Clinical Allergy, 1979, Volume 9, pages 213-219
Recurrent nocturnal asthmatic reactions to bronchial provocation tests
A. J. NEWMAN TAYLOR,* R. J. DAVIES,t D. J. HENDRICKJ and J. PEPYS* * Brompton Hospital, and-\St Bartholomew's Hospital, London, andXWest Virginia University, Virginia, U.S.A., and Cardiothoracic Institute, London (Received \2 July \918; accepted8 August 1978)
Introduction Nocturnal symptoms were described by Salter as an important feature of bronchial asthma in 1882 (Salter, 1882), and lung function measurements in asthmatic patients have confirmed the tendency for airflow obstruction to increase during the night and early morning (Clark & Hetzel, 1977). In a recently reported case, airflow obstruction was found to recur on several nights following a single exposure to the provoking agent, with maintenance of relatively normal lung function during the intervening days (Davies, Green & Schofield, 1976). Episodes of wheezing confined to the night-time have been reported in workers handling Western Red Cedar (Gandevia & Milne, 1970; Mitchell, 1970). Nevertheless, asthma recurring on several successive nights after a single short exposure to the provoking agent has only recently been recognized, and its mechanism is unknown. We reported four patients in whom recurrent nocturnal asthma followed a single exposure to the casual agent. Patients and methods Respiratory function tests The forces expiratory volume is one second (FEV^) and forced vital capacity (FVC) were measured using a dry spirometer (Vitalograph). Peak expiratory flow rates (PEFR) were measured with a Wright peak flow meter. Single breath carbon monoxide transfer was measured by the method of Cotes using a Respirometer Mark IV (P. K. Morgan Ltd., Chatham, Kent). Patient I Patient 1, a 52-year-oId woman, smoked twenty cigarettes a day all her adult life. In 1973 she was investigated for increasing effort dyspnoea associated with a persistent non-productive cough which often woke her from sleep at night. Her parents kept Correspondence: Professor J. Pepys, Department of Clinical Immunology, Cardiothoracic Institute, Brompton, London SW3 6HP. 0009-9090/79/0500-0213$02.00 © 1979 Blackwell Scientific Publications
213
214
A. J. Newman Taylor et al.
birds in the home during her childhood, and she had had intermittent avian exposure during her adult life. She dated her cough and breathlessness to within I month of acquiring a new budgerigar. On examination she had clubbing of the fingers and end inspiratory crackles audible at her lung bases. Lung function tests showed normal lung volumes, but impaired carbon monoxide gas transfer factor (65% of the predicted). The chest radiograph showed ill-defined basal nodular shadowing. Rheumatoid factor was present in her serum to a titre of more than 1/512 and tests for antiniiclear factor were strongly positive. Lung biopsy showed fibrosing alveoiitis of the mural pattern, with no evidence of granulomata. Skin prick tests were negative to twentythree common inhalant and food antigens: she gave positive immediate skin prick test reactions to budgerigar feathers and pigeon and budgerigar serum, and an intracutaneous test with l/IOO dilution of budgerigar serum elicited an immediate and late 'Arthus-type" skin reaction. Agar gel double diffusion tests gave negative reactions to pigeon and budgerigar serum. Inhalation testing Inhalation testing was performed with aerosols of the test agents as described by Pepys & Hutchcroft (1975) with only a single test made on any one day. On the control day. Coca's solution was inhaled for 5 min at which time 0 9 ml of the solution had been nebulized. On the next day, 10 ml of budgerigar serum diluted 1 :IOO in Coca's solution was nebulized and inhaled over a 5 min period without reaction. 2 days" later 0 9 ml of budgerigar serum 1:10 was inhaled for 5 min and provoked a small immediate asthmatic reaction with chest tightness (Fig. 1). This was followed after 5 hr by a non-immediate (late) reaction with chest tightness and breathlessness. She woke twice during the night with wheezing and breathlessness, which was improved rapidly by inhalation of salbutamol. She stayed in hospital but continued to be awakened at about the same time (02.00 to 03.00 hours) by wheezing and breathtessness for the next 8 nights, remaining free of symptoms during the day-time despite objective evidence of impaired lung function. There were significant changes in the carbon
24
(C)
(T)
22 20
^
^
12
0-8 0-6 0'4 02 0
12 00 12.00 12 00 12 00 12.00 12,00 00 00 00.00 00.00 0000 00.00 Doy 1 Day 2 Doy 3 Day 4 Day 5
Fig. I. Inhalation test with budgerigar serum. (C) Control; (T) test; (S) salbutanol (arrows show when given).
