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* From the Pulmonary/Critical Care Medicine Service (Dr. Niven), William Beaumont Army Medical Center, El Paso, TX; and the Department of Medicine (Dr. Argyros), Walter Reed Army Medical Center, Washington, DC.
Correspondence to: Alexander S. Niven, MD, Pulmonary Department, William Beaumont Army Medical Center, 5005 N Piedras St, El Paso, TX 79920-5001; e-mail: Alexander.Niven{at}amedd army.mil
Key Words: asthma therapy • cyclosporine • drug therapy • furosemide • gold • heparin • IVIG • methotrexate • troleandomycin
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Introduction |
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 TOP Introduction Difficult-To-Manage AsthmaAlternate Asthma TherapiesConclusionReferences |
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Although these agents are generally successful at controlling asthma symptoms, there remains a small but significant number of patients with persistent symptoms, frequent exacerbations, and objective pulmonary abnormalities despite maximum standard therapy. The long-term use of oral and high-dose inhaled corticosteroids can be associated with significant side effects, prompting research efforts to identify alternate agents that are effective in the treatment of asthma.
The purpose of this review is to characterize the type of patient who may benefit from alternate, nonsteroidal agents and to examine the current evidence behind their use. Although the use of a variety of alternate agents has been reported, we will focus in this article on agents that have been evaluated in prospective, randomized trials (Table 1 ) or have novel mechanisms of action. Anti-IgE and soluble interleukin (IL)-4 receptor therapy have been the subject of several reviews,2 3 4 and therefore will not be included in this discussion.
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Difficult-To-Manage Asthma |
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TOPIntroductionDifficult-To-Manage AsthmaAlternate Asthma TherapiesConclusionReferences |
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The treatment of concomitant gastroesophageal reflux5 and chronic sinusitis,6 7 and the removal of environmental triggers of asthma have been shown to improve asthma control. Glucocorticoid absorption and metabolism can be affected by thyroid disease and a variety of drugs, including antacids, rifampin, cholestyramine, and numerous antiepileptic agents.8 The increased detection of Mycoplasma pneumoniae and Chlamydia pneumoniae by polymerase chain reaction in the airways of patients with chronic asthma has led to questions regarding their role in pathogenesis,9 and several small case series10 11 have demonstrated statistically significant improvements in lung function and reductions in bronchial reactivity to histamine after treatment with macrolides. Due to the significant side effects of many alternate asthma therapies, it is essential to thoroughly address the above issues before embarking on a novel treatment strategy.
It is also important to distinguish the "difficult-to-manage" asthma patient from the patient who is steroid-resistant. This asthma subgroup, which was first described in 1968,12
is characterized by patients with larger than usual daily oral corticosteroid requirements and poor symptom control, a blunted eosinopenic response to cortisol-21-succinate, and increased clearance of cortisol. Other clinical characteristics that are associated with steroid resistance include African-American race, symptoms requiring oral glucocorticoid agents at an early age, and < 15% improvement in FEV1 following 7 to 14 days of treatment with high-dose (ie, 
40 mg daily) oral glucocorticoids.13
The molecular mechanisms behind steroid resistance were summarized in a recent review.8
The recognition and early identification of these patients may isolate a subgroup of patients who could benefit from early intervention with alternate asthma therapies with better long-term asthma control and reduction in corticosteroid side effects.
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Alternate Asthma Therapies |
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TOPIntroductionDifficult-To-Manage AsthmaAlternate Asthma TherapiesConclusionReferences |
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Clinical Trials:
The first case series describing the use of methotrexate in steroid-dependent asthma patients was published by Mullarkey et al21
in 1988. Ten other randomized trials22
23
24
25
26
27
28
29
30
31
have been published in article form (Table 2
) and three meta-analyses32
33
34
have been performed since then with mixed results.
