is widely recognized as a marker of airway inflammation in asthma. The degree of bronchial hyperresponsiveness following acute severe attacks of asthma and the time course of its recovery has not previously been studied. Bronchial responsiveness to histamine was measured in 18 unselected patients admitted to hospital because of acute severe asthma, during their acute admission, and geometric mean PD20 histamine was 0.08 (range 0.02-0.32)/~mol. In nine patients, further measurements were performed at 3-4 and 12 weeks following discharge. Geometric mean PD20 histamine was 0.09/~mol acutely, 0.23/xmol at 3-4 weeks (n = 9, P = 0"05 by analysis of variance) and 0.59/amol at 12 weeks (n = 8, P = 0.04). For the eight patients studied at 12 weeks, a mean 10.3-fold increase in PD20 was shown, with no suggestion of a maximum effect having been achieved. In contrast, spirometry had returned to the normal range by 4 weeks. The dissociation between improvement in bronchial hyperresponsiveness and spirometry is of interest. The delayed reduction in hyperresponsiveness may have important clinical implications for the duration of anti-inflammatory corticosteroid treatment following acute severe asthma.
Introduction
Acute severe asthma is one of commonest medical emergencies. Within the United Kingdom, there is broad agreement on the principles of its management (1). However, mortality from asthma in the U.K. is either static (2) or rising (3). Relapse following discharge from hospital is common (4~6) and difficult to predict (7,8). Indeed, recent hospitalization has been recognized as a risk factor for asthma death (3,9). Major differences in the management of asthmatics, following discharge from hospital after an acute attack, have been highlighted (5,6,9) and little information is available regarding optimal further management following discharge (10). Non-specific bronchial hyperresponsiveness is a cardinal feature of asthma, which is correlated with increased asthma symptoms and treatment requirements (11), diurnal variation in peak expiratory flow (PEF) (12), nocturnal wakening (13) and an increased risk of 'sudden death' from asthma (14). There is increasing evidence of an association between bronchial inflammation and hyperresponsiveness in asthma (15). The pathology of acute asthma in Received6 June 1991and acceptedin revisedform30January1992. *To whom correspondence should be addressed at: Respiratory Division,Departmentof Medicine,HammersmithHospital,Du Cane Road, LondonWI2 0HS,U.K. 0954-6111/93/010029+ 07 $08.00/0
patients who die reveals gross bronchial inflammation (16). For these reasons, bronchial hyperresponsiveness might be expected to occur in patients with acute severe asthma. However, there is no information on the degree of bronchial hyperresponsiveness in such patients, nor on the time course of its improvement in relation to treatment for the acute episode. The aim of this study was to measure bronchial responsiveness in patients shortly after admission to hospital with acute severe asthma and follow the time course of its improvement.
Patients and Methods
Eighteen consecutive patients (12 female), who consented to the study, were investigated following admission with acute asthma to Ealing and Hammersmith Hospitals. Their ages ranged from 18 to 66 (mean 32) years. On the basis of clinical history and possession of two or more positive skin tests to a battery of common aero-allergens, 13 were judged to be atopic. The mean duration of asthma in these patients was 15 years (range 1-40 years). Symptoms of the acute attack had been present for 3 days (mean), varying widely from 1 to 10 days. Their usual maintenance therapy was: inhaled fl2-agonists (18 patients), regular inhaled corticosteroids (13 patients), oral theophyllines (seven patients) and oral prednisolone (one 9 1993Bailli~reTindall
30
M. K. B. Whyte et al.
Table 1 Individual patient details, including usual therapy, age and duration of asthma in years and duration of acute symptoms prior to presentation in days
Patient
Age (years)
Duration of Duration of asthma symptoms Sex Atopy (years) (days)
1
30
F
+
2 3 4 5 6 7 8 9 10 I1 12 13 14 15 16 17 18
41 18 25 67 20 22 20 38 20 32 18 34 23 2l 66 61 32
F M F F F F F F F M F M F F M M M
+ + + + + + + + + + + +
15 20 17 10 20 17 10 20 30 10 20 7 15 11 10 40 1 i0
Inhaled //2-agonist
l0 3 2 4 6 1 4 3 4 1 3 1 1 5 1 2 3 2
Inhaled steroid
+
-
+ + + + + + + + + + + + + + + + +
+ + + + + + + + + + + + + -
Oral theophylline
Oral steroid
Initial PD20
+ + + + + + + + -
-
0.08 0.05 0.32 0.13 0.12 0.14 0.06 0.10 0.02 0.06 0.12 0.02 0.12 0"05 0.05 0"32 0.08 0.05
+ -
Patients 1 4 are those on whom follow-up studies were performed. patient). Patient details are summarized in Table 1. N o patient had been admitted to hospital with acute asthma in the 3 m o n t h s prior to the studies, which were performed outside the pollen season. Local Ethical Committee approval was obtained and patients gave written, informed consent. The patients were admitted by duty medical firms in the usual way and clinical m a n a g e m e n t was continued by the admitting physicians unless transfer to the Respiratory team was specifically requested. The acute attack was m a n a g e d conventionally, with oxygen, nebulized bronchodilators, including high doses o f salbutamol in all cases and ipratropium b r o m i d e in 15, parenteral corticosteroids in all cases and, in 13 patients, theophyllines, in 10 orally and by intravenous infusion in three. Bronchial hyperresponsiveness was measured on day 3-5 o f admission (median day 4). Measurements were performed 4 h after last dose o f nebulized f12" agonist. All studies were carried out in the Pulmonary F u n c t i o n laboratory, under medical supervision. Histamine challenge was a modification of the m e t h o d o f Yan et al. (17), using a hand-held De Vilbiss 40 glass nebuliser, the same nebuliser being used t h r o u g h o u t the study. In patients with mild asthma, PD20 histamine by this technique is reproducible within one doubling dilution. Histamine d i p h o s p h a t e salt was dissolved in normal saline to produce solutions at doubling concentrations from 2 to 32 mg ml ~. Initial
FEVt was measured prior to beginning the histamine challenge and then two puffs o f normal saline were administered as a control followed by m e a s u r e m e n t o f the baseline (i.e. post-saline) FEV~. The challenge was started at 2 m g ml ~, rising by doubling increments to a m a x i m u m concentration o f 32 mg ml - ~. F r o m the measured volume delivered by the nebulizer (0.003 + 0.0002 ml per puff, determined by weighing experiments) and the k n o w n concentration o f the solution the dose o f histamine delivered at the subject's m o u t h was calculated in/~mol o f histamine. The dose range was equivalent to 0-0~2.56r Increasing doses o f histamine were given at 2-rain intervals. Serial measurements o f FEV~, taken as the better o f two satisfactory attempts using a Vitalograph spirometer, were p e r f o r m e d until a greater than 20% fall in FEV~ was obtained. A t the end o f the challenge, 200/lg o f inhaled salbutamol was given by metered dose inhaler and spirometry repeated 5 and 10 min later. If a fall in FEV~ o f greater than 0.1 1 occurred with inhalation o f normal saline, the F E V 1 m e a s u r e m e n t was repeated until stable. The response to histamine was measured as percentage change in FEV~ from the baseline (post-saline) value. The cumulative dose o f histamine causing a 20% fall in FEVz (PD20 FEVI) was measured by linear interpolation. Following discharge from hospital, bronchial responsiveness was determined at 3-4 weeks and at 12 weeks in nine o f the H a m m e r s m i t h patients (Table 1,
Bronchial hyperresponsiveness in patients" recovering from acute severe asthma patients 1-9). All measurements were performed 4 h after last dose of inhaled fl2-agonist and at the same time of day as previous measurements. Clinical measurements and PEF and FEVL were expressed as arithmetic mean and 95% confidence intervals. PEF and FEV~ were also expressed as % predicted (18). PD20 values were logarithmically transformed and expressed as geometric mean with 95% confidence intervals. Statistical analysis was by analysis of variance (ANOVA) for repeated measures and paired t-tests.