Recurrent-asthmatic reactions and bronchial provocation tests
215
monoxide gas transfer factor from the pre-test values, either at the time of the asthmatic reaction during the afternoon of the test day, or on the following days at times when her ventilatory function was impaired. Her nocturnal asthma did not recur when she returned home after the budgerigar had been removed. However, treatment with propranolol for disabling angina a year later was followed by the return of the nocturnal symptoms, which resolved again when this was discontinued. Patient 1 Patient 2, a 55-year-old man, had worked for 15 years as a maintenance fitter in a factory manufacturing penicillin and its semi-synthetic derivatives. He had smoked twenty cigarettes a day all his adult life, and suffered from recurrent mucopurulent bronchitis. His general practitioner, appreciating his heavy exposure to penicillins at work, had always prescribed antibiotics other than penicillins for his chest infections. He presented in 1973 with a history of three severe attacks of wheezing, worst at night, waking him repeatedly from sleep. He required 2 weeks to recover from each episode before being able to return to work. The first two attacks followed exposure to antibiotic dust at work; the third occurred after his son, who worked in the same factory, returned home without changing his work clothes. He had no past or family history of eczema, rhinitis or asthma. On admission he was symptom-free, with lung function tests within predicted limits. Chest radiograph showed no abnormalities. Skin prick tests with twenty-three common inhalant and food antigens, as well as with ampicillin and related substances, gave no reactions. Inhalation testing Occupational-type dust exposure was performed for 30 min as described by Davies. Hendrick & Pepys (1974). On the control day he was exposed without reaction to the dust of well-dried lactose powder by tipping 250 g from one tray to another in a 6 0 m^ enclosed chamber. On the following day, he was exposed to the dust from a mixture of 10 mg pencillin G added to 250 g lactose. A reaction developed 16 hr later when he was awakened during the night by wheezing and breathlessness associated with a marked fall in FEVj {Fig. 2). Both symptoms and measurements of FEV, were improved the following morning, and the FEV, had returned to pre-test values by mid-day. This pattern of normal lung function during the afternoon and evening
00 Doy 1
Doy 2
Day 3
00,00
Day A
Fig. 2. Inhalation test (occupational type) with penicillin G in lactose. (C) Control; (T) test.
216
A.J. Newman Taylor et al.
followed by nocturnal and early morning symptoms associated with falls in FEV, persisted for 4 days and nights, but resolved on oral corticosteroid treatment. He has remained free of symptoms with normal lung function away from his previous place of work for over 2 years. Patient 3 Patient 3, a 31 -year-old man, had worked as an offset printer for 2 years. He had never smoked cigarettes and had no previous history of chest complaints. He had a 3 month history of cough and breathlessness, worst at night, which woke him from sleep. His symptoms tended to increase in severity during the working week, but persisted when away from work at weekends, only resolving completely during a 2 week holiday. He had no past or family history of eczema, hay fever or asthma. Chest radiograph was normal and lung function tests prior to inhalation testing were within predicted limits. Skin prick tests with twenty-three common inhalant and food antigens were negative. Occupational exposure Because the specific occupational agent responsible for his asthma had not been identified, regular PEFR measurements were made before, during and following the first day of his return to work after a 2 week holiday. No significant variation in PEFR was observed prior to his return to work. During the 8 hr shift on the following day, his PEFR fell (Fig. 3). He was twice awakened during the night by wheezing attacks 500 rAOO
E 300
200
100
J
12 00
12 00
12 00
12 00
00.00 00.00 0000 Control doy Day 1 Day 2 Day 3
Fig. 3. Effects on PEFR of return to work. (ES!) Work.