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The significance of the current available data is limited by small patient numbers, with the largest trial (Shiner et al22 ) enrolling 69 subjects. Many trials had significant dropout rates that were frequently not included in final data analysis (Table 2) . The tapering of oral corticosteroid therapy prior to treatment with methotrexate was performed in only two trials,25 29 and the use of inhaled corticosteroids and run-in periods to maximize asthma management prior to randomization was variable. No statistically significant changes in peak flow, spirometry, or mean values for the dose of methacholine provoking a 20% fall in FEV1 were observed in patients taking methotrexate.22 23 24 25 26 27 28 29 30 31 A reduction in steroid-related side effects also was not reported.
Although responses to methotrexate have been reported after 3 months in patients with immunologic diseases such as rheumatoid arthritis, treatment for 12 weeks may be insufficient to demonstrate an adequate therapeutic response in patients with asthma. Mullarkey et al35 and Shiner et al36 have both published prospective case series of 31 and 21 patients, respectively, who were treated with oral or IM doses of methotrexate, 15 mg, for 18 to 28 months and a mean (± SD) of 14.7 ± 3.7 months, respectively. Both studies reported statistically significant reductions in the baseline prednisone dose, with over half were weaned off all steroid therapy.
Adverse Effects:
Common side effects reported in trials using methotrexate (Table 2) included liver function test abnormalities, GI symptoms (including abdominal pain, nausea, and diarrhea), oral ulcers and stomatitis, constitutional symptoms (including fatigue and decreased concentration), headache, and rash. One patient receiving methotrexate died from Pneumocystis carinii pneumonia,23
a complication that has been reported in case report form in two other steroid-dependent asthma patients who had been treated with the drug.37
38
Another trial25
reported an increased incidence of bacterial pneumonia in its methotrexate group, and death from disseminated varicella zoster also has been described.39
Most studies reported that side effects were transient and reversible, and two studies24
27
reported only minimal side effects from the administration of low-dose methotrexate. No bone marrow toxicity was observed at the dosages used, and follow-up was too short to address issues of potential hepatic fibrosis. Methotrexate competes with the hepatic metabolism of theophylline, with an average decrease in theophylline clearance of 19% in one case series.18
Methotrexate is well-known to cause a variety of pulmonary manifestations, including drug-induced hypersensitivity reaction, chronic pneumonitis and fibrosis, bronchiolitis obliterans with organizing pneumonia, noncardiogenic pulmonary edema, and bronchospasm.40 The significance of these side effects in asthma patients has not been investigated, although it has raised significant editorial debate.41
Troleandomycin
Mechanism of Action:
Troleandomycin (TAO) is a macrolide antibiotic that was introduced in 1957 and was first described as a treatment for steroid-dependent asthma in 1974.42
The results of studies examining its mechanism of action have been conflicting, but the drug is believed to have a synergistic effect when administered with oral corticosteroids. In vitro data using its parent compound, oleandomycin, at a concentration of 5 µg/mL demonstrated a 44% reduction in the concentration of methylprednisolone that was required to inhibit human lymphocyte blast transformation by 50% (p < 0.005).43
It is believed that TAO alters corticosteroid bioavailability by decreasing hepatic metabolism and excretion. The addition of 14 mg/kg/d TAO to the regimen of 10 severe steroid-dependent asthma patients resulted in a reduction in clearance of IV methylprednisolone by a mean of 60 ± 18.7% (p < 0.001) with a loss of typical first-order kinetics during plasma concentration decline.44 The drug-specific nature of this action has been emphasized by other studies that have demonstrated no TAO effect on serum cortisol levels and urinary 17-ketogenic steroids,45 46 or on the peak and rate of decline of plasma cortisol levels following the infusion of 100 mg IV hydrocortisone in healthy subjects.46 Subjective patient improvement has not been correlated with evidence of infection using sputum culture, suggesting that a direct antimicrobial effect is less likely.42 46
Clinical Trials:
Clinical efficacy data on TAO was first published by Spector et al,42
who demonstrated an improvement in clinical symptoms and/or a reduction in corticosteroid dosage in 62 of 74 steroid-dependent asthma patients using 14 mg/kg/d TAO (maximum dose, 1 g) and methylprednisolone. Similar results were shown in later case series of 1447
and 16 patients.48
Wald et al49
demonstrated that prior difficulties with steroid-related and GI side effects could be avoided by reducing the starting dose of TAO to 250 mg once or twice daily with a rapid methylprednisolone taper to alternate-day dosing for > 4 to 8 days.