31
i[o ~oo 9o
!
80 7o
s 60 h_
5O Results There was considerable variation in the severity of asthma, though all patients were judged to require hospital admission by the clinicians responsible for their care. All patients had a clear diagnosis of asthma, based on a typical history and established reversibility of airflow obstruction after a fl2-agonist of >20% of FEV 1 or PEF. None of the patients studied had a history of chronic bronchitis or other significant lung disease. One patient (no. 18) had smoked previously. At the time of admission the nine patients who were subsequently followed up (Table 1, patients 1-9) had a tachycardia, with a mean heart rate (95% confidence intervals) of 114 (78-150) beats per minute, and tachypnoea, with a respiratory rate of 31 (17-45) per minute. Mean systolic blood pressure was 126 (102150) mmHg. PEF was markedly reduced with a mean of 145 (50-300) I rain I or 29 (9-49)% predicted. Mean arterial PCO 2was 4.0 (3.0-5.0) kPa and mean PO 2was 10.4 (3.6-17.2) kPa, but the latter data proved difficult to interpret as the percentage of oxygen inspired had not always been recorded. For the nine patients (Table 1, patients 10-18) on whom acute data only was obtained, the results were very similar: heart rate 106 (62-150) beats per minute, respiratory rate 30 (22-38) per minute, systolic blood pressure 141 (83-199) mmHg, peak expiratory flow 16l (40-280) 1 rain ~or 32 (6-58)% predicted, arterial PCO 2 4-9 (1.7-8-1) kPa and PO 2 13.4 (2.8 24) kPa. All patients received parenteral hydrocortisone, 200-1200 mg total dose, followed by oral prednisolone 30-40 mg daily and all but one patient was discharged on inhaled corticosteroids. Eight of the nine patients who were subsequently followed were on high-dose inhaled corticosteroids, mean 1200/~g per 24h, throughout the study period. All patients made an uncomplicated recovery from their acute exacerbation of asthma. ]=or the 18 patients studied during their acute admission, mean initial (pre-test) FEV Lwas 61% predicted (range 42-88%). Mean reduction in FEV~ by
40 30 20
h
Pre-histamine
[
Mfn. FEV~
I
Post-2OOzag salbutamol
Fig. 1 Safetyof histamine challenge during admission for acute asthma. FEV~ (as % predicted) is plotted as initial value, minimum value achieved during challenge and value 10 min followinginhalation of salbutamol 200/~g.
saline was 0.11 (mean 4.0% of initial FEV 1, range 016%, n = 18). Ten patients experienced no fall in FEV~ with administration of saline and only three patients had falls that were greater than 10% of their initial FEV 1 and all of these recovered within 10 min. PD20 FEV 1during the acute admission ranged from 0.02 to 0.32/~mol of histamine. Geometric mean initial PD20 histamine was 0.08 #tool (n = 18). The safety of the initial histamine challenge is emphasized by the complete reversibility of FEV 1 or PEF with 200,ug salbutamol inhaled at the end of the test (Fig. 1). Mean (95% confidence intervals) FEV 1 was 64 (42-98)% predicted immediately prior to the histamine challenge, falling to 46 (28-68)% on challenging and rising to 76 (43-114)% salbutamol. Of the initial 18 patients, nine were followed over a period of 12 weeks (Table 1, patients 1-9). Of the remaining nine patients, it was not possible to study the six from Ealing Hospital (Table 1, Patients 10, 11, 13, 14, 17, 18). Of the 12 Hammersmith Hospital patients, three could not be followed up (one readmitted, one psychiatric admission and one moved from the area immediately following discharge). However, on analysis of admission data, previous treatment and initial management of this attack, there were no differences between these two groups. Initial geometric mean (95% confidence intervals) PD20 histamine was also not significantly different [0.07 (0.03-0-16)/1mot for the nine not followed, 0.09 (0.04-0.19) /1moI for
32
M. K. B. Whyte et al. I0
I00
(a)
80 jl
E
~o /
.x:
i / /
4o
E W
o, u_o
I;
I-
u_
_--
20
$S-'-
I
I
I 0
I 2
s
I
I
I
I
I IO
I 12
[3-
o.oi
i 0
I 2
I 1 t 4 6 8 Time (weeks)
I I0
I i2
(b) i
Fig. 2 Time course of recovery ofPD20 FEV t (dose of histamine in ~tmol producing a 20% fall in FEVI) for the nine patients at time 0 (acute admission), then at 3-4 and 12 weeks later. Log PD20 histamine is plotted against time in weeks. ( ) Individual patients; ( A - - A ) geometric mean values at the different time points.
0.1
o
the nine who were, P=0.70]. Moreover, follow-up spirometry within the 4~ 12 week period was available for the six Ealing Hospital patients and was not significantly different [FEV~ 81 (61 101)% predicted, compared with values for the nine patients followed of 80 (50-110: n = 9 , P=0"98) at 3~ , weeks and 80% (48 112: n = 8 , P = 0 . 9 2 ) at 12 weeks. In the nine patients who were followed, a gradual increase in PD20 histamine occurred over 12 weeks. This contrasts with the values for FEV~ shown above, which were improved at 3-4 weeks but showed no further improvement thereafter (Fig. 3). Mean PEF (95% confidence intervals) was 270 (80-460) 1rain -1 [60 (33 87)% predicted, n = 8] immediately prior to the acute challenge, rising to 351 (280420) 1 rain -~ [77 ( 6 5 ~ 9 ) % , n = 7 ] at 4 weeks and 314 (210-418)1 min 1 [73 (5591)%, n = 5] at 12 weeks. The improvement at 4 weeks was statistically significant (P < 0.001) but there was no further improvement at 12 weeks (P = 0.90). The time course of improvement in bronchial hyperresponsiveness is shown in Fig. 2. At 3-4 weeks, geometric mean PD20 histamine was 0"23/~mol ( n = 9 ) , compared with 0"09 ymol for these same nine patients during the acute admission. This difference was statistically significant (P < 0"003 by paired t-test, P = 0-05 by ANOVA). At 12 weeks, PD20 histamine had increased to 0.59/tmot (n = 8), which was also significant compared with the acute values in these eight patients (P<0.0001 by paired t-test and ANOVA) with there also being a significant improvement over the 3-4 week value (P<0-004 by t-test, P = 0 - 0 4 by ANOVA). There was a mean 10.3-fold increase (calculated as the ratio of final over initial PD20 histamine for
db O_
0.01
I I I 4 6 8 Time (weeks)
Fig. 3 a, Time course recovery of FEV~ as % predicted, (mean + sD). b, Time course of recovery of geometric mean (6M) PD20 FEV~ (with 95% confidence intervals). All results for the nine patients in whom follow-up measurements were obtained at 3-4 and 12 weeks following their acute admission. At time 0 and 3-4 weeks n =9 and at 12 weeks n = 8,
each individual) in PD20 over 3 months, with no suggestion of a maximum value being achieved. The progressive improvement in bronchial responsiveness is contrasted with the initial FEV 1 as % predicted which showed no further improvement after 4 weeks (Fig. 3). In Fig. 4, PD20 FEV1 is plotted against prechallenge FEV 1 (for the initial challenge). There was no correlation between initial bronchial responsiveness and the degree of airflow obstruction (n = 18, r = -0.33). In the nine patients who underwent repeat histamine challenges, there was again no correlation between initial (pre-test) FEV 1 and PD20 ( r : +0-42, P ys, 26 data points). The degree of bronchial hyperresponsiveness, as determined by PD20, did not correlate with severity of asthma, as judged by heart rate or P E F (as 1 rain- 1or as % predicted); nor did it correlate with the duration of the acute episode of asthma. Discussion
We have demonstrated that bronchial responsiveness to histamine is greatly increased in patients
Bronchial hyperresponsiveness in patients recovering from acute severe asthma I00
80
60
% U_l h
40
I Q..