associated with further falls in PEFR. His symptoms and PEFR had improved by morning, but without further occupational exposure he was again awakened twice during the following night and early morning with episodes of wheezing, with decreases in PEFR. This pattern of nocturnal asthmatic attacks with improvement in symptoms and PEFR continued over a period of 1 week before resolving spontaneously. Patient 4 Patient 4, a 32-year-old female nursing auxiliary, had suffered from hay fever since early childhood, as well as short episodes of wheezing provoked by 'colds' and expo-
Recurrent-asthmatic reactions and bronchial provocation tests
217
sure to house dust. She had never smoked. Within 6 months of working on a renal dialysis unit she developed severe and frequent wheezy attacks from which she would require up to 2 weeks before recovering fully. Between attacks she remained well, though occasionally she was mildly wheezy. Pulmonary function tests and chest radiographs were normal when she was without symptoms. Skin prick tests with twelve common allergens gave immediate reactions to grass pollen, house dust and the house dust mite (D. pteronyssinus). Inhalation testing On the control day the patient was tested by exposure to water, which she brushed on to a board. On the test day she carried out the same manoeuvre with a 25% solution of formalin for 8 min (Hendrick & Lane, 1977). No significant change in lung function followed her exposure to water. Exposure to formalin provoked a non-immediate asthmatic reaction, the maximum fall in PEFR occurring in the early hr of the following morning {Fig. 4). The asthma continued for 8 days, during which time her airflow obstruction was symptomatically and functionally more severe during the night. 500 r-
(C)
(T)
400
300
200
100
J
L
-J
\
I
L
J
I
12 00^ 12.00 12.00 12.00 12.00 12.00 12 00 12 00
00,00 00.00 00.00 0 0 0 0 00.00 00.00 00.00 0 0 0 0 Dayi Day 2 Day 3 Doy 4 Doy 5 Day 6 Doy 7 Day 3
Fig. 4. Inhalation test {occupational type) to formalin. (C) Control; (T) test.
Discussion In each of the four patients described in this report a single short exposure elicited respiratory reactions which recurred on several successive nights without any further exposure to the causal agent. Although this has been described previously (Gandevia & Milne, 1970; Mitchell, 1970), measurements of lung function have only been made during the nocturnal reactions in one other study (Davies et al, 1976). All the respiratory reactions described in this report were characterized by wheezing and breathlessness and associated with reversible fails in PEFR or FEV,, suggesting the diagnosis of asthma. Our first patient had biopsy-proven fibrosing alveoiitis, but measurements of her single breath carbon monoxide gas transfer at times when her ventilatory function was impaired showed no significant change. This implies that the reaction to the inhaled budgerigar serum was primarily asthmatic in nature, although our measurements cannot exclude a coexisting alveolar reaction. The factors responsible for nocturnal asthmatic attacks have yet to be identified.