These benefits, however, were less convincingly demonstrated in the only prospective, double-blind, randomized, placebo-controlled trial of TAO efficacy to date.50 In that trial, 75 steroid-dependent asthma patients who were receiving maximal medical therapy were randomized to TAO, 250 mg daily, or placebo. The steroid dose was tapered by 25% every other day unless peak flow measurements and symptoms mandated a slower rate of decline. The results were limited by significant patient dropout (at 1 year: TAO group, 7 patients; placebo group, 11 patients; and at 2 years: TAO group, 20 patients; placebo group, 30 patients), and no intention-to-treat analysis was performed. Although the remaining TAO patients tolerated lower steroid doses at 1 year (p < 0.03), the number of hospitalizations and emergency department visits were not changed significantly. TAO patients also had more cases of bone loss (p < 0.01) and higher cholesterol levels (p < 0.05) than did placebo subjects. The authors concluded that patients who had been randomized to TAO experienced no advantage and appeared to develop greater steroid-related side effects than did placebo subjects.
Adverse Effects:
Steroid-related side effects are common with the use of TAO, especially in earlier trials when patients were given doses of 1 g daily.47
48
Cushingoid features, weight gain, fluid retention, and glucose intolerance were the most common findings. GI distress and hepatotoxicity, ranging from transient liver enzyme abnormalities51
to prolonged cholestasis52
and jaundice,53
have been reported, predominantly at higher doses. The doses of theophylline and other medications with hepatic metabolism must be adjusted to avoid toxicity. Decreased IgG levels were identified in the TAO group (p < 0.05) by Nelson et al,50
and one case of varicella zoster has been reported.48
Gold
Mechanism of Action:
Gold is an immunomodulatory agent that has been used commonly in the past for the treatment of a variety of inflammatory and autoimmune conditions. Although the complete me-chanism of anti-inflammatory activity is unknown, gold has been demonstrated to decrease neutrophil and macrophage phagocytosis, and lymphocyte reactivity to antigenic stimulation.54
It also has been shown to inhibit antibody production and lysosomal enzyme release from phagocytic leukocytes.55
Gold inactivates C1 (complement), decreases prostaglandin and leukotriene production in vitro, and inhibits IgE-mediated release of histamine from isolated basophils and lung mast cells.54
55
56
57
58
The enhancement of eosinophil survival with IL-5 is inhibited by the presence of gold.59
Clinical Trials:
The beneficial effects of gold in treating asthma were reported as early as 1932, and improvements in bronchial reactivity and oral corticosteroid requirements have been noted in several small series60
61
62
that used oral or parenteral gold treatment for 12 to 22 weeks. There have been three prospective randomized studies examining the efficacy of gold. Muranaka et al63
randomized a mixed group of 79 asthma patients to placebo or weekly parenteral gold therapy, starting at a dose of 10 mg and increasing to 100 mg by the end of 30 weeks. Seventy-one percent of the treated group improved vs 44% of the control subjects, with patients who had extrinsic asthma accounting for the majority of the benefits observed. In another small trial64
of 32 steroid-dependent asthma patients, the administration of auranofin, 3 mg twice daily for 26 weeks, compared to placebo resulted in greater reductions in oral corticosteroid use (4 mg vs 0.3 mg, respectively) and fewer exacerbations (0.9 vs 2.1, respectively).
The Auranofin Multicenter Drug Trial65
has been the largest clinical trial to examine the efficacy of oral gold to date. After a 4-week observation period, 275 patients with daily oral prednisone requirements of 10 mg were randomized to auranofin, 3 mg twice daily, or placebo for a period of 6 months. The results were limited by a significant patient dropout rate (auranofin group, 40%; placebo group, 46%) due to adverse effects, protocol violations, and voluntary withdrawals, and no intention-to-treat analysis was performed. No significant differences were found in symptoms or objective measurements of pulmonary function, although more patients treated with gold were able to reduce their daily oral corticosteroid dose by 50% compared to those receiving placebo (60% vs 32%, respectively; p < 0.001). Statistically significant reductions in serum IgE level (reduction, 44.63 IU/mL; p = 0.003) were also observed in the auranofin group.