20-
~
I
-L-o
[
-2-o
Log PO2o FEV I
s
Scattergram of FEV~ (as % predicted) for individual patients before initial acute histamine test, plotted against log PD2o FEV~ determined in that test. This shows the lack of correlation between FEV1and PD20(r = -0.33, P = ys). with acute asthma, 3-5 days after their admission to hospital. Geometric mean initial PD20 was 0-08/~mol (n= 18), which corresponds well with values found in studies of patients with severe asthma using similar techniques (19,20). However, these studies were performed in patients who were not acutely ill. PD20 FEVj to histamine in normal subjects has been shown to be greater than 10/tmol (21) and our patients are, therefore, on average 100-fold more responsive to histamine than normal subjects. The degree of bronchial hyperresponsiveness shown is necessarily underestimated because treatment of acute asthma could not be withheld. Reduction of bronchial responsiveness continued over the 12 weeks of the study, with a mean 10.3-fold increase in PD20 histamine (3.1 doubling dilutions) and no suggestion of a maximum effect being achieved by the end of the study. Airflow obstruction, however, as judged by spirometry or PEF, had returned to the normal range by 4 weeks. For the sake of uniformity, all measurements of PD20 were made 4 h after last nebulized flz-agonist treatment. Other studies suggest that, at this time, there would still be a small residual fl2-agonist effect, leading to some antagonism of histamine response and thus underestimation of PD20 (22,23). Reproducibility data for the measurement of histamine responsiveness was not obtained in our patients with acute asthma. In other studies in our laboratory (unpublished data), we have confirmed that the Yah method for determination of PD20 histamine is reproducible within one doubling dilution. The major abnormalities in acute severe asthma are airway narrowing, oedema, inflammatory cell
33
infiltrates and bronchial obstruction by mucus. The contribution of bronchial hyperresponsiveness in this situation is unclear. Possible mechanisms of bronchial hyperresponsiveness in acute asthma include increased smooth muscle mass or contractility, increased cholinergic, a-adrenergic or non-adrenergic non-cholinergic excitatory activity or reduced fl-adrenergic or nonadrenergic inhibitory control (24). Epithelial damage with loss of modulating influences, increased bronchial mucosal permeability and exposure of sensory nerves may be important (16,25). An apparent increase in bronchial responsiveness due to enhanced central deposition of histamine aerosol could occur in acute airways obstruction. However, the lack of correlation in this study between PEF or FEVI and PD20 histamine (Fig. 4) and the dissociation between improvement in airway calibre and recovery of bronchial hyperresponsiveness (Fig. 3) argue strongly against this, although the number of subjects studied is small and more sensitive tests of airway calibre have not been examined. There is undoubtedly a general association between reduced baseline airway diameter and bronchial hyperresponsiveness, but starting airway calibre does not determine responsiveness in asthmatics (26). Moreover, bronchial responsiveness after allergen challenge is usually increased and is dissociated from airway calibre as a result of bronchial inflammation (15). Over the time course of recovery from acute asthma, the alterations in airway diameter observed in our patients are unlikely to be the major mechanism of bronchial hyperresponsiveness. Other interpretations of the reduction in bronchial hyperresponsiveness in this study need to be considered. Regression towards the mean does not explain the graded improvement over 12 weeks. The group of patients who were followed were self-selected but they did not differ in any way from the group as a whole. Statistical analysis of dropouts in a small study of this kind is difficult but all patients improved at all time points. Improvement of bronchial hyperresponsiveness was not an artefact of an effect of repeated FEV 1manoeuvres. This effect was minimized by taking the higher of two readings and, of course, more measurements were performed at followup studies as responsiveness improved. A change in airway-parenchymal hysteresis or deep breath bronchodilation with recovery from acute asthma cannot be excluded as part of the mechanism of reduced bronchial response to histamine. Although markedly enhanced bronchial responsiveness to histamine in patients recovering from acute asthma is not surprising, this study is the first to document it. As bronchial responsiveness was not determined prior to admission, the contribution of the acute exacerbation is not known. However, our
34
M. K. B. W h y t e et al.
Table 2 FEV 1in litres and as % predicted and PD20 (provocative dose of histamine causing a 20% fall in FEVI) for nine individual patients during their acute admission and then 3 4 and 12 weeks later
Acute admission
4 weeks
12 weeks
Patient
PD20
FEV~
FEV, (%)
PD20
FEV~
FEV~(%)
PD20
FEV,
FEV, (%)
1 *2 3 *4 *5 6 7 *8 9
0.08 0.05 0.32 0.13 0.12 0.14 0.06 O.10 0-02
2.2 1.1 2-1 2.1 1.0 1-8 2-6 1-8 1.5
76 48 42 61 54 60 75 55 53
0.11 0.13 0.64 1.10 0.50 0.14 0.14 0.27 0.04
2.5 1.4 3.6 3.5 1.4 2.0 2.5 3.4 2.2
86 61 72 101 76 67 72 103 77
0.47 1.70
2.7 1-4
93 61
1.00 1.28 0.32 0.35 0.68 0.18
3.4 1-2 2.0 2.4 3.3 2.4
99 65 67 70 100 84
For patient 3, no 12-weekmeasurements are available. *Patients given theophyllines during the acute admission.
