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

Antihistamines in the treatment of asthma

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

Antihistamines in the treatmelll of asthma. J. Bousquet, Ph. Godard, F.B. Michel. ABSTRACT: Histamine Is an Important mediator of asthma. The new anti­histamines which block histamine at the Hlreceptor level also possess some anti­allergic properties. At cut·rent dosages they appear to be safe. These drugs are effective In the treatment of rhinitis and conjunctivitis but their role in asthma is still under Investigation. At a dose higher than usually recommended, they were shown to block exercise-induced asthma and, inconstantly, the early phase reaction after allergen challenge. Their effect on the late phase allergic reaction as well as their clinical efficacy during trials is, however, less consist­ent. The indication of H

1-blockers in the tr eatment of asthma is therefore lim­

ited, especially since doses higher than r ecommended may lead to adverse reactions.

Clinique des Maladies Respiratoire, Hapita l l'Aiguelongue, Centre Hospitalier Universitaire, Montpellier, France

Correspondence: J. Bousquet Clinique des Maladies Respiratoires H6pital l'Aiguelongue Centre Hospitalier Universitaire 34059-Montpellier-Cedex, France

Keywords: Anti-histamines, asthma, H1-blockers, histamine

Received: May 12 1992 Eur Respir J., 1992, 5, 1137-1142.

Antihistamines, which block histamine at the H1-

receptor level, have been used for the treatment of allergic and nonallergic rhinitis, conjunctivitis and skin diseases, in which histamine has been shown to play an important role.

In asthma, the use of antihistamines is still under investigation. Not only do some investigators deny that antihistamines are beneficial but ScHULLER [1] pro­posed that they might even be harmful. Based on a very small number of asthmatic children, who appar­ently deteriorated during treatment with a drug possessing both an H1-blocking activity and anti­cholinergic properties, her report lead to the contrain­dication of these drugs in asthma in the US. However, a Position Paper issued by the American Academy of Allergy and Immunology [2] proposed that the drugs are safe and may be used in the treat­ment 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 10 yrs [3-5].

Points in favour of a r ole of antihistamines in asthma

Histamine plays a role in the pathogenesis of asthma

Histamine plays a role in the mechanisms of asthma [6). It is released during the early and late phase allergic reactions following bronchial challenge with allergen [7]; mast cells are present in lhe biopsies of allergic and nonallergic asthmatics [8] and histamine

Accepted after revision June 16 1992

levels are increased in the bronchoalveolar lavage (BAL) fluid of asthmatics [9]. Moreover, a signifi­cant correlation has been demonstrated between non­specific bronchial hyperreactivity and histamine levels in BAL fluid [9].

Histamine can induce the secretion of mucus by bronchial glands, cause extravasation of plasma pro­teins leading to airways mucosal oedema, contract the airway smooth muscle f6] and may play a role in the immunomodulation of the immunoglobulin E (lgE) immune response r 10], as well as in the regulation of the airway inflammation by the activation of epithe­lial cells and macrophages and possibly by inducing smooth muscle hyperplasia.

The inhalation of histamine induces a broncho­constrictive response in most subjects, but asthmatic patients are hyperreactive to histamine [11 ].

Antihistamines possess some "anti-allergic" properties

Antihistamines block histamine at its H1-receptor level but many drugs possess other properties that may be relevant for their efficacy [12]. Loratadine and terfenadine reduce, in a dose-dependent manner, the release of eicosanoids from human dispersed lung cells and reduce the release of histamine and prostaglandin D2 (PGD2) during nasal challenge with allergen. After allergen challenge, cetirizinc decreases the eosi­nophil influx into the skin but it is not yet clear if it has the same effect on nasal and bronchial cells. Al­though the exact significance of these properties is still not fully understood, they might be involved in asthma.

1138 J. BOUSQUET, Ph. GODARD, F.B. MICHEL

Links between asthma and rhinitis

Many patients with allergic rhinitis present both rhinitis and asthma. Many patients with allergic rhini­tis alone have an increased nonspecific bronchial hyperreactivity [13]. Finally, sinusitis is thought to be a causative factor in asthma [14]. Although the exact links between the nose and the lung are far from understood, it has been proposed that the treatment of the nasal symptoms may improve asthma.