Adverse Effects:
Gold has been associated with a variety of side effects, including GI upset and diarrhea, pruritic rash, cytopenias, oral ulcerations, proteinuria, and frank nephrotic syndrome. Nearly 40% of patients in the prospective randomized trials that were detailed earlier63
64
65
experienced side effects from therapy. GI and skin symptoms were the most common, and side effects were significantly increased in the treatment group compared to the placebo group. All side effects were self-limited with discontinuation or reduction of therapy. Some experts54
have argued that the relative lack of severe side effects with gold therapy, compared to methotrexate therapy, make it a preferable agent for the treatment of severe, glucocorticoid-dependent asth-ma, but no clear consensus exists on this issue.
Cyclosporine
Mechanism of Action:
Cyclosporine, which is well-known for its immunomodulatory and anti-inflammatory effects, is a fungal metabolite that is commonly used in organ transplantation. Cyclosporine binds to cyclophilin, inhibiting cytokine messenger RNA trans-cription and CD4+ T-cell activation.66
The drug also reduces the synthesis and release of inflammatory mediators from mast cells and basophils, and it decreases B-cell IgE synthesis and release.67
Cyclosporine has been demonstrated to reduce the macrophage synthesis of IL-1, tumor necrosis factor, superoxide, and hydrogen peroxide, and has been shown to decrease neutrophil chemotaxis and serum soluble IL-2 receptor concentrations.54
68
The production of granulocyte macrophage colony-stimulating factor and IL-5 from stimulated monocytes is also reduced with drug therapy, inhibiting eosinophil proliferation and survival activity.69
70
Clinical Trials:
Increasing recognition of the prominent role of T cells in the pathogenesis of asthma prompted investigation into the use of cyclosporine. Cyclosporine has been shown to block the late asthmatic reaction and to inhibit the production of eosinophil-related cytokines after allergen challenge.66
71
Small case series72
have demonstrated statistically significant improvements in airway hyperreactivity in steroid-dependent asthma patients after 12 weeks of therapy with cyclosporine.
There have been three prospective randomized trials that have examined the effect of cyclosporine in asthma patients. Alexander et al73 randomized 33 steroid-dependent asthma patients in a 12-week crossover trial of cyclosporine (initial dose, 5 mg/kg/d) or placebo. Patients receiving cyclosporine demonstrated a 12% increase in morning peak expiratory flow rates (PEFRs) (p < 0.004), a 17.6% increase in FEV1 (p < 0.001), and a 48% reduction in exacerbations requiring increased steroid dosing (p < 0.02) compared to those receiving placebo. In a similarly designed study,74 treatment with cyclosporine (initial dose, 5 mg/kg/d) for 36 weeks in 16 patients with severe asthma resulted in a statistically significant reduction in the median daily prednisolone dosage (62% vs 25%, respectively; p = 0.043) along with improvements in PEFR. However, a third study75 involving 34 patients with severe asthma and a longer follow-up period demonstrated no statistically significant effects of cyclosporine using the objective markers of pulmonary function and steroid-sparing effects.
Adverse Effects:
The side effects of cyclosporine are well-known and include dose-dependent nephrotoxicity, tremor, hirsutism, hypertension, gum hyperplasia, and infectious complications. The majority of these side effects were not observed in the low doses that were used in the trial listed above,73
74
75
although several patients did experience hypertrichosis and a worsening of preexisting hypertension that resulted in the discontinuation of therapy.74
Cyclosporine toxicity was relatively common in one case series76
of low-dose therapy in 12 steroiddependent asthma patients, and treatment-limited neuropathy also has been observed.