patients showed major improvements in bronchial responsiveness, with a mean 10.3-fold (3.1 doubling dilutions) increase in PD20 histamine. This improvement occurred gradually over the period of the study, reflecting either response to treatment or the natural history of recovery from acute asthma. Minor differences in treatment of the acute episode are thus unlikely to have greatly affected the improvement in bronchial responsiveness seen over the 12-week period. In previous studies of asthmatic patients, in a more stable clinical state, inhaled corticosteroids have been shown to decrease bronchial responsiveness over a period of ~ 8 weeks by 1-2 doubling dilutions (20,27,28). The mechanisms of the beneficial effects of steroids in asthma are not established but this action is considered to be an anti-inflammatory effect. Eight of the nine patients completing the study were managed in the asthma clinic, on high dose inhaled corticosteroids, mean 1200 (range 401~2000)/tg per 24h beclomethasone dipropionate or budesonide. Previously, budesonide 1600 ltg daily has been shown to be superior to 400/zg daily in reducing bronchial hyperresponsiveness (29). The extent of reduction in bronchial responsiveness (29) was less than that seen in our patients but this may relate to the lower initial PD20 in our study. If bronchial hyperresponsiveness is closely related to bronchial inflammation in acute asthma, then the implication of our findings is that this persists after an acute exacerbation. This, too, is not surprising, since bronchical hyperresponsiveness is found, in association with bronchial inflammation, in subjects with very mild asthma (30). Previous guidelines for studying bronchial responsiveness suggest that subjects should have initial lung function greater than 80% predicted (31). However,
histamine challenge in this study, performed under medical supervision in a lung function laboratory, proved safe. All patients showed rapid reversal of histamine-induced bronchoconstriction by a standard dose of inhaled salbutamol. No patient experienced any adverse effect or was unwilling to undergo further testing. The reduced number of patients at the later study point reflects the difficulty in motivating young, fit people to reattend once they feel well. Considerable attention has focused on the immediate management of acute asthma but little is known about the natural history of recovery from acute attacks (32). Current treatment of acute severe asthma emphasizes the importance of determination of airway calibre, by measurements such as PEF, in monitoring treatment response (33). However, this study has demonstrated a dissociation between recovery of spirometry and that of bronchial hyperresponsiveness, which may reflect the persistence of airway inflammation. The slow improvement in bronchial hyperresponsiveness observed in patients in this study may suggest a need for more prolonged anti-inflammatory treatment following acute attacks than would be indicated by measurement of spirometry alone. Sequential determination of bronchial responsiveness over a longer period might thus be useful in managing acute asthmatics after discharge from hospital and a further prospective study is planned. References
1. Clark TJ. Acute severe asthma. In: Clark TJ, Godfrey S. eds. Asthma. 2rid edn. London: Chapman & Hall, 1983; 392M14. 2. British Thoracic Association. Deaths from asthma in two regions of England. Br MedJ 1982; 285:1251 1255.
Bronchial hyperresponsiveness in patients recovering f r o m acute severe asthma 3. MacDonald JB, MacDonald ET, Seaton A, Williams DA. Asthma deaths in Cardiff 1963-74:53 deaths in hospital. Br MedJ 1976; 1: 721-723. 4. MacDonald JB, Seaton A, Williams DA, Asthma deaths in Cardif 1963-74:90 deaths outside hospital. Br M e d J 1976; 2: 1493-1495. 5. Osman J, Ormerod P, Stableforth D. Management of acute asthma: a survey of hospital practice and comparison between thoracic and general physicians in Birmingham and Manchester. Br J Dis Chest 1987; 81: 232 24l. 6. Bucknall CE, Robertson C, Moran F, Stevenson RD. Management of asthma in hospital: a prospective audit. Br M e d J 1988; 296:1637 1639. 7. Arnold AG, Lane D J, Zapata E. Acute severe asthma: factors that influence hospital referral by the general practitioner and self-referral by the patient. Br J Dis Chest 1983; 77" 51 59. 8. Centor RM, Yarbrough B, Wood JP. Inability to predict relapse in acute asthma. N Engl J Med 1984; 310: 577 580. 9. Ormerod LP, Stableforth DE. Asthma mortality in Birmingham 1975 7:53 deaths. Br Med J 1980; 280: 687 690. 10. Bucknall CE, Robertson C, Moran F, Stevenson RD. Differences in hospital asthma management. Lancet 1988; i: 748 750. 11. Hargreave FE, Ryan G, Thomson NC et al. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin lmmuno11981; 68: 347-355. 12. 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 calibre. Thorax 1982; 37: 423~429. 13. Juniper EF, Frith PA, Hargreave FE. Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma. Thorax 1981; 36: 575-579. 14. Bateman JRM, Clarke SW. Sudden death in asthma. Thorax 1979; 34: 40~44. 15. Chung KF. Role of inflammation in the hyperreactivity of the airways in asthma. Thorax 1986; 41: 657-662. 16. Dunnill MS. The pathology of asthma, with special reference to changes in the bronchial mucosa. J Clin Pathol 1960; 13: 27--33. 17. Yan K, Salome C, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. Thorax 1983; 38:760 765. 18. Cotes JE. Lung function: assessment and application in medicine, 4th edn. Oxford: Blackwell Scientific, 1979; 329-388.
35
19. Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in asthma but oral theophylline does not. Am Rev Respir Dis" 1987; 136: 1174-I 178. 20. Woolcock A J, Yan K, Salome CM. Effect of therapy on bronchial hyperresponsivenessin the long-term management of asthma. Clin Allergy 1988; 18:165 176. 21. Woolcock AJ, Salome CM, Yah K. The shape of the dose-response curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis" 1984; 130: 71-75. 22. Salome CM, Schoeffel RE, Woolcock AJ. Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects. Thorax 1981; 36: 580-584. 23. Tattersfield A E Effect ofbeta-agonistsand anticholinergic drugs on bronchial reactivity. Am Rev Respir Dis 1987; 136: 564-568. 24. Ollerenshaw S, Jarvis D, Woolcock AJ, Sullivan C, Scheibner T. Absence of immunoreactive vasoactive intestinal polypeptide in tissue from the lungs of patients with asthma. N Engl J Med 1989; 320" 1244-1248. 25. Hogg JC. Bronchial mucosal permeability and its relationship to airways hyperreactivity. J Allergy Clin lmmuno11981; 67: 421~425. 26. Chung KF, Morgan B, Keyes SJ, Snashall PD. Histamine dose-response relationships in normal and asthmatic subjects: the importance of starting airway calibre. Am Rev Respir Dis 1982; 126:849 854. 27. Ryan G, Latimer KM, Juniper EF, Roberts RS, Hargreave FE. Effect of beclomethasone dipropionate on bronchial responsiveness to histamine in controlled non-steroid dependent asthma. J Allergy Clin Immunol 1985; 75: 25-30. 28. Kraan J, Koeter GH, Mark ThW, Sluiter H J, De Vries K. Changes in bronchial hyperreactivity induced by four weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J Allergy Clin Immunol 1985; 76: 628 636. 29. Kraan J, Koeter GH, Mark ThW et al. Dosage and time effects of inhaled budesonide on bronchial hyperreactivity. Am Rev Respir DB 1988; 137: 44-48. 30. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985; 131:599 606. 31. Chai H, Farr RS, Froehlich LA et al. Standardisation of bronchial inhalation challenge procedures. JAllergy Clin Immuno11975; 56:323 327. 32. Jenkins PF, Benfield GFA, Smith AP. Predicting recovery from acute severe asthma. Thorax 1981; 36: 835-84l. 33. Petheram IS, Jones DA, Collins JV. Patterns of recovery of airflow obstruction in severe acute asthma. Postgrad MedJ 1979; 55:887 880.
Bronchial hyperresponsiveness in patients recovering from acute severe asthma M. K. B. WHYTE, N. B. CHOUDRY AND P. W. IND*
Department of Medicine (Respiratory Division), Royal Postgraduate Medical School, Hammersmith Hospital, London W12 OHS, U.K.