218
A. J. Newman Taylor et al.
Clark & Hetzel {1977) were unable to demonstrate any relationship between nocturnal asthma and house dust mite allergy or to recumbency in bed at night. They did find a definite association with sleep. The PEFR fell during sleep whatever time this occurred in a 24 hr period. In a study of bronchial lability in asthmatic and bronchitic patients, de Vries et al. (1962) found that up to thirty-two times less histamine was required to elicit a given fall in FEV, at midnight and 04.00 hours than during the rest of the day. The relationship between sleep and circadian variation in endocrine secretions has led to suggestions that airways calibre may be influenced by the fluctuations in circulating hormone levels. Soutar et al. (1975) eliminated the normal circadian variation of plasma cortisol in a group of asthmatic patients by continuous infusion of this hormone. This did not prevent falls in night time PEFR, implying that diurnal changes in plasma cortisol were not responsible for temporally related airway narrowing. However, it is possible that nocturnal asthmatic reactions may be a consequence of a decrease in autonomic support of labile airways during sleep. Soutar, Carruthers & Pickering (1977) found a close relationship between the fall in PEFR during the night and the decrease in urinary catecholamine excretion in all but one of the seven asthmatic patients. Whether elimination of this diurnal variation in circulating catecholamines would prevent nocturnal asthma has still to be demonstrated. In our first patient the nocturnal asthmatic attacks provoked by contact with budgerigars recurred after she was prescribed the beta adrenoceptor-blocking agent propranolol. When this treatment was stopped, the nocturnal asthma ceased. It is possible that the recurrent nocturnal asthmatic reactions observed in our patients were the results of increased lability, initially provoked by an immunological reaction in the airways, which became manifest during sleep when autonomic support for the airways was at a minimum. Immediate asthmatic reactions follow within minutes of exposure to the causal agent and readily suggest the cause of the reaction to both patient and doctor. Nonimmediate or late asthmatic reactions develop several hours after exposure, when the patient is often no longer in contact with the provoking agent. This makes the association between causal agent and asthmatic attack diflicult to recognize. Wheezing and chest tightness, which are well recognized symptoms of asthma, are prominent in immediate reactions. However, patients with non-immediate reactions may only complain of unusual breathlessness on exertion or cough. The relationship between exposure and reaction in such cases, particularly if the causal agent is met in the workplace, may only be appreciated when the patient is away from exposure at weekends or on holiday. In each of the four patients described in this report, asthmatic symptoms, particularly at night, persisted for several successive days despite avoidance of exposure to the causal agent. This made identification of the responsible agent particularly difficult. The diagnosis was only made with certainty by inhalation testing with the suspected agent. This provoked the recurring nocturnal asthmatic reactious of which the patient has complained. References CLARK, T.J.H. & HETZEL, M . R . (1977) Diurtial variation of Asthma. British Journal of Diseases of the Chest, 71, 87. 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. Clinical Allergy, 4, 227. DAVIES, R.J., GREEN, M . & SCHOFIELD, N.MCC. (1976) Recurrent nocturnal asthma after exposure to grain dust. American Review of Respiratory Disease, 114, 1011.
Recurrent-athmatic reactions and bronchial provocation tests
219
GANDEVIA. J. & MILNE, J. (1970) Occupational asthma and rhinitis due to Western Red Cedar (Thuja plicata) with special reference to bronchial reactivity. British Journal of I>,du.strial Medicine, 11, , D.J. & LANE, D.J. (1977) Occupational formalin asthma. British Journal of Industrial
Medicine,
3 4 , 11.
MITCHELL, C. (1970) Occupational asthma due to Western or Canadian Red Cedar {Thuja plicata) Medical Jimrnal Iff AiLstralia, 2, 233.
PEPYS J. & HUTCHCROFT. B.J. (1975) Bronchial provocation tests in aeiiologic diagnosis and analysis of aslhma. American Review of Respiratory Disease, 112, 829. SALTER, H . H . (1882) Asthma: Its pathology and Treatment, 1st edn, p. 33. William Wood SOUTAR C.A., COSTELLO. J.. IJADULO, O . & TURNER WARWICK, M . (1975) Nocturnal and morning
asthma: relationship to plasma corlicosteroid and response to cortisol infusion Thorax 30 436 SOUTAR, C.A., CARRUTHERS. M . & PICKERING, C . A . C . (1977) Nocturnal asthma and urinary adrena-
line and noradrenaline excrelion. Thorax, 32, 677. VHIES, K . DE, GOEI. J.T. BOOIJ-NOORD, H. & ORIE, N . G . M . (1962) Changes during 24 hours in the
lung funcljon and histamine hyperactivity of ihe bronchial tree in asthmatic and bronchitic paiienis. International Archives of Allergy and Applied Immunology, 20, 93.