Points against a role of antihistamines in asthma

Histamine is only one of the mediators of asthma and does not explain chronic inflammation of the airways

Histamine is one of the mediators of "allergic" and/ or "asthmatic" inflammation. It is likely to play a role in the spasmogenic phase of asthma but its importance in chronic inflammation of the airways remains to be determined. Moreover, mast cells and basophils are not the only cell types involved in airways inflamma­tion in asthma [15] and many other cells, mediators, toxic metabolites, cytokines and growth factors appear to be more important than histamine and/or metachro­matic cells. Finally, asthma is not only an inflamma­tory disease but remodels the airways inducing permanent abnormalities (16). Thus, it appears that antihistamines may only be partly effective in the treatment of chronic asthma and poorly effective in either long-standing asthma or in the most severe patients.

Anti-allergic drugs are usually poorly effective in the treatment of severe asthma

Sodium cromoglycate appears to be more effective in young asthmatics and in patients with mild asthma. It is usually less effective in the treatment of severe asthmatics (17]. The results obtained with ketotifen are less consistent but similar conclusions may be drawn [18) .

Clinical relevance of antihistamines in asthma

Bronchodilating activity of antihistamines

The bronchodilating activity of a single dose of an­tihistamine was reported in the early 1980s [19) and confirmed in some but not all studies [20-26]. Many studies found a significant difference between the bronchodilating activity of the placebo and the active drug, but they do not appear to be clinically relevant, since differences are usually small. In studies show­ing a significant effect of antihistamines, there was no dose-response effect [26]. Long-term studies

specifically examining this bronchodilating effect are lacking and long-term clinical studies of antihistamines in asthma suggest that this activity disappears after one or two weeks.

Thus, the bronchodilating activity of antihistamines may be limited in intensity and duration and, with our current knowledge, it does not support their use in asthma.

Provocative challenges

Exercise and cold air challenges. Several studies have been performed to assess the protective effect of anti­histamines in exercise-induced asthma and related chal­lenges such as nebulized water, hypertonic saline or cold air (table 1) [27-40]. Many of these studies show that antihistamines result in significant protec­tion, but in some studies the effect, although signifi­cant, is very small and does not appear to be clinically relevant. Moreover, in such situations, calcium antago­nists and a-blockers were found to be effective in the laboratory but had little or no effect when they were administered to patients in an attempt to improve asthma.

Allergen challenge. Many studies have also been per­formed in allergic asthmatics in order to prove the efficacy of antihistamines during the early and late phase allergic reactions. However, there have been discrepancies in the results published. Terfenadine (41, 42] and astemizole [ 43 ], but not loratadine [ 44] and cetirizine [ 45), have been shown to reduce the early phase reaction, but even with terfenadine the response was usually small and varied considerably between subjects.

Studies attempting to demonstrate an effect on the late phase reaction have been carried out on a very small number of patients and results are highly vari­able [ 46-48). At best, the effect is again small. It is, therefore, impossible to ascribe any clinically rel­evant protective effect of antihistamines on the late phase reaction.

Nonspecific airway challenge. Nonspecific bronchial hyperreactivity is a cardinal feature of asthma and drugs such as inhaled corticosteroids and, to a lesser extent, nedocromil sodium or sodium cromoglycate have been found to reduce the magnitude of histamine and/or methacholine inhalation challenge. Histamine challenge has no value for testing the effect of anti­histamines on nonspecific bronchial hyperreactivity depending on the intrinsic activity of the drugs. Stud­ies performed using methacholine challenge did not show any difference before and after treatment although it may be argued that the duration of the studies was too short to observe any significant effect [ 49-51]. Antihistamines can block challenge with adenosine [52] or platelet-activating factor (PAF) [53] but the clinical relevance of such challenges needs to 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 Go No [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

Only studies performed during seasonal or perennial asthma make it possible to assess the value of anti­histamines in the treatment of asthma. Many incon­clusive studies in both seasonal and perennial asthma have been performed but never published and this rep­resents a major gap in our knowledge of the efficacy of antihistamines in asthma.

Seasonal asthma

Difficulties in designing the studies. There are several drawbacks in the studies examining the effects of antihistamines in the treatment of seasonal asthma.