Bronchial hyperresponsiveness is widely recognized as a marker of airway inflammation in asthma. The degree of bronchial hyperresponsiveness following acute severe attacks of asthma and the time course of its recovery has not previously been studied. Bronchial responsiveness to histamine was measured in 18 unselected patients admitted to hospital because of acute severe asthma, during their acute admission, and geometric mean PD20 histamine was 0.08 (range 0.02-0.32)/~mol. In nine patients, further measurements were performed at 3-4 and 12 weeks following discharge. Geometric mean PD20 histamine was 0.09/~mol acutely, 0.23/xmol at 3-4 weeks (n = 9, P = 0"05 by analysis of variance) and 0.59/amol at 12 weeks (n = 8, P = 0.04). For the eight patients studied at 12 weeks, a mean 10.3-fold increase in PD20 was shown, with no suggestion of a maximum effect having been achieved. In contrast, spirometry had returned to the normal range by 4 weeks. The dissociation between improvement in bronchial hyperresponsiveness and spirometry is of interest. The delayed reduction in hyperresponsiveness may have important clinical implications for the duration of anti-inflammatory corticosteroid treatment following acute severe asthma.
Introduction
Acute severe asthma is one of commonest medical emergencies. Within the United Kingdom, there is broad agreement on the principles of its management (1). However, mortality from asthma in the U.K. is either static (2) or rising (3). Relapse following discharge from hospital is common (4~6) and difficult to predict (7,8). Indeed, recent hospitalization has been recognized as a risk factor for asthma death (3,9). Major differences in the management of asthmatics, following discharge from hospital after an acute attack, have been highlighted (5,6,9) and little information is available regarding optimal further management following discharge (10). Non-specific bronchial hyperresponsiveness is a cardinal feature of asthma, which is correlated with increased asthma symptoms and treatment requirements (11), diurnal variation in peak expiratory flow (PEF) (12), nocturnal wakening (13) and an increased risk of 'sudden death' from asthma (14). There is increasing evidence of an association between bronchial inflammation and hyperresponsiveness in asthma (15). The pathology of acute asthma in Received6 June 1991and acceptedin revisedform30January1992. *To whom correspondence should be addressed at: Respiratory Division,Departmentof Medicine,HammersmithHospital,Du Cane Road, LondonWI2 0HS,U.K. 0954-6111/93/010029+ 07 $08.00/0
patients who die reveals gross bronchial inflammation (16). For these reasons, bronchial hyperresponsiveness might be expected to occur in patients with acute severe asthma. However, there is no information on the degree of bronchial hyperresponsiveness in such patients, nor on the time course of its improvement in relation to treatment for the acute episode. The aim of this study was to measure bronchial responsiveness in patients shortly after admission to hospital with acute severe asthma and follow the time course of its improvement.
Patients and Methods
Eighteen consecutive patients (12 female), who consented to the study, were investigated following admission with acute asthma to Ealing and Hammersmith Hospitals. Their ages ranged from 18 to 66 (mean 32) years. On the basis of clinical history and possession of two or more positive skin tests to a battery of common aero-allergens, 13 were judged to be atopic. The mean duration of asthma in these patients was 15 years (range 1-40 years). Symptoms of the acute attack had been present for 3 days (mean), varying widely from 1 to 10 days. Their usual maintenance therapy was: inhaled fl2-agonists (18 patients), regular inhaled corticosteroids (13 patients), oral theophyllines (seven patients) and oral prednisolone (one 9 1993Bailli~reTindall
30
M. K. B. Whyte et al.
Table 1 Individual patient details, including usual therapy, age and duration of asthma in years and duration of acute symptoms prior to presentation in days
Patient
Age (years)
Duration of Duration of asthma symptoms Sex Atopy (years) (days)
1
30
F
+
2 3 4 5 6 7 8 9 10 I1 12 13 14 15 16 17 18
41 18 25 67 20 22 20 38 20 32 18 34 23 2l 66 61 32
F M F F F F F F F M F M F F M M M
+ + + + + + + + + + + +
15 20 17 10 20 17 10 20 30 10 20 7 15 11 10 40 1 i0
Inhaled //2-agonist
l0 3 2 4 6 1 4 3 4 1 3 1 1 5 1 2 3 2
Inhaled steroid
+
-
+ + + + + + + + + + + + + + + + +
+ + + + + + + + + + + + + -
Oral theophylline
Oral steroid
Initial PD20
+ + + + + + + + -
-
0.08 0.05 0.32 0.13 0.12 0.14 0.06 0.10 0.02 0.06 0.12 0.02 0.12 0"05 0.05 0"32 0.08 0.05
+ -
Patients 1 4 are those on whom follow-up studies were performed. patient). Patient details are summarized in Table 1. N o patient had been admitted to hospital with acute asthma in the 3 m o n t h s prior to the studies, which were performed outside the pollen season. Local Ethical Committee approval was obtained and patients gave written, informed consent. The patients were admitted by duty medical firms in the usual way and clinical m a n a g e m e n t was continued by the admitting physicians unless transfer to the Respiratory team was specifically requested. The acute attack was m a n a g e d conventionally, with oxygen, nebulized bronchodilators, including high doses o f salbutamol in all cases and ipratropium b r o m i d e in 15, parenteral corticosteroids in all cases and, in 13 patients, theophyllines, in 10 orally and by intravenous infusion in three. Bronchial hyperresponsiveness was measured on day 3-5 o f admission (median day 4). Measurements were performed 4 h after last dose o f nebulized f12" agonist. All studies were carried out in the Pulmonary F u n c t i o n laboratory, under medical supervision. Histamine challenge was a modification of the m e t h o d o f Yan et al. (17), using a hand-held De Vilbiss 40 glass nebuliser, the same nebuliser being used t h r o u g h o u t the study. In patients with mild asthma, PD20 histamine by this technique is reproducible within one doubling dilution. Histamine d i p h o s p h a t e salt was dissolved in normal saline to produce solutions at doubling concentrations from 2 to 32 mg ml ~. Initial
FEVt was measured prior to beginning the histamine challenge and then two puffs o f normal saline were administered as a control followed by m e a s u r e m e n t o f the baseline (i.e. post-saline) FEV~. The challenge was started at 2 m g ml ~, rising by doubling increments to a m a x i m u m concentration o f 32 mg ml - ~. F r o m the measured volume delivered by the nebulizer (0.003 + 0.0002 ml per puff, determined by weighing experiments) and the k n o w n concentration o f the solution the dose o f histamine delivered at the subject's m o u t h was calculated in/~mol o f histamine. The dose range was equivalent to 0-0~2.56r Increasing doses o f histamine were given at 2-rain intervals. Serial measurements o f FEV~, taken as the better o f two satisfactory attempts using a Vitalograph spirometer, were p e r f o r m e d until a greater than 20% fall in FEV~ was obtained. A t the end o f the challenge, 200/lg o f inhaled salbutamol was given by metered dose inhaler and spirometry repeated 5 and 10 min later. If a fall in FEV~ o f greater than 0.1 1 occurred with inhalation o f normal saline, the F E V 1 m e a s u r e m e n t was repeated until stable. The response to histamine was measured as percentage change in FEV~ from the baseline (post-saline) value. The cumulative dose o f histamine causing a 20% fall in FEVz (PD20 FEVI) was measured by linear interpolation. Following discharge from hospital, bronchial responsiveness was determined at 3-4 weeks and at 12 weeks in nine o f the H a m m e r s m i t h patients (Table 1,
Bronchial hyperresponsiveness in patients" recovering from acute severe asthma patients 1-9). All measurements were performed 4 h after last dose of inhaled fl2-agonist and at the same time of day as previous measurements. Clinical measurements and PEF and FEVL were expressed as arithmetic mean and 95% confidence intervals. PEF and FEV~ were also expressed as % predicted (18). PD20 values were logarithmically transformed and expressed as geometric mean with 95% confidence intervals. Statistical analysis was by analysis of variance (ANOVA) for repeated measures and paired t-tests.