Recurrent nocturnal asthmatic reactions to bronchial provocation tests
A. J. NEWMAN TAYLOR,* R. J. DAVIES,t D. J. HENDRICKJ and J. PEPYS* * Brompton Hospital, and-\St Bartholomew's Hospital, London, andXWest Virginia University, Virginia, U.S.A., and Cardiothoracic Institute, London (Received \2 July \918; accepted8 August 1978)
Introduction Nocturnal symptoms were described by Salter as an important feature of bronchial asthma in 1882 (Salter, 1882), and lung function measurements in asthmatic patients have confirmed the tendency for airflow obstruction to increase during the night and early morning (Clark & Hetzel, 1977). In a recently reported case, airflow obstruction was found to recur on several nights following a single exposure to the provoking agent, with maintenance of relatively normal lung function during the intervening days (Davies, Green & Schofield, 1976). Episodes of wheezing confined to the night-time have been reported in workers handling Western Red Cedar (Gandevia & Milne, 1970; Mitchell, 1970). Nevertheless, asthma recurring on several successive nights after a single short exposure to the provoking agent has only recently been recognized, and its mechanism is unknown. We reported four patients in whom recurrent nocturnal asthma followed a single exposure to the casual agent. Patients and methods Respiratory function tests The forces expiratory volume is one second (FEV^) and forced vital capacity (FVC) were measured using a dry spirometer (Vitalograph). Peak expiratory flow rates (PEFR) were measured with a Wright peak flow meter. Single breath carbon monoxide transfer was measured by the method of Cotes using a Respirometer Mark IV (P. K. Morgan Ltd., Chatham, Kent). Patient I Patient 1, a 52-year-oId woman, smoked twenty cigarettes a day all her adult life. In 1973 she was investigated for increasing effort dyspnoea associated with a persistent non-productive cough which often woke her from sleep at night. Her parents kept Correspondence: Professor J. Pepys, Department of Clinical Immunology, Cardiothoracic Institute, Brompton, London SW3 6HP. 0009-9090/79/0500-0213$02.00 © 1979 Blackwell Scientific Publications
213
214
A. J. Newman Taylor et al.
birds in the home during her childhood, and she had had intermittent avian exposure during her adult life. She dated her cough and breathlessness to within I month of acquiring a new budgerigar. On examination she had clubbing of the fingers and end inspiratory crackles audible at her lung bases. Lung function tests showed normal lung volumes, but impaired carbon monoxide gas transfer factor (65% of the predicted). The chest radiograph showed ill-defined basal nodular shadowing. Rheumatoid factor was present in her serum to a titre of more than 1/512 and tests for antiniiclear factor were strongly positive. Lung biopsy showed fibrosing alveoiitis of the mural pattern, with no evidence of granulomata. Skin prick tests were negative to twentythree common inhalant and food antigens: she gave positive immediate skin prick test reactions to budgerigar feathers and pigeon and budgerigar serum, and an intracutaneous test with l/IOO dilution of budgerigar serum elicited an immediate and late 'Arthus-type" skin reaction. Agar gel double diffusion tests gave negative reactions to pigeon and budgerigar serum. Inhalation testing Inhalation testing was performed with aerosols of the test agents as described by Pepys & Hutchcroft (1975) with only a single test made on any one day. On the control day. Coca's solution was inhaled for 5 min at which time 0 9 ml of the solution had been nebulized. On the next day, 10 ml of budgerigar serum diluted 1 :IOO in Coca's solution was nebulized and inhaled over a 5 min period without reaction. 2 days" later 0 9 ml of budgerigar serum 1:10 was inhaled for 5 min and provoked a small immediate asthmatic reaction with chest tightness (Fig. 1). This was followed after 5 hr by a non-immediate (late) reaction with chest tightness and breathlessness. She woke twice during the night with wheezing and breathlessness, which was improved rapidly by inhalation of salbutamol. She stayed in hospital but continued to be awakened at about the same time (02.00 to 03.00 hours) by wheezing and breathtessness for the next 8 nights, remaining free of symptoms during the day-time despite objective evidence of impaired lung function. There were significant changes in the carbon
24
(C)
(T)
22 20
^
^
12
0-8 0-6 0'4 02 0
12 00 12.00 12 00 12 00 12.00 12,00 00 00 00.00 00.00 0000 00.00 Doy 1 Day 2 Doy 3 Day 4 Day 5
Fig. I. Inhalation test with budgerigar serum. (C) Control; (T) test; (S) salbutanol (arrows show when given).
