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Bronchial hyperreactivity and cough induced by angiotensin-converting enzyme-inhibitor therapy
Correspondence
Ketotifen and systemic mastocytosis To the Editor: The article by Kettelhut et al.’ demonstrated that ketotifen, 2 mg daily, offers no advantage over hydroxyzine in the treatment of pediatric mastocytosis. However, I wonder whether the dose of ketotifen used in their study is indeed the optimal dose. I have followed a 42-year-old white man with systemic mastocytosis for several years. During the past 12 months, his cutaneous symptoms were fairly well controlled by doxepin, 50 mg, four times a day (q.i.d.), ranitidine, 150 mg three times a day, and hydroxyzine, 50 mg at bedtime. However, neuropsychiatric symptoms such as short attention span and inability to concentrate and diarrhea are not controlled by the above medications. Commercially available cromolyn capsules, up to 200 mg q.i.d. for a few weeks, only alleviated gastrointestinal symptoms. A compassionate-use trial of ketotifen, 2 mg q.i.d. daily, controlled his cutaneous, neuropsychiatric, and gastrointestinal symptoms. Flare up of symptoms always occurred if ketotifen was decreased to 6 mg daily; 24-hour urinary histamine level before the initiation of ketotifen therapy was 228 p.gl24 hours and decreased to 116 pgl24 hours after 2 weeks of ketotifen therapy. It further decreased to 64 p,g/24 hours after 6 weeks of ketotifen therapy, 8 mg daily. My patient wrote “Dear Dr. Ting: I would like to thank you for your help and patience in helping me to better manage my mastocytosis. The Zaditen has worked a miracle on me. I feel like a person who is on a furlough after being in a chemical prison for over 20 years. I don’t think I have felt better since my senior year in high school 25 years ago. I have finished my secondmanuscript in 2 months and starting on the third. Again thank you. signed RE.” In 1983 Czarnetzki’ reported in a double-blind, crossover study that ketotifen, 2 mg daily, significantly reduced the daily symptom scores of pruritus and whealing; however, none of the 10 adult patients with u&aria pigmentosa that she studied had gastrointestinal or neuropsychiatric symptoms. In addition, no urinary histamine data were available to augment her clinical findings. It appears that larger doses of ketotifen are needed to control this patient’s multisystem symptoms that are presumably related to the pharmacologic effects of released mediators from mast cells.’ A large-scale, clinical, doubleblind study should be done in the future to evaluate the efficacy/safety of high-dose ketotifen in patients with systemic mastocytosis who have multisystem symptoms and fail to respond to H, and H, antagonists and oral cromo1yn.4 Stanislaus Ting, MD 1141 Mall Drive Las Cruces, NM 88001
818
REFERENCES Kettelhut BV, Berkebile C, Bradley D, Metcalfe DD. A doubleblind, placebo-controlled,crossovertrial of ketotifen versushydroxyzine in the treatmentof pediatric mastocytosis.J ALLERGY CLIN IMMUNOL 1989;83:866.
Czarnetzki BM. A double-blind, crossover study of the effect of ketotifen in u&aria pigmentosa. Dermatologica 1983;166: 44. Lewis RA. Mastocytosis. J ALLERGY CLIN IMMUNOL 1984;74: 755. Lichtenstein LM, Fauci AS. Current therapy in allergy, immunology, and rheumatology. Toronto: BC Decker, 198% 198651.