Seasonal asthma is mainly caused by pollens and the major symptoms of pollinosis are usually related to rhinoconjunctivitis, with asthma occurring in the most severe cases. There have been a number of trials performed in which no treatment for the nose or eyes was administered and, as a result, most of the placebo­treated patients dropped out of the study (54-55]. Nasal and ocular symptoms should be treated during any asthma trial with drugs not affecting the interpre­tation of the study. There is no commonly accepted treatment for nasal or ocular symptoms during asthma trials and the choice depends on many parameters: topical or oral drugs; all patients treated identically (56] or only patients who require a treatment for severe symptoms; treatment applied during the whole trial or only during the peak of the season.

Administration of the antihistamine may start before the season in a prophylactic treatment or very soon after the patients develop asthma. It is critical that long-standing asthmatics should be excluded from such studies since antihistamines are likely to have maxi­mal effect on patients who have a low degree of bron­chial inflammation.

Inclusion criteria are not standardized but it is

commonly accepted that patients should present a reversibility of the airway obstruction after the inha­lation of ~2-agonists. However, in grass pollen asthma, few patients have a reversible airways obstruc­tion of > 15% of forced expiratory volume in one second (FEV1).

The grass pollen season lasts 6-8 weeks in most countries but it is highly heterogeneous, pollen counts 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 vari­able from year to year. The ragweed pollen season is the most constant in terms of onset, peak and duration but it lasts only 4--6 weeks. It is, therefore, difficult to propose crossover trials with washout periods between treatments.

The analysis of the data is not easy. All trials examine symptom and medication scores, some evalu­ate the evolution of the pulmonary function tests or peak flow rates. However, in grass pollen asthma mean peak flow rates usually show little decrease of this interesting parameter. Ther~ is no study of non­specific bronchial hyperreactivity available.

Results of double-blind studies with control or placebo groups. Table 2 summarizes the results of the con­trolled studies performed with cetirizine and terfenadine in seasonal asthma [54- 62). It must be pointed out that the doses of antihistamines were always greater than those administered for rhino­conjunctivitis and, in the study of RAFFERTY et al. [60) the dose was 4.5 fold greater than recommended. If this increased dose is to become the recommended dose for asthma, the short- and long-term safety of the drug should be monitored in specific studies.

In two studies, the patients received no treatment for rhinitis and most of those under placebo dropped out from the study. These studies cannot be analysed fur­ther since it is unclear whether the patients dropped 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 BRUT MAN [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 or 30 mg daily) or a rescue medication given to all patients in the control group, terfenadine, at a dose that was suggested to be ineffective in asthma (60 mg b.i.d.). The results of the study of BousauET et al. [54] are not very convincing, possibly because the control group was under terfenadine. Finally, there are only two studies published in detail showing some efficacy of antihistamines in asthma [56, 60]. How­ever, not all parameters were improved and the pul­monary function, peak flow rates or ~2-agonist rescue medication were similar in the treated and placebo groups.

These studies show a moderate effect of antihista­mines 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 reached.

Perennial asthma

Difficulties in designing the studies. There are also several drawbacks in the studies examining the effects of antihistamines in the treatment of perennial asthma [28, 57, 60-62].

The design of the trial is critical. Asthma is a chronic inflammatory disease leading to a remodelling of the airways. It is, therefore, suggested that anti­histamines will be more effective in patients with mild asthma and in the younger asthmatics. In perennial asthma, rhinitis and conjunctivitis are not always se­vere and nasal or ocular treatments are not required by most patients. Anti-inflammatory drugs should be carefully avoided for a long period of time, since it is unlikely that antihistamines will add significant ben­efit to inhaled corticosteroids. The duration of the run-in period is critical, since asthma is highly vari­able. The study may be performed in parallel groups or in a cross-over manner but in the latter case the washout period is critical.

Results of double-blind studies with control group. The study of TAYTARD et al. [61] is the only published study showing a favourable effect of antihistamines in chronic symptoms of perennial asthma. Using terfenadine at a dose of 120 mg b.i.d. in a cross-over study carried out in mild asthmatics, they observed that when patients were treated with the antihistamine they presented significantly less symptoms, needed signifi­cantly less ~2-agonists and presented an improvement in pulmonary function as assessed by FEV1 and peak flow rates. However, the improvement in pulmonary function was small and may have little clinical rel­evance. Many other inconclusive studies have been performed but never published.

Indications for antihistamines in asthma

The indications for antihistamines in the treatment of asthma are still vague and more data are needed before a firm conclusion can be drawn. New studies are needed to compare the efficacy of antihistamines with accepted anti-asthma treatment.

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