IVIG
Mechanism of Action:
Experience with IVIG therapy in asthma patients is limited, and the mechanisms involved in its postulated glucocorticoid-sparing effects are largely unknown. IVIG has been shown to reduce immediate skin test reactivity to allergens, to decrease total serum IgE levels, to inhibit lymphocyte activation and the production of IL-2 and IL-4 in vivo, and to suppress cytokine-dependent lymphocyte proliferation in vitro.77
78
79
IVIG also has been shown to increase lymphocyte sensitivity to the suppressive effects of dexamethasone, even in patients with prior documented steroid resistance.80
Clinical Trials:
Increased interest in the use of IVIG therapy in asthma patients was sparked by an open-label trial77
of monthly administration of high-dose IVIG in eight pediatric patients with severe steroid-dependent asthma. Over the 6-month trial period, treatment resulted in a threefold reduction in the oral glucocorticoid dose, a reduction in symptoms, and in improved PEFRs with decreases in serum total IgE levels and skin test reactivity to allergens. These steroid-sparing effects also have been seen in small case series81
82
that included both adult and pediatric asthma patients.
Two prospective randomized trials have examined the effects of IVIG in asthma. Salmun et al83 randomized 38 patients with severe steroid-dependent asthma to either a 2 g/kg loading dose of IVIG followed by a regimen of 400 mg/kg IVIG every 3 weeks or IV albumin. After 3 months of therapy, the oral corticosteroid doses were systematically reduced as tolerated. Only 28 patients completed the study. Seven patients withdrew voluntarily and were not further characterized. Among the subjects who completed the study, there was no overall difference in the amount of steroid reduction. In a post hoc subgroup analysis, patients requiring high-dose, long-term corticosteroid therapy (ie, > 2,000 mg in the year prior to the study) demonstrated a statistically significant reduction in oral glucocorticoid requirements compared to that in placebo subjects (median reduction, 16.4 to 3 mg/d; p = 0.0078). Another multicenter trial84 randomized 40 pediatric and adult patients with severe asthma to IVIG doses of 2 g/kg per month, 1 g/kg per month, or 2 g IV albumin per month. The trial was stopped early after three patients who had been randomized to high-dose IVIG were hospitalized with aseptic meningitis, while interim analysis failed to identify a significant difference in steroid dose reductions, pulmonary function testing results, or the number of clinical exacerbations among patients in the IVIG groups and the placebo group.84
Adverse Effects:
The minor adverse effects of therapy include headache and nausea, which generally occur with the infusion and are self-limiting. Although current commercial preparations should have no risk of transmission of viral hepatitis, there remains the remote possibility of IVIG transmission of a yet-undefined viral illness. More serious reactions can be associated with patients who have IgA deficiency, and IVIG administration should be avoided in this population. It also has been rarely associated with interstitial nephritis and aseptic meningitis, as was mentioned above.84
Heparin
Mechanism of Action:
Heparin is an endogenous glycosaminoglycan that is widely used in medicine for its anticoagulant properties. Its flexible structure and high anionic charge allow heparin to interact with a variety of molecules in vivo, and the recognition of its presence in high concentrations in preformed cytoplasmic mast cell granules in endobronchial tissue first led to speculation about its involvement in airway inflammation.85
Elevated levels of heparin-like anticoagulants have been demonstrated in atopic asthma patients86
and have been induced in some patients after antigen inhalational challenge,87
leading to further interest in investigating the role of heparin in this disease.
Heparin has been shown to bind and inhibit a variety of cytotoxic and inflammatory mediators, including eosinophilic cation protein and peroxidase.88 It also increases the association rate of secretory leukocyte protease inhibitor with human neutrophil elastase and cathepsin G, reducing their activity.89 Heparin has been associated with the inhibition of lymphocyte activation,90 neutrophil chemotaxis,91 smooth muscle growth, and vascular tone.92 It also has been reported93 to reduce complement activation.