Recurrent-asthmatic reactions and bronchial provocation tests
215
monoxide gas transfer factor from the pre-test values, either at the time of the asthmatic reaction during the afternoon of the test day, or on the following days at times when her ventilatory function was impaired. Her nocturnal asthma did not recur when she returned home after the budgerigar had been removed. However, treatment with propranolol for disabling angina a year later was followed by the return of the nocturnal symptoms, which resolved again when this was discontinued. Patient 1 Patient 2, a 55-year-old man, had worked for 15 years as a maintenance fitter in a factory manufacturing penicillin and its semi-synthetic derivatives. He had smoked twenty cigarettes a day all his adult life, and suffered from recurrent mucopurulent bronchitis. His general practitioner, appreciating his heavy exposure to penicillins at work, had always prescribed antibiotics other than penicillins for his chest infections. He presented in 1973 with a history of three severe attacks of wheezing, worst at night, waking him repeatedly from sleep. He required 2 weeks to recover from each episode before being able to return to work. The first two attacks followed exposure to antibiotic dust at work; the third occurred after his son, who worked in the same factory, returned home without changing his work clothes. He had no past or family history of eczema, rhinitis or asthma. On admission he was symptom-free, with lung function tests within predicted limits. Chest radiograph showed no abnormalities. Skin prick tests with twenty-three common inhalant and food antigens, as well as with ampicillin and related substances, gave no reactions. Inhalation testing Occupational-type dust exposure was performed for 30 min as described by Davies. Hendrick & Pepys (1974). On the control day he was exposed without reaction to the dust of well-dried lactose powder by tipping 250 g from one tray to another in a 6 0 m^ enclosed chamber. On the following day, he was exposed to the dust from a mixture of 10 mg pencillin G added to 250 g lactose. A reaction developed 16 hr later when he was awakened during the night by wheezing and breathlessness associated with a marked fall in FEVj {Fig. 2). Both symptoms and measurements of FEV, were improved the following morning, and the FEV, had returned to pre-test values by mid-day. This pattern of normal lung function during the afternoon and evening
00 Doy 1
Doy 2
Day 3
00,00
Day A
Fig. 2. Inhalation test (occupational type) with penicillin G in lactose. (C) Control; (T) test.
216
A.J. Newman Taylor et al.
followed by nocturnal and early morning symptoms associated with falls in FEV, persisted for 4 days and nights, but resolved on oral corticosteroid treatment. He has remained free of symptoms with normal lung function away from his previous place of work for over 2 years. Patient 3 Patient 3, a 31 -year-old man, had worked as an offset printer for 2 years. He had never smoked cigarettes and had no previous history of chest complaints. He had a 3 month history of cough and breathlessness, worst at night, which woke him from sleep. His symptoms tended to increase in severity during the working week, but persisted when away from work at weekends, only resolving completely during a 2 week holiday. He had no past or family history of eczema, hay fever or asthma. Chest radiograph was normal and lung function tests prior to inhalation testing were within predicted limits. Skin prick tests with twenty-three common inhalant and food antigens were negative. Occupational exposure Because the specific occupational agent responsible for his asthma had not been identified, regular PEFR measurements were made before, during and following the first day of his return to work after a 2 week holiday. No significant variation in PEFR was observed prior to his return to work. During the 8 hr shift on the following day, his PEFR fell (Fig. 3). He was twice awakened during the night by wheezing attacks 500 rAOO
E 300
200
100
J
12 00
12 00
12 00
12 00
00.00 00.00 0000 Control doy Day 1 Day 2 Day 3
Fig. 3. Effects on PEFR of return to work. (ES!) Work.