Bronchial hyperreactivity and cough induced by angiotensin-converting enzyme-inhibitor therapy To the Editor: Cough is a recognized side effect of angiotensinconverting enzyme inhibitors (ACEIs). I-3The mechanism(s) of action of ACEI-induced coughing remain(s) unclear. Recent studies suggest that ACEIs increase the sensitivity of cough reflex.+ * The existence of bronchial hyperreactivity in patients who cough after receiving ACE1 is controversial. There have been occasional case reports of increased wheezing associated with ACE1 therapy in subjects with asthma. The results of inhalation challenges in patients with no prior history of asthma have been mixed with a study of negative methacholine challenges6 and studies of positive methacholine’ and histamine* challenges in patients with prior bronchial hyperreactivity, which increased after ACE1 treatment.8 Recently, we have studied two hypertensive sisters without asthma, aged 63 and 65 years, respectively. They developed persistent cough during captopril treatment, which resolved when the therapy was stopped. Two months after the resolution of coughs, we rechallenged both patients with captopril, 150 mg daily, for the following 5 weeks. Both lung function and methacholineinhaled tests were performed 7 days before the challenge and, later, were measured weekly for the next 9 weeks. At the same time, patients daily monitored morning and evening peak expiratory flow rate and recorded the occurrence of cough and other respiratory symptoms on a scale of 0 to 3. A few days after the captopril rechallenge, both patients complained of a dry cough, which progressively increased until the drug was withdrawn. They made no reference to dyspnea or wheezes. Before rechallenge, lung function and methacholineinhaled tests revealed no abnormalities. Two weeks after the introduction of captopril, one patient had a significant fall in airway conductance that did not return to normal
VOLUME NUMBER
.----. .-16 15 14 13 2
12
‘,
II
2
IO
Correspondence
65 4
. P*TIENT1 \I PATIENT 2 ----lI / I /’ // I I : I I : I I ? I I / II /’ I 1’ I I .I 8: I II I /’ I / I I 7’ I I I , /’ \ .w:_ --we/J
819
bradykinin and other peptides participating in inflammation. Therapy for the inhibition of ACE could potentiate the effects of these substances in airways.“~ I’ Consequently, we hypothesize that ACE-inhibitory therapy causes cough and bronchial hyperreactivity in susceptible patients and that both effects can enhance each other. Moreover, ACE1 could be a powerful pharmacologic probe in the further investigations of mechanisms of cough and bronchial hyperreactivity. Miguel Hinojosa, MD Santiago Quirce, MD Jestis Puyana, MD Department of Allergy Javier Codina, MD Department of Cardiology
Iwk
4 ONSET
2wk
3wk
4wk
5uk
6wk
7wk
8wk
Sergio Garcia Rull, MD Department of Pneumology Servicio de Alergia Hospital Ram& y Cajal Carretera Colmenar Km. 9,l 28034 Madrid, Spain
9wk
4 WrrnDRAwAL
FIG. 1. Cough score and provocative dose of methacholine causing a fall in FEV, values during captopril challenge and after withdrawal of the drug.
REFERENCES I. SesokoS, Kaneyo Y. Cough associatedwith the use of cap-
topril. Arch Intern Med 1985;145:1.524. 2. Coulter DM, EdwardslR. Cough associatedwith captopril and
values until therapy was stopped. Both patients demonstrated marked bronchial hyperreactivity in the second week of treatment, as reflected by the provocative concentration of methachcrline causing a 20% fall in FEV, values (Fig. I). Bronchial responses did not become normal until 1 month after Icaptopril withdrawal. Peak expiratory flow rates and the other lung function tests were normal. Cough is a prominent symptom of bronchial asthma and, indeed, may be the only symptom that is first observed. It is known that cough receptors are functionally different from irritant receptors and also that cough may occur independently of bronchoconstriction in subjects with asthma. However, cough and bronchoconstriction reflexes are closely related and can potentiate each other. However, neither is entirely dependent on the other for its action. Coughing causes large variations in intrathoracic pressure that deforms the airways. Such deformation will produce a further stimulation of the deeper cough receptors, leading to more coughing and bronchoconstriction. This vicious circle explains how coughing may precipitate bronchoconstriction in bronchial-hyperreactive individuals, such as subjects with stable asthma.’ In fact, a characteristic of the patients with cough associated with ACEI compared with the control subjects in twcl previous studies’, * was the initial bronchial hyperreactivity of the former group. It is worth noting that neither of our patients had prior bronchial hyperreactivity; nevertheless, a clear relationship could be established between captopril treatment and the developmen: of both bronchial hyperreactivity and cough. ACE is identical to kininase II, an enzyme that degradates