31
i[o ~oo 9o
!
80 7o
s 60 h_
5O Results There was considerable variation in the severity of asthma, though all patients were judged to require hospital admission by the clinicians responsible for their care. All patients had a clear diagnosis of asthma, based on a typical history and established reversibility of airflow obstruction after a fl2-agonist of >20% of FEV 1 or PEF. None of the patients studied had a history of chronic bronchitis or other significant lung disease. One patient (no. 18) had smoked previously. At the time of admission the nine patients who were subsequently followed up (Table 1, patients 1-9) had a tachycardia, with a mean heart rate (95% confidence intervals) of 114 (78-150) beats per minute, and tachypnoea, with a respiratory rate of 31 (17-45) per minute. Mean systolic blood pressure was 126 (102150) mmHg. PEF was markedly reduced with a mean of 145 (50-300) I rain I or 29 (9-49)% predicted. Mean arterial PCO 2was 4.0 (3.0-5.0) kPa and mean PO 2was 10.4 (3.6-17.2) kPa, but the latter data proved difficult to interpret as the percentage of oxygen inspired had not always been recorded. For the nine patients (Table 1, patients 10-18) on whom acute data only was obtained, the results were very similar: heart rate 106 (62-150) beats per minute, respiratory rate 30 (22-38) per minute, systolic blood pressure 141 (83-199) mmHg, peak expiratory flow 16l (40-280) 1 rain ~or 32 (6-58)% predicted, arterial PCO 2 4-9 (1.7-8-1) kPa and PO 2 13.4 (2.8 24) kPa. All patients received parenteral hydrocortisone, 200-1200 mg total dose, followed by oral prednisolone 30-40 mg daily and all but one patient was discharged on inhaled corticosteroids. Eight of the nine patients who were subsequently followed were on high-dose inhaled corticosteroids, mean 1200/~g per 24h, throughout the study period. All patients made an uncomplicated recovery from their acute exacerbation of asthma. ]=or the 18 patients studied during their acute admission, mean initial (pre-test) FEV Lwas 61% predicted (range 42-88%). Mean reduction in FEV~ by
40 30 20
h
Pre-histamine
[
Mfn. FEV~
I
Post-2OOzag salbutamol
Fig. 1 Safetyof histamine challenge during admission for acute asthma. FEV~ (as % predicted) is plotted as initial value, minimum value achieved during challenge and value 10 min followinginhalation of salbutamol 200/~g.
saline was 0.11 (mean 4.0% of initial FEV 1, range 016%, n = 18). Ten patients experienced no fall in FEV~ with administration of saline and only three patients had falls that were greater than 10% of their initial FEV 1 and all of these recovered within 10 min. PD20 FEV 1during the acute admission ranged from 0.02 to 0.32/~mol of histamine. Geometric mean initial PD20 histamine was 0.08 #tool (n = 18). The safety of the initial histamine challenge is emphasized by the complete reversibility of FEV 1 or PEF with 200,ug salbutamol inhaled at the end of the test (Fig. 1). Mean (95% confidence intervals) FEV 1 was 64 (42-98)% predicted immediately prior to the histamine challenge, falling to 46 (28-68)% on challenging and rising to 76 (43-114)% salbutamol. Of the initial 18 patients, nine were followed over a period of 12 weeks (Table 1, patients 1-9). Of the remaining nine patients, it was not possible to study the six from Ealing Hospital (Table 1, Patients 10, 11, 13, 14, 17, 18). Of the 12 Hammersmith Hospital patients, three could not be followed up (one readmitted, one psychiatric admission and one moved from the area immediately following discharge). However, on analysis of admission data, previous treatment and initial management of this attack, there were no differences between these two groups. Initial geometric mean (95% confidence intervals) PD20 histamine was also not significantly different [0.07 (0.03-0-16)/1mot for the nine not followed, 0.09 (0.04-0.19) /1moI for
32
M. K. B. Whyte et al. I0
I00
(a)
80 jl
E
~o /
.x:
i / /
4o
E W
o, u_o
I;
I-
u_
_--
20
$S-'-
I
I
I 0
I 2
s
I
I
I
I
I IO
I 12
[3-
o.oi
i 0
I 2
I 1 t 4 6 8 Time (weeks)
I I0
I i2
(b) i
Fig. 2 Time course of recovery ofPD20 FEV t (dose of histamine in ~tmol producing a 20% fall in FEVI) for the nine patients at time 0 (acute admission), then at 3-4 and 12 weeks later. Log PD20 histamine is plotted against time in weeks. ( ) Individual patients; ( A - - A ) geometric mean values at the different time points.
0.1
o
the nine who were, P=0.70]. Moreover, follow-up spirometry within the 4~ 12 week period was available for the six Ealing Hospital patients and was not significantly different [FEV~ 81 (61 101)% predicted, compared with values for the nine patients followed of 80 (50-110: n = 9 , P=0"98) at 3~ , weeks and 80% (48 112: n = 8 , P = 0 . 9 2 ) at 12 weeks. In the nine patients who were followed, a gradual increase in PD20 histamine occurred over 12 weeks. This contrasts with the values for FEV~ shown above, which were improved at 3-4 weeks but showed no further improvement thereafter (Fig. 3). Mean PEF (95% confidence intervals) was 270 (80-460) 1rain -1 [60 (33 87)% predicted, n = 8] immediately prior to the acute challenge, rising to 351 (280420) 1 rain -~ [77 ( 6 5 ~ 9 ) % , n = 7 ] at 4 weeks and 314 (210-418)1 min 1 [73 (5591)%, n = 5] at 12 weeks. The improvement at 4 weeks was statistically significant (P < 0.001) but there was no further improvement at 12 weeks (P = 0.90). The time course of improvement in bronchial hyperresponsiveness is shown in Fig. 2. At 3-4 weeks, geometric mean PD20 histamine was 0"23/~mol ( n = 9 ) , compared with 0"09 ymol for these same nine patients during the acute admission. This difference was statistically significant (P < 0"003 by paired t-test, P = 0-05 by ANOVA). At 12 weeks, PD20 histamine had increased to 0.59/tmot (n = 8), which was also significant compared with the acute values in these eight patients (P<0.0001 by paired t-test and ANOVA) with there also being a significant improvement over the 3-4 week value (P<0-004 by t-test, P = 0 - 0 4 by ANOVA). There was a mean 10.3-fold increase (calculated as the ratio of final over initial PD20 histamine for
db O_
0.01
I I I 4 6 8 Time (weeks)
Fig. 3 a, Time course recovery of FEV~ as % predicted, (mean + sD). b, Time course of recovery of geometric mean (6M) PD20 FEV~ (with 95% confidence intervals). All results for the nine patients in whom follow-up measurements were obtained at 3-4 and 12 weeks following their acute admission. At time 0 and 3-4 weeks n =9 and at 12 weeks n = 8,
each individual) in PD20 over 3 months, with no suggestion of a maximum value being achieved. The progressive improvement in bronchial responsiveness is contrasted with the initial FEV 1 as % predicted which showed no further improvement after 4 weeks (Fig. 3). In Fig. 4, PD20 FEV1 is plotted against prechallenge FEV 1 (for the initial challenge). There was no correlation between initial bronchial responsiveness and the degree of airflow obstruction (n = 18, r = -0.33). In the nine patients who underwent repeat histamine challenges, there was again no correlation between initial (pre-test) FEV 1 and PD20 ( r : +0-42, P ys, 26 data points). The degree of bronchial hyperresponsiveness, as determined by PD20, did not correlate with severity of asthma, as judged by heart rate or P E F (as 1 rain- 1or as % predicted); nor did it correlate with the duration of the acute episode of asthma. Discussion
We have demonstrated that bronchial responsiveness to histamine is greatly increased in patients
Bronchial hyperresponsiveness in patients recovering from acute severe asthma I00
80
60
% U_l h
40
I Q..