associated with further falls in PEFR. His symptoms and PEFR had improved by morning, but without further occupational exposure he was again awakened twice during the following night and early morning with episodes of wheezing, with decreases in PEFR. This pattern of nocturnal asthmatic attacks with improvement in symptoms and PEFR continued over a period of 1 week before resolving spontaneously. Patient 4 Patient 4, a 32-year-old female nursing auxiliary, had suffered from hay fever since early childhood, as well as short episodes of wheezing provoked by 'colds' and expo-
Recurrent-asthmatic reactions and bronchial provocation tests
217
sure to house dust. She had never smoked. Within 6 months of working on a renal dialysis unit she developed severe and frequent wheezy attacks from which she would require up to 2 weeks before recovering fully. Between attacks she remained well, though occasionally she was mildly wheezy. Pulmonary function tests and chest radiographs were normal when she was without symptoms. Skin prick tests with twelve common allergens gave immediate reactions to grass pollen, house dust and the house dust mite (D. pteronyssinus). Inhalation testing On the control day the patient was tested by exposure to water, which she brushed on to a board. On the test day she carried out the same manoeuvre with a 25% solution of formalin for 8 min (Hendrick & Lane, 1977). No significant change in lung function followed her exposure to water. Exposure to formalin provoked a non-immediate asthmatic reaction, the maximum fall in PEFR occurring in the early hr of the following morning {Fig. 4). The asthma continued for 8 days, during which time her airflow obstruction was symptomatically and functionally more severe during the night. 500 r-
(C)
(T)
400
300
200
100
J
L
-J
\
I
L
J
I
12 00^ 12.00 12.00 12.00 12.00 12.00 12 00 12 00
00,00 00.00 00.00 0 0 0 0 00.00 00.00 00.00 0 0 0 0 Dayi Day 2 Day 3 Doy 4 Doy 5 Day 6 Doy 7 Day 3
Fig. 4. Inhalation test {occupational type) to formalin. (C) Control; (T) test.
Discussion In each of the four patients described in this report a single short exposure elicited respiratory reactions which recurred on several successive nights without any further exposure to the causal agent. Although this has been described previously (Gandevia & Milne, 1970; Mitchell, 1970), measurements of lung function have only been made during the nocturnal reactions in one other study (Davies et al, 1976). All the respiratory reactions described in this report were characterized by wheezing and breathlessness and associated with reversible fails in PEFR or FEV,, suggesting the diagnosis of asthma. Our first patient had biopsy-proven fibrosing alveoiitis, but measurements of her single breath carbon monoxide gas transfer at times when her ventilatory function was impaired showed no significant change. This implies that the reaction to the inhaled budgerigar serum was primarily asthmatic in nature, although our measurements cannot exclude a coexisting alveolar reaction. The factors responsible for nocturnal asthmatic attacks have yet to be identified.