Ahmed et al94 have suggested that the sulfate groups on the heparin molecule may attenuate antigen-induced bronchoconstriction via the inhibition of inositol 1,4,5 triphosphate-dependent, IgE-mediated mast cell histamine release. Other studies85 have hypothesized that heparin that is bound to cell surface proteins in the airway epithelium may modulate smooth muscle tone either by inhibiting inositol 1,4,5 triphosphate-mediated calcium release or by preventing C-fiber stimulation, decreasing bronchial responsiveness, and reducing airway hyperreactivity.
Clinical Trials:
Several studies95
96
97
in the 1960s first reported subjective improvement in asthma symptoms with the use of IV heparin. Bardana et al98
performed the first trial of inhaled heparin in 10 patients with mild-to-severe asthma, observing subjective but no objective improvement. Further human studies using inhaled heparin were not published until the early 1990s, after Ahmed et al99
demonstrated that pretreatment with 1,000 U/kg heparin attenuated the increase in the lung resistance of previously sensitized sheep by 91% on allergen reexposure.
A follow-on study of 12 patients with exercise-induced asthma demonstrated that inhaled heparin therapy administered at the same dose (maximum, 80,000 U) preserved specific airway conductance (sGaw) better than did 20 mg inhaled cromolyn or placebo following exercise (p < 0.05) but not following histamine challenge.100 Another small study101 confirmed this effect, demonstrating that inhaled heparin was superior in preserving sGaw in patients with exercise-induced asthma when administered up to 3 h prior to exercise. A statistically significant benefit in sGaw, however, was observed only for 5 to 15 min postexercise compared to placebo.101 Inhaled enoxaparin, 1 mg/kg, demonstrated similar protective effects following exercise and was superior to 80,000 U unfractionated heparin at higher doses (48% inhibition of exercise-induced decrease in FEV1 vs placebo; p < 0.05).102
Conflicting data exist regarding the effects of heparin pretreatment on the early asthmatic response to inhaled allergen challenge (dust mite extract), with mild but statistically significant protective effects in FEV1 seen 7 to 8 h postchallenge (p < 0.05).103 104 Trials examining the effects of inhaled heparin on bronchoprovocation using methacholine also have yielded mixed results, with variable effects on the provocative concentration of methacholine causing a 20% fall in FEV1, but with no significant effects on FEV1, airway resistance, or sGaw postchallenge.105 106 107 Two cases of corticosteroid-resistant asthma patients who responded to 100,000 U inhaled heparin during asthma exacerbations have been reported.108
Adverse Effects:
No adverse effects associated with the use of inhaled heparin at the doses described above have been reported. Heparin inhalation alone has not been demonstrated to affect baseline FEV1 despite the frequent use of isotonic saline solution as its carrier.104
No bleeding complications have been reported, and no significant changes in serum partial prothrombin time100
or anti-factor Xa activity102
have been observed with unfractionated and low-molecular-weight heparin, respectively. Five of 15 previously sensitized subjects who received low-dose (ie, 20,000 U) inhaled heparin followed by challenge with dust mite extract experienced greater sensitivity to the allergen in one trial.103
The significance of this finding is uncertain.
Furosemide and Other Diuretics
Mechanism of Action:
Changes in water concentration and surface osmolarity of the airway epithelium have been well-accepted as contributing factors to exercise-induced bronchospasm and have prompted the first use of inhaled frusemide (ie, furosemide) as a potential treatment for asthma.109
Furosemide is a loop diuretic that acts in the kidney by inhibiting the Na+/K+/2 Cl- cotransporter in the ascending limb of the loop of Henle. Despite early speculations about the effects of furosemide on airway water concentration, its mechanism of action does not appear to be related to the diuretic effects of the drug. Furosemide is not effective against asthma when administered orally at the usual diuretic doses and must be inhaled at relatively high doses (ie, 20 to 40 mg) for significant antiasthma effects.109
In vitro data have suggested that furosemide may attenuate bronchoconstriction by reducing apical chloride channel activity and by decreasing the potential difference and short-circuit current in airway epithelial cells.110 111 The drug’s inhibition of chloride transport also appears to inhibit the release of eosinophil mediators112 and may be related to the modulatory effects observed on presynaptic neuropeptide release from noncholinergic, nonadrenergic sensory nerves and cholinergic neural responses in animal models.113 A short report114 has described furosemide inhibiting the release of histamine and leukotrienes from passively sensitized human lung.