20-
~
I
-L-o
[
-2-o
Log PO2o FEV I
s
Scattergram of FEV~ (as % predicted) for individual patients before initial acute histamine test, plotted against log PD2o FEV~ determined in that test. This shows the lack of correlation between FEV1and PD20(r = -0.33, P = ys). with acute asthma, 3-5 days after their admission to hospital. Geometric mean initial PD20 was 0-08/~mol (n= 18), which corresponds well with values found in studies of patients with severe asthma using similar techniques (19,20). However, these studies were performed in patients who were not acutely ill. PD20 FEVj to histamine in normal subjects has been shown to be greater than 10/tmol (21) and our patients are, therefore, on average 100-fold more responsive to histamine than normal subjects. The degree of bronchial hyperresponsiveness shown is necessarily underestimated because treatment of acute asthma could not be withheld. Reduction of bronchial responsiveness continued over the 12 weeks of the study, with a mean 10.3-fold increase in PD20 histamine (3.1 doubling dilutions) and no suggestion of a maximum effect being achieved by the end of the study. Airflow obstruction, however, as judged by spirometry or PEF, had returned to the normal range by 4 weeks. For the sake of uniformity, all measurements of PD20 were made 4 h after last nebulized flz-agonist treatment. Other studies suggest that, at this time, there would still be a small residual fl2-agonist effect, leading to some antagonism of histamine response and thus underestimation of PD20 (22,23). Reproducibility data for the measurement of histamine responsiveness was not obtained in our patients with acute asthma. In other studies in our laboratory (unpublished data), we have confirmed that the Yah method for determination of PD20 histamine is reproducible within one doubling dilution. The major abnormalities in acute severe asthma are airway narrowing, oedema, inflammatory cell
33
infiltrates and bronchial obstruction by mucus. The contribution of bronchial hyperresponsiveness in this situation is unclear. Possible mechanisms of bronchial hyperresponsiveness in acute asthma include increased smooth muscle mass or contractility, increased cholinergic, a-adrenergic or non-adrenergic non-cholinergic excitatory activity or reduced fl-adrenergic or nonadrenergic inhibitory control (24). Epithelial damage with loss of modulating influences, increased bronchial mucosal permeability and exposure of sensory nerves may be important (16,25). An apparent increase in bronchial responsiveness due to enhanced central deposition of histamine aerosol could occur in acute airways obstruction. However, the lack of correlation in this study between PEF or FEVI and PD20 histamine (Fig. 4) and the dissociation between improvement in airway calibre and recovery of bronchial hyperresponsiveness (Fig. 3) argue strongly against this, although the number of subjects studied is small and more sensitive tests of airway calibre have not been examined. There is undoubtedly a general association between reduced baseline airway diameter and bronchial hyperresponsiveness, but starting airway calibre does not determine responsiveness in asthmatics (26). Moreover, bronchial responsiveness after allergen challenge is usually increased and is dissociated from airway calibre as a result of bronchial inflammation (15). Over the time course of recovery from acute asthma, the alterations in airway diameter observed in our patients are unlikely to be the major mechanism of bronchial hyperresponsiveness. Other interpretations of the reduction in bronchial hyperresponsiveness in this study need to be considered. Regression towards the mean does not explain the graded improvement over 12 weeks. The group of patients who were followed were self-selected but they did not differ in any way from the group as a whole. Statistical analysis of dropouts in a small study of this kind is difficult but all patients improved at all time points. Improvement of bronchial hyperresponsiveness was not an artefact of an effect of repeated FEV 1manoeuvres. This effect was minimized by taking the higher of two readings and, of course, more measurements were performed at followup studies as responsiveness improved. A change in airway-parenchymal hysteresis or deep breath bronchodilation with recovery from acute asthma cannot be excluded as part of the mechanism of reduced bronchial response to histamine. Although markedly enhanced bronchial responsiveness to histamine in patients recovering from acute asthma is not surprising, this study is the first to document it. As bronchial responsiveness was not determined prior to admission, the contribution of the acute exacerbation is not known. However, our
34
M. K. B. W h y t e et al.
Table 2 FEV 1in litres and as % predicted and PD20 (provocative dose of histamine causing a 20% fall in FEVI) for nine individual patients during their acute admission and then 3 4 and 12 weeks later
Acute admission
4 weeks
12 weeks
Patient
PD20
FEV~
FEV, (%)
PD20
FEV~
FEV~(%)
PD20
FEV,
FEV, (%)
1 *2 3 *4 *5 6 7 *8 9
0.08 0.05 0.32 0.13 0.12 0.14 0.06 O.10 0-02
2.2 1.1 2-1 2.1 1.0 1-8 2-6 1-8 1.5
76 48 42 61 54 60 75 55 53
0.11 0.13 0.64 1.10 0.50 0.14 0.14 0.27 0.04
2.5 1.4 3.6 3.5 1.4 2.0 2.5 3.4 2.2
86 61 72 101 76 67 72 103 77
0.47 1.70
2.7 1-4
93 61
1.00 1.28 0.32 0.35 0.68 0.18
3.4 1-2 2.0 2.4 3.3 2.4
99 65 67 70 100 84
For patient 3, no 12-weekmeasurements are available. *Patients given theophyllines during the acute admission.
