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Home , Antihistamine, Cetirizine, H1 antagonist

Eur Resplr J 1992, 5, 1137-1142 SHORT REVIEW

Antihistamines in the treatment of

J. Bousquet, Ph . Godard, F. B. Michel

Antihistamines in the treatmelll of asthma. J. Bousquet, Ph. Godard, F.B. Michel. Clinique des Maladies Respiratoire, ABSTRACT: Is an Important mediator of asthma. The new anti­ Hapital l'Aiguelon gue, Centre which block histamine at the Hlreceptor level also possess some anti­ Hospitalier Universitaire, Montpellier, allergic properties. At cut·rent dosages they appear to be safe. These France are effective In the treatment of and but their role in Correspondence: J. Bousquet asthma is still under Investigation. At a dose higher than usually recommended, Clinique des Maladies Respiratoires they were shown to block exercise-induced asthma and, inconstantly, the early H6pital l'Aiguelongue phase reaction after challenge. Their effect on the late phase allergic Centre Hospitalier Universitaire reaction as well as thei r clinical during trials is, however, less co nsist­ 34059-Montpellier-Cedex, France Keywords: Anti-histamines, asthma, ent. The indication of H1-blockers in the treatment of asthma is therefore lim­ ited, especially since doses higher than recommended may lead to adverse H 1-blockers, histamine reactions. Received: May 12 1992 Eur Respir J., 1992, 5, 1137-1142. Accepted after revision June 16 1992

Antihistamines, which block histamine at the H1- levels are increased in the bronchoalveolar lavage level, have been used for the treatment of (BAL) fluid of asthmatics [9]. Moreover, a signifi­ allergic and , conjunctivitis and cant correlation has been demonstrated between non­ diseases, in which histamine has been shown to play specific bronchial hyperreactivity and histamine levels an important role. in BAL fluid [9]. In asthma, the use of antihistamines is still under Histamine can induce the secretion of mucus by investigation. Not only do some investigators deny bronchial glands, cause extravasation of plasma pro­ that antihistamines are beneficial but ScHULLER [1] pro­ teins leading to airways mucosal oedema, contract the posed that they might even be harmful. Based on a airway f6] and may play a role in the very small number of asthmatic children, who appar­ immunomodulation of the (lgE) ently deteriorated during treatment with a immune response r10], as well as in the regulation of possessing both an H1-blocking activity and anti­ the airway inflammation by the activation of epithe­ properties, her report lead to the contrain­ lial cells and macrophages and possibly by inducing dication of these drugs in asthma in the US. smooth muscle hyperplasia. However, a Position Paper issued by the American The inhalation of histamine induces a broncho­ Academy of and Immunology [2] proposed constrictive response in most subjects, but asthmatic that the drugs are safe and may be used in the treat­ patients are hyperreactive to histamine [11 ]. ment of asthma. The efficacy of an tihistamines in asthma needs to be reconsidered, as new drugs largely devoid of side-effects have been available for the past Antihistamines possess some "anti-allergic" properties 10 yrs [3-5]. Antihistamines block histamine at its H1-receptor level but many drugs possess other properties that may Points in favour of a r ole of antihistamines in be relevant for their efficacy [12]. and asthma reduce, in a dose-dependent manner, the release of from human dispersed lung cells and reduce the release of histamine and prostaglandin Histamine plays a role in the pathogenesis of asthma D2 (PGD2) during nasal challenge with allergen. After allergen challenge, cetirizinc decreases the eosi­ Histamine plays a role in the mechanisms of asthma nophil influx into the skin but it is not yet clear if it [6). It is released during the early and late phase has the same effect on nasal and bronchial cells. Al­ allergic reactions following bronchial challenge with though the exact significance of these properties is still allergen [7]; mast cells are present in lhe biopsies of not fully understood, they might be involved in allergic and nonallergic asthmatics [8] and histamine asthma. 1138 J. BOUSQUET, Ph. GODARD, F.B. MICHEL

Links between asthma and rhinitis specifically examining this bronchodilating effect are lacking and long-term clinical studies of antihistamines Many patients with present both in asthma suggest that this activity disappears after one rhinitis and asthma. Many patients with allergic rhini­ or two weeks. tis alone have an increased nonspecific bronchial Thus, the bronchodilating activity of antihistamines hyperreactivity [13]. Finally, is thought to be may be limited in intensity and duration and, with our a causative factor in asthma [14]. Although the exact current knowledge, it does not support their use in links between the nose and the lung are far from asthma. understood, it has been proposed that the treatment of the nasal symptoms may improve asthma. Provocative challenges