enalapril. Br Med J 1987;294:1521. 3. SemplePF, Herd GW. Cough and wheezecausedby inhibitors
of angiotensin-convertingenzyme. N Engl J Med 1986;314:61. 4. Fuller RW, Choundry NBC. Increasedcough reflex associated
with angiotensin-convertingenzyme-inhibitor cough. Br Med J 1987;295:1025. 5. Morice AH, Brown MJ, Lowry R, Higenbottam T. Angiotensin-converting enzyme and the cough reflex. Lancet 1987;2:1116. 6. Town GI, Hallwright CP, Mailing T. Angiotensin-converting enzyme inhibitors and cough. N Z Med J 1987;100:161. I. Bucknall CE, Neilly CB, Carter R, StevensonRD, SemplePF. Bronchial hyperreactivity in patientswho cough after receiving angiotensin-converting enzyme inhibitors. Br Med J 1988; 2%:86. 8. Kaufman J, CasanovaJE, Riendl P, Schlueter DP. Bronchial
hrperreactivity and cough due to angiotensin-convertingenzyme inhibitors. Chest 1989;95:544. 9. Cough and wheezein asthma:are they interdependent?Lancet 1988;1:447. 10. Fuller RW, Dixon CMS, Cuss FMC, Barnes PJ. Bradykinininduced bronchcconsmctionin humans. Am Rev Respir Dis 1987;135:176. II. Femer RE, SimpsonJM, Rawlins MD. Effects of intradermal bradykinin after inhibition of angiotensin-convertingenzyme. Br Med J 1987;294:1119-20.
Pollinosis
in Brazil:
Changing
concepts
To the Editor: Soon after I began to practice in Curitiba, Brazil, it became clear that some patients had symptoms of classic seasonal allergic rhinitis and conjunctivitis during the spring
Ketotifen and systemic mastocytosis To the Editor: The article by Kettelhut et al.’ demonstrated that ketotifen, 2 mg daily, offers no advantage over hydroxyzine in the treatment of pediatric mastocytosis. However, I wonder whether the dose of ketotifen used in their study is indeed the optimal dose. I have followed a 42-year-old white man with systemic mastocytosis for several years. During the past 12 months, his cutaneous symptoms were fairly well controlled by doxepin, 50 mg, four times a day (q.i.d.), ranitidine, 150 mg three times a day, and hydroxyzine, 50 mg at bedtime. However, neuropsychiatric symptoms such as short attention span and inability to concentrate and diarrhea are not controlled by the above medications. Commercially available cromolyn capsules, up to 200 mg q.i.d. for a few weeks, only alleviated gastrointestinal symptoms. A compassionate-use trial of ketotifen, 2 mg q.i.d. daily, controlled his cutaneous, neuropsychiatric, and gastrointestinal symptoms. Flare up of symptoms always occurred if ketotifen was decreased to 6 mg daily; 24-hour urinary histamine level before the initiation of ketotifen therapy was 228 p.gl24 hours and decreased to 116 pgl24 hours after 2 weeks of ketotifen therapy. It further decreased to 64 p,g/24 hours after 6 weeks of ketotifen therapy, 8 mg daily. My patient wrote “Dear Dr. Ting: I would like to thank you for your help and patience in helping me to better manage my mastocytosis. The Zaditen has worked a miracle on me. I feel like a person who is on a furlough after being in a chemical prison for over 20 years. I don’t think I have felt better since my senior year in high school 25 years ago. I have finished my secondmanuscript in 2 months and starting on the third. Again thank you. signed RE.” In 1983 Czarnetzki’ reported in a double-blind, crossover study that ketotifen, 2 mg daily, significantly reduced the daily symptom scores of pruritus and whealing; however, none of the 10 adult patients with u&aria pigmentosa that she studied had gastrointestinal or neuropsychiatric symptoms. In addition, no urinary histamine data were available to augment her clinical findings. It appears that larger doses of ketotifen are needed to control this patient’s multisystem symptoms that are presumably related to the pharmacologic effects of released mediators from mast cells.’ A large-scale, clinical, doubleblind study should be done in the future to evaluate the efficacy/safety of high-dose ketotifen in patients with systemic mastocytosis who have multisystem symptoms and fail to respond to H, and H, antagonists and oral cromo1yn.4 Stanislaus Ting, MD 1141 Mall Drive Las Cruces, NM 88001
818
REFERENCES Kettelhut BV, Berkebile C, Bradley D, Metcalfe DD. A doubleblind, placebo-controlled,crossovertrial of ketotifen versushydroxyzine in the treatmentof pediatric mastocytosis.J ALLERGY CLIN IMMUNOL 1989;83:866.