patients showed major improvements in bronchial responsiveness, with a mean 10.3-fold (3.1 doubling dilutions) increase in PD20 histamine. This improvement occurred gradually over the period of the study, reflecting either response to treatment or the natural history of recovery from acute asthma. Minor differences in treatment of the acute episode are thus unlikely to have greatly affected the improvement in bronchial responsiveness seen over the 12-week period. In previous studies of asthmatic patients, in a more stable clinical state, inhaled corticosteroids have been shown to decrease bronchial responsiveness over a period of ~ 8 weeks by 1-2 doubling dilutions (20,27,28). The mechanisms of the beneficial effects of steroids in asthma are not established but this action is considered to be an anti-inflammatory effect. Eight of the nine patients completing the study were managed in the asthma clinic, on high dose inhaled corticosteroids, mean 1200 (range 401~2000)/tg per 24h beclomethasone dipropionate or budesonide. Previously, budesonide 1600 ltg daily has been shown to be superior to 400/zg daily in reducing bronchial hyperresponsiveness (29). The extent of reduction in bronchial responsiveness (29) was less than that seen in our patients but this may relate to the lower initial PD20 in our study. If bronchial hyperresponsiveness is closely related to bronchial inflammation in acute asthma, then the implication of our findings is that this persists after an acute exacerbation. This, too, is not surprising, since bronchical hyperresponsiveness is found, in association with bronchial inflammation, in subjects with very mild asthma (30). Previous guidelines for studying bronchial responsiveness suggest that subjects should have initial lung function greater than 80% predicted (31). However,
histamine challenge in this study, performed under medical supervision in a lung function laboratory, proved safe. All patients showed rapid reversal of histamine-induced bronchoconstriction by a standard dose of inhaled salbutamol. No patient experienced any adverse effect or was unwilling to undergo further testing. The reduced number of patients at the later study point reflects the difficulty in motivating young, fit people to reattend once they feel well. Considerable attention has focused on the immediate management of acute asthma but little is known about the natural history of recovery from acute attacks (32). Current treatment of acute severe asthma emphasizes the importance of determination of airway calibre, by measurements such as PEF, in monitoring treatment response (33). However, this study has demonstrated a dissociation between recovery of spirometry and that of bronchial hyperresponsiveness, which may reflect the persistence of airway inflammation. The slow improvement in bronchial hyperresponsiveness observed in patients in this study may suggest a need for more prolonged anti-inflammatory treatment following acute attacks than would be indicated by measurement of spirometry alone. Sequential determination of bronchial responsiveness over a longer period might thus be useful in managing acute asthmatics after discharge from hospital and a further prospective study is planned. References
1. Clark TJ. Acute severe asthma. In: Clark TJ, Godfrey S. eds. Asthma. 2rid edn. London: Chapman & Hall, 1983; 392M14. 2. British Thoracic Association. Deaths from asthma in two regions of England. Br MedJ 1982; 285:1251 1255.
Bronchial hyperresponsiveness in patients recovering f r o m acute severe asthma 3. MacDonald JB, MacDonald ET, Seaton A, Williams DA. Asthma deaths in Cardiff 1963-74:53 deaths in hospital. Br MedJ 1976; 1: 721-723. 4. MacDonald JB, Seaton A, Williams DA, Asthma deaths in Cardif 1963-74:90 deaths outside hospital. Br M e d J 1976; 2: 1493-1495. 5. Osman J, Ormerod P, Stableforth D. Management of acute asthma: a survey of hospital practice and comparison between thoracic and general physicians in Birmingham and Manchester. Br J Dis Chest 1987; 81: 232 24l. 6. Bucknall CE, Robertson C, Moran F, Stevenson RD. Management of asthma in hospital: a prospective audit. Br M e d J 1988; 296:1637 1639. 7. Arnold AG, Lane D J, Zapata E. Acute severe asthma: factors that influence hospital referral by the general practitioner and self-referral by the patient. Br J Dis Chest 1983; 77" 51 59. 8. Centor RM, Yarbrough B, Wood JP. Inability to predict relapse in acute asthma. N Engl J Med 1984; 310: 577 580. 9. Ormerod LP, Stableforth DE. Asthma mortality in Birmingham 1975 7:53 deaths. Br Med J 1980; 280: 687 690. 10. Bucknall CE, Robertson C, Moran F, Stevenson RD. Differences in hospital asthma management. Lancet 1988; i: 748 750. 11. Hargreave FE, Ryan G, Thomson NC et al. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin lmmuno11981; 68: 347-355. 12. 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 calibre. Thorax 1982; 37: 423~429. 13. Juniper EF, Frith PA, Hargreave FE. Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma. Thorax 1981; 36: 575-579. 14. Bateman JRM, Clarke SW. Sudden death in asthma. Thorax 1979; 34: 40~44. 15. Chung KF. Role of inflammation in the hyperreactivity of the airways in asthma. Thorax 1986; 41: 657-662. 16. Dunnill MS. The pathology of asthma, with special reference to changes in the bronchial mucosa. J Clin Pathol 1960; 13: 27--33. 17. Yan K, Salome C, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. Thorax 1983; 38:760 765. 18. Cotes JE. Lung function: assessment and application in medicine, 4th edn. Oxford: Blackwell Scientific, 1979; 329-388.
35
19. Dutoit JI, Salome CM, Woolcock AJ. Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in asthma but oral theophylline does not. Am Rev Respir Dis" 1987; 136: 1174-I 178. 20. Woolcock A J, Yan K, Salome CM. Effect of therapy on bronchial hyperresponsivenessin the long-term management of asthma. Clin Allergy 1988; 18:165 176. 21. Woolcock AJ, Salome CM, Yah K. The shape of the dose-response curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis" 1984; 130: 71-75. 22. Salome CM, Schoeffel RE, Woolcock AJ. Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects. Thorax 1981; 36: 580-584. 23. Tattersfield A E Effect ofbeta-agonistsand anticholinergic drugs on bronchial reactivity. Am Rev Respir Dis 1987; 136: 564-568. 24. Ollerenshaw S, Jarvis D, Woolcock AJ, Sullivan C, Scheibner T. Absence of immunoreactive vasoactive intestinal polypeptide in tissue from the lungs of patients with asthma. N Engl J Med 1989; 320" 1244-1248. 25. Hogg JC. Bronchial mucosal permeability and its relationship to airways hyperreactivity. J Allergy Clin lmmuno11981; 67: 421~425. 26. Chung KF, Morgan B, Keyes SJ, Snashall PD. Histamine dose-response relationships in normal and asthmatic subjects: the importance of starting airway calibre. Am Rev Respir Dis 1982; 126:849 854. 27. Ryan G, Latimer KM, Juniper EF, Roberts RS, Hargreave FE. Effect of beclomethasone dipropionate on bronchial responsiveness to histamine in controlled non-steroid dependent asthma. J Allergy Clin Immunol 1985; 75: 25-30. 28. Kraan J, Koeter GH, Mark ThW, Sluiter H J, De Vries K. Changes in bronchial hyperreactivity induced by four weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J Allergy Clin Immunol 1985; 76: 628 636. 29. Kraan J, Koeter GH, Mark ThW et al. Dosage and time effects of inhaled budesonide on bronchial hyperreactivity. Am Rev Respir DB 1988; 137: 44-48. 30. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis 1985; 131:599 606. 31. Chai H, Farr RS, Froehlich LA et al. Standardisation of bronchial inhalation challenge procedures. JAllergy Clin Immuno11975; 56:323 327. 32. Jenkins PF, Benfield GFA, Smith AP. Predicting recovery from acute severe asthma. Thorax 1981; 36: 835-84l. 33. Petheram IS, Jones DA, Collins JV. Patterns of recovery of airflow obstruction in severe acute asthma. Postgrad MedJ 1979; 55:887 880.