218
A. J. Newman Taylor et al.
Clark & Hetzel {1977) were unable to demonstrate any relationship between nocturnal asthma and house dust mite allergy or to recumbency in bed at night. They did find a definite association with sleep. The PEFR fell during sleep whatever time this occurred in a 24 hr period. In a study of bronchial lability in asthmatic and bronchitic patients, de Vries et al. (1962) found that up to thirty-two times less histamine was required to elicit a given fall in FEV, at midnight and 04.00 hours than during the rest of the day. The relationship between sleep and circadian variation in endocrine secretions has led to suggestions that airways calibre may be influenced by the fluctuations in circulating hormone levels. Soutar et al. (1975) eliminated the normal circadian variation of plasma cortisol in a group of asthmatic patients by continuous infusion of this hormone. This did not prevent falls in night time PEFR, implying that diurnal changes in plasma cortisol were not responsible for temporally related airway narrowing. However, it is possible that nocturnal asthmatic reactions may be a consequence of a decrease in autonomic support of labile airways during sleep. Soutar, Carruthers & Pickering (1977) found a close relationship between the fall in PEFR during the night and the decrease in urinary catecholamine excretion in all but one of the seven asthmatic patients. Whether elimination of this diurnal variation in circulating catecholamines would prevent nocturnal asthma has still to be demonstrated. In our first patient the nocturnal asthmatic attacks provoked by contact with budgerigars recurred after she was prescribed the beta adrenoceptor-blocking agent propranolol. When this treatment was stopped, the nocturnal asthma ceased. It is possible that the recurrent nocturnal asthmatic reactions observed in our patients were the results of increased lability, initially provoked by an immunological reaction in the airways, which became manifest during sleep when autonomic support for the airways was at a minimum. Immediate asthmatic reactions follow within minutes of exposure to the causal agent and readily suggest the cause of the reaction to both patient and doctor. Nonimmediate or late asthmatic reactions develop several hours after exposure, when the patient is often no longer in contact with the provoking agent. This makes the association between causal agent and asthmatic attack diflicult to recognize. Wheezing and chest tightness, which are well recognized symptoms of asthma, are prominent in immediate reactions. However, patients with non-immediate reactions may only complain of unusual breathlessness on exertion or cough. The relationship between exposure and reaction in such cases, particularly if the causal agent is met in the workplace, may only be appreciated when the patient is away from exposure at weekends or on holiday. In each of the four patients described in this report, asthmatic symptoms, particularly at night, persisted for several successive days despite avoidance of exposure to the causal agent. This made identification of the responsible agent particularly difficult. The diagnosis was only made with certainty by inhalation testing with the suspected agent. This provoked the recurring nocturnal asthmatic reactious of which the patient has complained. References CLARK, T.J.H. & HETZEL, M . R . (1977) Diurtial variation of Asthma. British Journal of Diseases of the Chest, 71, 87. 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. Clinical Allergy, 4, 227. DAVIES, R.J., GREEN, M . & SCHOFIELD, N.MCC. (1976) Recurrent nocturnal asthma after exposure to grain dust. American Review of Respiratory Disease, 114, 1011.
Recurrent-athmatic reactions and bronchial provocation tests
219
GANDEVIA. J. & MILNE, J. (1970) Occupational asthma and rhinitis due to Western Red Cedar (Thuja plicata) with special reference to bronchial reactivity. British Journal of I>,du.strial Medicine, 11, , D.J. & LANE, D.J. (1977) Occupational formalin asthma. British Journal of Industrial
Medicine,
3 4 , 11.
MITCHELL, C. (1970) Occupational asthma due to Western or Canadian Red Cedar {Thuja plicata) Medical Jimrnal Iff AiLstralia, 2, 233.
PEPYS J. & HUTCHCROFT. B.J. (1975) Bronchial provocation tests in aeiiologic diagnosis and analysis of aslhma. American Review of Respiratory Disease, 112, 829. SALTER, H . H . (1882) Asthma: Its pathology and Treatment, 1st edn, p. 33. William Wood SOUTAR C.A., COSTELLO. J.. IJADULO, O . & TURNER WARWICK, M . (1975) Nocturnal and morning
asthma: relationship to plasma corlicosteroid and response to cortisol infusion Thorax 30 436 SOUTAR, C.A., CARRUTHERS. M . & PICKERING, C . A . C . (1977) Nocturnal asthma and urinary adrena-
line and noradrenaline excrelion. Thorax, 32, 677. VHIES, K . DE, GOEI. J.T. BOOIJ-NOORD, H. & ORIE, N . G . M . (1962) Changes during 24 hours in the
lung funcljon and histamine hyperactivity of ihe bronchial tree in asthmatic and bronchitic paiienis. International Archives of Allergy and Applied Immunology, 20, 93.