Points against a role of antihistamines in asthma Exercise and cold air challenges. Several studies have been performed to assess the protective effect of anti­ histamines in exercise-induced asthma and related chal­ Histamine is only one of the mediators of asthma and lenges such as nebulized water, hypertonic or does not explain chronic inflammation of the airways cold air (table 1) [27-40]. Many of these studies show that antihistamines result in significant protec­ Histamine is one of the mediators of "allergic" and/ tion, but in some studies the effect, although signifi­ or "asthmatic" inflammation. It is likely to play a role cant, is very small and does not appear to be clinically in the spasmogenic phase of asthma but its importance relevant. Moreover, in such situations, calcium antago­ in chronic inflammation of the airways remains to be nists and a-blockers were found to be effective in the determined. Moreover, mast cells and are laboratory but had little or no effect when they were not the only cell types involved in airways inflamma­ administered to patients in an attempt to improve tion in asthma [15] and many other cells, mediators, asthma. toxic , cytokines and growth factors appear to be more important than histamine and/or metachro­ Allergen challenge. Many studies have also been per­ matic cells. Finally, asthma is not only an inflamma­ formed in allergic asthmatics in order to prove the tory disease but remodels the airways inducing efficacy of antihistamines during the early and late permanent abnormalities (16). Thus, it appears that phase allergic reactions. However, there have been antihistamines may only be partly effective in the discrepancies in the results published. Terfenadine (41, treatment of chronic asthma and poorly effective in 42] and [43 ], but not loratadine [44] and either long-standing asthma or in the most severe [45), have been shown to reduce the early patients. phase reaction, but even with terfenadine the response was usually small and varied considerably between subjects. Anti-allergic drugs are usually poorly effective in the Studies attempting to demonstrate an effect on the treatment of severe asthma late phase reaction have been carried out on a very small number of patients and results are highly vari­ Sodium cromoglycate appears to be more effective able [ 46-48). At best, the effect is again small. It in young asthmatics and in patients with mild asthma. is, therefore, impossible to ascribe any clinically rel­ It is usually less effective in the treatment of severe evant protective effect of antihistamines on the late asthmatics (17]. The results obtained with are phase reaction. less consistent but similar conclusions may be drawn [18) . Nonspecific airway challenge. Nonspecific bronchial hyperreactivity is a cardinal feature of asthma and drugs such as inhaled and, to a lesser Clinical relevance of antihistamines in asthma extent, sodium or sodium cromoglycate have been found to reduce the magnitude of histamine and/or inhalation challenge. Histamine Bronchodilating activity of antihistamines challenge has no value for testing the effect of anti­ histamines on nonspecific bronchial hyperreactivity The bronchodilating activity of a single dose of an­ depending on the of the drugs. Stud­ tihistamine was reported in the early 1980s [19) and ies performed using methacholine challenge did not confirmed in some but not all studies [20-26]. Many show any difference before and after treatment studies found a significant difference between the although it may be argued that the duration of the bronchodilating activity of the placebo and the active studies was too short to observe any significant effect drug, but they do not appear to be clinically relevant, [49-51]. Antihistamines can block challenge with since differences are usually small. In studies show­ adenosine [52] or -activating factor (PAF) [53] ing a significant effect of antihistamines, there was but the clinical relevance of such challenges needs to no dose-response effect [26]. Long-term studies be characterized. ANTIHISTAMINES IN ASTHMA TREATMENT 1139

Table 1. - Effect of antihistamines in exercise challenge and related challenges First Ref. Drug Dose Duration n Group of Challenge p Clinical author mg patients relevance