Conflicting data exist regarding the effects of furosemide on airway prostaglandins. Furosemide is well-known to enhance renal synthesis of prostaglandin E2,115 and some studies116 have proposed that the stimulation of inhibitory prostaglandins from the airway epithelium may be the cause of its protective role in some challenges. Other data117 have suggested that the drug inhibits the production of bronchoconstricting prostaglandins. Data on the effects of cyclooxygenase inhibitors on the activity of furosemide have been mixed,118 119 reinforcing the lack of clarity in this area.
Other postulated mechanisms of action based on animal data include the reduction of airway temperature variation through local airway vasodilation following dry air challenge120 and the enhancement of paracellular water movement in response to an osmotic stimulus.121 However, other data have shown that furosemide has little122 or no effect123 on mucociliary clearance, an indirect measure of the rate of recovery of periciliary fluid volume after isocapnic hyperventilation.
Clinical Trials:
Published clinical trials using furosemide have focused largely on its influence over the effects of a variety of bronchoconstrictor agents in asthma patients. Furosemide appears to attenuate the effects of indirect bronchoconstrictor mechanisms, including early and late responses to allergen124
and the effects of exercise,109
distilled water,125
adenosine 5'-monophosphate,126
sodium metabisulfite,127
128
aspirin,128
and propranolol.129
Bronchoconstrictors that work directly on airway smooth muscle like histamine,126
methacholine,127
130
and prostaglandin F2
131
have not been demonstrated to be affected by furosemide use. The similarities between the protective spectrum of furosemide and cromolyn have led to speculation about a common mechanism of action, although cromolyn has been shown to have a statistically greater protective effect on airway reactivity when equal doses of the two inhaled drugs were compared.133
Inhaled furosemide has been shown to inhibit the cough response induced by the inhalation of low-chloride-content solutions134 in healthy volunteers, but not in asthmatic patients.135 The presumed effect of the drug is due to changing the local concentration of chloride ions in the vicinity of myelinated afferent nerve fibers that are acting as cough receptors at the airway surface.136
Only two clinical trials using furosemide therapy for the treatment of chronic asthma were identified through literature review. Bianco et al137 demonstrated a significant steroid-sparing effect using a combination of lysine acetylsalicylate (LASA) and furosemide on a small group of patients with severe steroid-dependent asthma for 10 to 28 weeks. In a follow-up, double-blind, randomized, crossover trial,138 nine patients with mild-to-moderate asthma who were receiving standard therapy were treated with sequential inhaled doses of LASA, 720 mg, and furosemide, 40 mg, or placebo twice daily with scheduled reductions in inhaled corticosteroid therapy as tolerated. After approximately 2 months, treatment with furosemide/LASA resulted in a mean dose reduction of 71 ± 7% in the amount of inhaled beclomethasone that was required to maintain asthma control, and two patients were able to discontinue therapy with inhaled steroids completely.138
Three clinical trials have examined the role of inhaled furosemide in acute asthma exacerbations, with mixed results. Karpel et al139 enrolled 24 patients who presented to the emergency department with asthma exacerbations and randomized them to receive inhaled furosemide, 40 mg, or inhaled metaproterenol, 15 mg, in a blinded fashion. Serial FEV1 measurements showed a mean increase of 14.9 ± 10.5% in FEV1 with furosemide therapy alone (difference not significant) compared to an increase of 42.9 ± 15.2% with metaproterenol therapy (p = 0.003) and no additive benefit with combination therapy. Similar results were reported by Pendino et al140 in a trial of 42 patients comparing salbutamol with either furosemide or placebo therapy, although post hoc subgroup analysis identified statistically significant improvements in PEFRs using furosemide in patients who reported a duration of symptoms of < 8 h (p = 0.014). In contrast, Ono et al141 reported statistically significant improvements in PEFRs (p < 0.05) in a group of 40 patients with acute asthma exacerbations who had been treated with IV aminophylline and hydrocortisone and were randomized to receive either inhaled furosemide or placebo. They also identified 6 of the 20 patients who had been treated with furosemide in whom FEV1 had increased by > 2 SDs compared to those receiving placebo, although no differences between the good responders and the poor responders could be identified. A follow-up case series142 by one of the coauthors reported clinical improvement in 9 of 11 patients with severe asthma exacerbations that were refractory to conventional medical therapy with the addition of inhaled furosemide.