Czarnetzki BM. A double-blind, crossover study of the effect of ketotifen in u&aria pigmentosa. Dermatologica 1983;166: 44. Lewis RA. Mastocytosis. J ALLERGY CLIN IMMUNOL 1984;74: 755. Lichtenstein LM, Fauci AS. Current therapy in allergy, immunology, and rheumatology. Toronto: BC Decker, 198% 198651.
Bronchial hyperreactivity and cough induced by angiotensin-converting enzyme-inhibitor therapy To the Editor: Cough is a recognized side effect of angiotensinconverting enzyme inhibitors (ACEIs). I-3The mechanism(s) of action of ACEI-induced coughing remain(s) unclear. Recent studies suggest that ACEIs increase the sensitivity of cough reflex.+ * The existence of bronchial hyperreactivity in patients who cough after receiving ACE1 is controversial. There have been occasional case reports of increased wheezing associated with ACE1 therapy in subjects with asthma. The results of inhalation challenges in patients with no prior history of asthma have been mixed with a study of negative methacholine challenges6 and studies of positive methacholine’ and histamine* challenges in patients with prior bronchial hyperreactivity, which increased after ACE1 treatment.8 Recently, we have studied two hypertensive sisters without asthma, aged 63 and 65 years, respectively. They developed persistent cough during captopril treatment, which resolved when the therapy was stopped. Two months after the resolution of coughs, we rechallenged both patients with captopril, 150 mg daily, for the following 5 weeks. Both lung function and methacholineinhaled tests were performed 7 days before the challenge and, later, were measured weekly for the next 9 weeks. At the same time, patients daily monitored morning and evening peak expiratory flow rate and recorded the occurrence of cough and other respiratory symptoms on a scale of 0 to 3. A few days after the captopril rechallenge, both patients complained of a dry cough, which progressively increased until the drug was withdrawn. They made no reference to dyspnea or wheezes. Before rechallenge, lung function and methacholineinhaled tests revealed no abnormalities. Two weeks after the introduction of captopril, one patient had a significant fall in airway conductance that did not return to normal
VOLUME NUMBER
.----. .-16 15 14 13 2
12
‘,
II
2
IO
Correspondence
65 4
. P*TIENT1 \I PATIENT 2 ----lI / I /’ // I I : I I : I I ? I I / II /’ I 1’ I I .I 8: I II I /’ I / I I 7’ I I I , /’ \ .w:_ --we/J
819
bradykinin and other peptides participating in inflammation. Therapy for the inhibition of ACE could potentiate the effects of these substances in airways.“~ I’ Consequently, we hypothesize that ACE-inhibitory therapy causes cough and bronchial hyperreactivity in susceptible patients and that both effects can enhance each other. Moreover, ACE1 could be a powerful pharmacologic probe in the further investigations of mechanisms of cough and bronchial hyperreactivity. Miguel Hinojosa, MD Santiago Quirce, MD Jestis Puyana, MD Department of Allergy Javier Codina, MD Department of Cardiology
Iwk
4 ONSET
2wk
3wk
4wk
5uk
6wk
7wk
8wk
Sergio Garcia Rull, MD Department of Pneumology Servicio de Alergia Hospital Ram& y Cajal Carretera Colmenar Km. 9,l 28034 Madrid, Spain
9wk
4 WrrnDRAwAL
FIG. 1. Cough score and provocative dose of methacholine causing a fall in FEV, values during captopril challenge and after withdrawal of the drug.