AzEVEDO (27] T 180 1 dose 30 UNDW <0.001 Yes BACKER (28] A 30 o.d. 22 days 20 Children Exercise NS Yes BAD!ER [29] T 120 b.i.d. 1 week 11 Adult Hyperventilation <0.001 Yes in cold air BARBERIO (30] T Variable 1 dose 14 Children Exercise NS Yes BEWTRA (31] T 240 1 dose 12 ? Cold air <0.05 No CLEE [32] A 10 o.d. 1 week 9 19-33 yrs Exercise <0.05 Yes FINNERTY (33] T 180 1 dose 10 Adults Exercise =0.03 Abstract FJNNERTY (34] T 180 1 dose 9 21-40 yrs Hypertonic saline <0.001 Yes FlNNEY [35] T 180 1 dose 12 Adults Nonisotonic aerosol <0.02 Yes GHOSH (36] c 10 b.i.d. 1 week 12 Adults Exercise NS Yes GoNo [37] c 5, 10, 20 1 dose 16 25-52 yrs Exercise + cold air NS Yes HOPP (38] T 240 1 dose 12 19-42 yrs UNDW <0.02 NS results* O'HJCKEY (39] T 120 2 doses 10 Adults Hypertonic saline <0.02 Minimal PATEL [40] T 180 1 dose 10 16-50 yrs Exercise <0.01 Yes UNDW: ultrasonized distilled water; T: terfenadine; A: astemizole; C: cetirizine; Ns: nonsignificant; •: when recalculated.

Clinical studies commonly accepted that patients should present a reversibility of the airway obstruction after the inha­ Only studies performed during seasonal or perennial lation of ~ 2 -. However, in grass asthma make it possible to assess the value of anti­ asthma, few patients have a reversible airways obstruc­ histamines in the treatment of asthma. Many incon­ tion of > 15% of forced expiratory volume in one clusive studies in both seasonal and perennial asthma second (FEV1). have been performed but never published and this rep­ The grass pollen season lasts 6-8 weeks in most resents a major gap in our knowledge of the efficacy countries but it is highly heterogeneous, pollen counts of antihistamines in asthma. varying daily and from year to year. The tree pollen season (birch primarily) is shorter, usually intense in terms of pollen counts and symptoms, but highly vari­ Seasonal asthma able from year to year. The ragweed pollen season is the most constant in terms of onset, peak and Difficulties in designing the studies. There are duration but it lasts only 4--6 weeks. It is, therefore, several drawbacks in the studies examining the effects difficult to propose crossover trials with washout of antihistamines in the treatment of seasonal asthma. periods between treatments. Seasonal asthma is mainly caused by and the The analysis of the data is not easy. All trials major symptoms of pollinosis are usually related to examine symptom and scores, some evalu­ rhinoconjunctivitis, with asthma occurring in the most ate the evolution of the pulmonary function tests or severe cases. There have been a number of trials peak flow rates. However, in grass pollen asthma performed in which no treatment for the nose or eyes mean peak flow rates usually show little decrease of was administered and, as a result, most of the placebo­ this interesting parameter. Ther~ is no study of non­ treated patients dropped out of the study (54-55]. specific bronchial hyperreactivity available. Nasal and ocular symptoms should be treated during any asthma trial with drugs not affecting the interpre­ Results of double-blind studies with control or placebo tation of the study. There is no commonly accepted groups. Table 2 summarizes the results of the con­ treatment for nasal or ocular symptoms during asthma trolled studies performed with cetirizine and trials and the choice depends on many parameters: terfenadine in seasonal asthma [54- 62). It must be topical or oral drugs; all patients treated identically pointed out that the doses of antihistamines were (56] or only patients who require a treatment for always greater than those administered for rhino­ severe symptoms; treatment applied during the whole conjunctivitis and, in the study of RAFFERTY et al. [60) trial or only during the peak of the season. the dose was 4.5 fold greater than recommended. If Administration of the may start before this increased dose is to become the recommended the season in a prophylactic treatment or very soon dose for asthma, the short- and long-term safety of the after the patients develop asthma. It is critical that drug should be monitored in specific studies. long-standing asthmatics should be excluded from such In two studies, the patients received no treatment for studies since antihistamines are likely to have maxi­ rhinitis and most of those under placebo dropped out mal effect on patients who have a low degree of bron­ from the study. These studies cannot be analysed fur­ chial inflammation. ther since it is unclear whether the patients dropped Inclusion criteria are not standardized but it is out because of nasal or bronchial symptoms [55, 59). 1140 J. BOUSQUET, Ph. GODARD, F.B. MICHEL

Table 2. - Controlled studies examining the efficacy of oral antihistamines In the treatment of asthma First Ref. Drug Dose Duration n Age Study Asthma Stat. Clinical author mg yrs design sign. relevance