Adverse Effects:
Furosemide is well-known to cause allergic reactions due to its incorporated sulfa moiety and has been reported to cause ototoxicity with high-dose rapid IV infusion. None of the clinical trials using inhaled furosemide have reported significant side effects, and no diuretic effect has been reported.
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Conclusion |
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Of the agents that have been examined in prospective randomized trials, methotrexate and gold appear to be the most promising in terms of steroid-sparing and side-effect profiles. Methotrexate has been shown to reduce oral corticosteroid requirements modestly in steroid-dependent asthma patients in some short-term, randomized, clinical trials, although its mechanism of action remains unclear and the data examining this issue remain limited and conflicting. Two case series have suggested that longer term therapy with methotrexate may be required to demonstrate objective benefit, but this issue has not been addressed in a prospective randomized trial. Gold appears to have significant steroid-sparing effects in patients with high daily corticosteroid requirements, but this conclusion must be made with caution due to the confounding effects of the high dropout rate in the Auranofin Multicenter Drug Trial. Side effects with gold therapy are common but generally are minor and self-limited with dose reduction or the cessation of therapy. Until further data from controlled clinical trials are available, however, it is unclear whether methotrexate or gold offers a significant risk/benefit ratio compared to close follow-up, intensive standard therapy, and patient education alone.
Cyclosporine offers an attractive mechanism of action and reasonable efficacy data in two of three small prospective randomized trials, but it also carries with it a significant side effect profile. Because of the risk of permanent renal damage and the need for intensive monitoring, further studies with larger prospective randomized trials should be performed before cyclosporine is considered as an appropriate alternate agent for asthma therapy.
Although TAO appears to be an effective methylprednisolone dose-reducing agent, the drug has not been shown to significantly improve asthma control or to reduce steroid-related side effects, and it was associated with an increased rate of osteoporosis and hypercholesterolemia in one clinical trial. Data demonstrating the beneficial effects of IVIG also are limited, while cost, convenience, and a possible risk of aseptic meningitis are all potential detractors to this therapy. At this time, the use of TAO appears to offer no advantage over conventional asthma therapy and patient education, and therapy with IVIG should be limited to clinical trials.
Although its postulated mechanism of action and effects on exercise-induced bronchospasm are intriguing, the majority of clinical data currently available on inhaled heparin therapy is limited to single-blind trials involving < 20 patients. The enoxaparin data suggest that the accepted dosing regimens may be too low to demonstrate a full therapeutic effect, and larger prospective placebo-controlled trials are needed to determine the efficacy, dose, and patient population that may benefit from this therapy. Furosemide and other loop diuretics appear to attenuate a variety of indirect bronchoconstrictor mechanisms, although their exact mechanism of action remains unknown. The fact that loop diuretics seem to have little direct effect on bronchial smooth muscle is a likely explanation for their lack of effect as a single agent or in combination with ß-agonists alone in patients with asthma exacerbations. The current data and the lack of significant side effects make them potential steroid-sparing agents in the long-term treatment of mild persistent-to-severe asthma. The current clinical data are limited, however, and larger randomized trials are necessary to confirm the efficacy of loop diuretics and their role in the treatment of asthma.
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Footnotes |
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This article was written by the authors as part of their official duties for the Department of Defense. Its contents are in the public domain, and therefore copyright ownership cannot be transferred. The findings in this report are not to be construed as the official position of Department of the Army unless so designated by other authorized documents.
Received for publication July 22, 2002. Accepted for publication August 12, 2002.
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