REFERENCES I. SesokoS, Kaneyo Y. Cough associatedwith the use of cap-
topril. Arch Intern Med 1985;145:1.524. 2. Coulter DM, EdwardslR. Cough associatedwith captopril and
values until therapy was stopped. Both patients demonstrated marked bronchial hyperreactivity in the second week of treatment, as reflected by the provocative concentration of methachcrline causing a 20% fall in FEV, values (Fig. I). Bronchial responses did not become normal until 1 month after Icaptopril withdrawal. Peak expiratory flow rates and the other lung function tests were normal. Cough is a prominent symptom of bronchial asthma and, indeed, may be the only symptom that is first observed. It is known that cough receptors are functionally different from irritant receptors and also that cough may occur independently of bronchoconstriction in subjects with asthma. However, cough and bronchoconstriction reflexes are closely related and can potentiate each other. However, neither is entirely dependent on the other for its action. Coughing causes large variations in intrathoracic pressure that deforms the airways. Such deformation will produce a further stimulation of the deeper cough receptors, leading to more coughing and bronchoconstriction. This vicious circle explains how coughing may precipitate bronchoconstriction in bronchial-hyperreactive individuals, such as subjects with stable asthma.’ In fact, a characteristic of the patients with cough associated with ACEI compared with the control subjects in twcl previous studies’, * was the initial bronchial hyperreactivity of the former group. It is worth noting that neither of our patients had prior bronchial hyperreactivity; nevertheless, a clear relationship could be established between captopril treatment and the developmen: of both bronchial hyperreactivity and cough. ACE is identical to kininase II, an enzyme that degradates
enalapril. Br Med J 1987;294:1521. 3. SemplePF, Herd GW. Cough and wheezecausedby inhibitors
of angiotensin-convertingenzyme. N Engl J Med 1986;314:61. 4. Fuller RW, Choundry NBC. Increasedcough reflex associated
with angiotensin-convertingenzyme-inhibitor cough. Br Med J 1987;295:1025. 5. Morice AH, Brown MJ, Lowry R, Higenbottam T. Angiotensin-converting enzyme and the cough reflex. Lancet 1987;2:1116. 6. Town GI, Hallwright CP, Mailing T. Angiotensin-converting enzyme inhibitors and cough. N Z Med J 1987;100:161. I. Bucknall CE, Neilly CB, Carter R, StevensonRD, SemplePF. Bronchial hyperreactivity in patientswho cough after receiving angiotensin-converting enzyme inhibitors. Br Med J 1988; 2%:86. 8. Kaufman J, CasanovaJE, Riendl P, Schlueter DP. Bronchial
hrperreactivity and cough due to angiotensin-convertingenzyme inhibitors. Chest 1989;95:544. 9. Cough and wheezein asthma:are they interdependent?Lancet 1988;1:447. 10. Fuller RW, Dixon CMS, Cuss FMC, Barnes PJ. Bradykinininduced bronchcconsmctionin humans. Am Rev Respir Dis 1987;135:176. II. Femer RE, SimpsonJM, Rawlins MD. Effects of intradermal bradykinin after inhibition of angiotensin-convertingenzyme. Br Med J 1987;294:1119-20.
Pollinosis
in Brazil:
Changing
concepts
To the Editor: Soon after I began to practice in Curitiba, Brazil, it became clear that some patients had symptoms of classic seasonal allergic rhinitis and conjunctivitis during the spring