BACKER [28] A 20 o.d. 22 days 20 fr15 DB-PC-CO Chronic NS Yes BousQUET [54] c 10, 15 b.i.d. 14 days 80 18-73 DP-PG* Pollen s Minimal BRUTMAN [55] c 15 o.d. 14 days 57 19-40 DB-PC-PG Pollen s Too many dropouts DIRKMAN [56} c 10 b.i.d. 6 weeks 43 12-74 DB-PG• Pollen s Yes DIIKSEN [57] L 10 o.d. 8 weeks 17 25-63 DB-PC-CO Chronic NS Yes KuRZEJA [58] c 10 b.i.d. ? 20 ? DB-PG• Birch pollen s ? PEDRALI (59) c 10 b.i.d. 28 days 60 ? DB-PC-PG Pollen s Too many dropouts RAFFERTY [60] T 180 t.i.d. 4 weeks 18 34.7:t5.6 DB-PC-CO Pollen s Very high dose TAYTARD [61] T 120 b.i.d. 2 weeks 46 12-53 DB-PC-CO Mite s Yes TEALE [62] T 120 1 dose 8 29-72 DB-PC Nocturnal s Minimal

A: astemizole; C: cetirizine; L: Joratadine; T: terfenadine; DB: double-blind; PC: placebo-controlled; CO: cross-over; PG: parallel group; Stat. sign.: statistical significance; Ns: nonsignificant; s: significant. *: the control group received T 60 mg b.i.d. to control nasal and ocular symptoms.

In other studies, patients received either cetirizine (20 Results of double-blind studies with control group. or 30 mg daily) or a rescue medication given to all The study of TAYTARD et al. [61] is the only published patients in the control group, terfenadine, at a dose study showing a favourable effect of antihistamines in that was suggested to be ineffective in asthma (60 mg chronic symptoms of perennial asthma. Using b.i.d.). The results of the study of BousauET et al. terfenadine at a dose of 120 mg b.i.d. in a cross-over [54] are not very convincing, possibly because the study carried out in mild asthmatics, they observed that control group was under terfenadine. Finally, there are when patients were treated with the antihistamine they only two studies published in detail showing some presented significantly less symptoms, needed signifi­ efficacy of antihistamines in asthma [56, 60]. How­ cantly less ~ 2 -agonists and presented an improvement ever, not all parameters were improved and the pul­ in pulmonary function as assessed by FEV1 and peak monary function, peak flow rates or ~ 2 - rescue flow rates. However, the improvement in pulmonary medication were similar in the treated and placebo function was small and may have little clinical rel­ groups. evance. Many other inconclusive studies have been These studies show a moderate effect of antihista­ performed but never published. mines in the treatment of seasonal asthma but, since many inconclusive studies have not been published, more data are needed before a firm conclusion can be Indications for antihistamines in asthma reached. The indications for antihistamines in the treatment Perennial asthma of asthma are still vague and more data are needed before a firm conclusion can be drawn. New studies Difficulties in designing the studies. There are also are needed to compare the efficacy of antihistamines several drawbacks in the studies examining the effects with accepted anti-asthma treatment. of antihistamines in the treatment of perennial asthma [28, 57, 60-62]. The design of the trial is critical. Asthma is a References chronic inflammatory disease leading to a remodelling of the airways. It is, therefore, suggested that anti­ 1. Schuller DE. - The spectrum of antihistamines ad­ histamines will be more effective in patients with mild versely affecting pulmonary function in asthmatic children. asthma and in the younger asthmatics. In perennial J Allergy Clin lmmunol, 1983; 71: 147-150. asthma, rhinitis and conjunctivitis are not always se­ 2. Sly RM, Kemp JP, Anderson JA et al. - The use of vere and nasal or ocular treatments are not required antihistamines in patients with asthma. Position statement by most patients. Anti-inflammatory drugs should be of the Committee on Drugs of the American Academy of carefully avoided for a long period of time, since it Allergy and Immunology. J Allergy C/in lmmunol, 1988; 83: 481-482. is unlikely that antihistamines will add significant ben­ 3. Rafferty P. - Antihistamines in the treatment of clini­ efit to inhaled corticosteroids. The duration of the cal asthma. J Allergy Clin lmmunol, 1990; 88: 647-650. run-in period is critical, since asthma is highly vari­ 4. Pierson WE, Virant FS. - Antihistamines in asthma. able. The study may be performed in parallel groups Ann Allergy, 1989; 63: 601-608. or in a cross-over manner but in the latter case the 5. Holgate ST, Finnerty JP. - Antihistamines in asthma. washout period is critical. J Allergy C/in lmmunol, 1989; 83 (2: Pt 2): 537- 547. ANTIHISTAMINES IN ASTHMA TREATMENT 1141

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