Abstract
Background
For the majority of chronic asthmatics, symptoms are best controlled using inhaled steroids, but for a small group of asthma sufferers, symptoms cannot be controlled using inhaled steroids and instead continuous use of high dosage oral steroids (corticosteroids) are required. However, using high dosage oral steroids for long periods is associated with severe side effects. Steroid‐sparing treatments have been sought and one of these is chloroquine. Chloroquine is an anti‐inflammatory agent, also used in the treatment of malarial infection and as a second‐line therapy in the treatment of rheumatoid arthritis, sarcoidosis and systemic lupus erythematosus. All these diseases are associated with immunologic abnormalities hence the speculation that chloroquine might be used to control severe, poorly controlled bronchial asthma. There is a need to systematically evaluate the evidence regarding its use to reduce or eliminate oral corticosteroid use in asthma.
Objectives
The object of this review was to assess the efficacy of adding chloroquine to oral corticosteroids in patients with chronic asthma who are dependent on oral corticosteroids with the intention of minimising or eventually eliminating the use of these oral steroids.
Search methods
Searches of the Cochrane Airways Group Specialised Register were undertaken with predefined search terms. Searches are current as of February 2011.
Selection criteria
Only studies with a randomised placebo‐controlled design met the inclusion criteria for the review.
Data collection and analysis
Two reviewers independently assessed studies for suitable in the review. Data were extracted and entered into RevMan 5.
Main results
One small study was included in the review. No significant findings were reported. An update search conducted in February 2007 did not identify any new studies.
Authors' conclusions
There is insufficient evidence to support the use of chloroquine as an oral steroid‐sparing agent in chronic asthma. Further trials should optimise oral steroid dosage before addition of the steroid‐sparing agent.
Keywords: Humans, Adrenal Cortex Hormones, Adrenal Cortex Hormones/administration & dosage, Asthma, Asthma/drug therapy, Chloroquine, Chloroquine/therapeutic use, Hydroxychloroquine, Hydroxychloroquine/therapeutic use, Randomized Controlled Trials as Topic
Plain language summary
Chloroquine as a steroid sparing agent for asthma
Asthma can be treated with drugs which aim to reduce inflammation in the airways. Inhaled corticosteroids are frequently used, but occasionally individuals require oral steroids for adequate control. However, oral steroids are frequently associated with severe side‐effects. Chloroquine has been suggested as a useful 'add‐on' therapy to oral steroid treatment with the aim of reducing the dose requirement in such asthma. This review found one small cross‐over study but this did not provide adequate evidence to decide whether chloroquine should be offered to reduce or eliminate oral steroid treatment. There is a need for well‐designed trials addressing this question before recommendations can be made.
Background
The recognition that asthma is a consequence of airway inflammation has focused treatment objectives towards anti‐inflammatory agents. Whilst inhaled corticosteroids are of proven benefit, there are, however, a group of asthmatics who continue to have symptoms despite high doses of inhaled steroids and require maintenance treatment with oral corticosteroids. Whilst these patients are in the minority, in the order of 1‐2%, they constitute a significant number and consume a considerable and disproportionate fraction of the health care resources. Furthermore those patients are at risk from the unwanted effects of long term treatment with systemic corticosteroids. These include osteoporosis, diabetes, hypertension and neuropsychiatric disorders. As a result of this clinical dilemma there have been a number of clinical trials examining the use of 'second‐line' steroid‐sparing agents. The concept that these drugs may be of benefit in asthma has arisen from studies showing their benefits in other inflammatory conditions such as rheumatoid arthritis and psoriasis. Various medications have been used included methotrexate, cyclosporin, and chloroquine. Methotrexate and cyclosporin have already been the subject of a systematic review. To date, the evidence to support the use of chloroquine with chronic oral steroid dependent asthma has not been established.
Chloroquine is a member of the anti‐inflammatory agents known as the "antimalarials" so named because this group of drugs was first applied to the treatment of malarial infection. It is also used as a second‐line therapy in the treatment of rheumatoid arthritis, sarcoidosis and systemic lupus erythematosus. All these diseases are associated with immunologic abnormalities hence the speculation that they might be used to control severe, poorly controlled bronchial asthma.
The drugs chloroquine and hydroxychloroquine are known to be immuno modulators that stabilize lysosomal membranes in inflammatory cells and act as inhibitor of phospholipase A2, an enzyme involved in the release of arachidonic acid from membrane phospholipids. Its anti‐inflammatory properties might be a result of its ability to decrease leukotriene and prostaglandin synthesis. Goldstein 1983 reported a case study which suggested that hydroxychloroquine had corticosteroid‐ sparing properties in the treatment of asthma. In an open study (Charous 1998) there were small but significant improvements in FEV1 and FVC together with a decrease in mean IgE levels. The importance of IgE reduction for asthmatic patients and the mechanism by which it occurs remains to be established (Ruhl 1993).
Chloroquine is usually well tolerated and appears to have greater safety in long‐term use than oral corticosteroids. The major adverse effect, whilst rare, is related to the selective accumulation of the drug in the retina which may subsequently result in irreversible, progressive visual impairment and even blindness. The risk is usually dose‐related and exceedingly rare or nonexistent with doses of hydroxychloroquine of 5 to 6 mg/kg/d or less.
Whilst narrative reviews of the use of chloroquine in asthma suggest that it is of benefit, evidence from open and randomised controlled trials give conflicting results. To date, no systematic review has been carried out to evaluate the evidence regarding chloroquine as an adjunct to oral corticosteroids in asthma.
Objectives
The objective of this review was to assess the effects of adding chloroquine to oral corticosteroids in adults with stable asthma who are dependent on oral corticosteroids.
Methods
Criteria for considering studies for this review
Types of studies
Randomised double‐blind placebo‐controlled trials in stable steroid dependent asthmatics met the inclusion criteria for the review.
Types of participants
Inclusion criteria
All trial patients should have a clinical diagnosis of asthma.
Initial therapy should include chronic use of oral prednisone or another oral corticosteroid preparation. Minimum duration of prior therapy with oral corticosteroids to be at least three months.
Duration of therapy should have been sufficient to allow for any benefit accruing from these agents to appear.
Exclusion criteria
Subjects not on chronic oral corticosteroids prior to trial.
Types of interventions
The addition of chloroquine or placebo in a blinded randomised fashion.
Types of outcome measures
Primary outcomes
Steroid consumption
Secondary outcomes
Pulmonary function testing (PEF, FEV1 & any others)
Symptoms
Use of rescue medications (e.g. bronchodilators)
Frequency of asthma exacerbation
Side effects and adverse effects
Hospital admissions
Search methods for identification of studies
Electronic searches
Trials were identified using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and handsearching of respiratory journals and meeting abstract (please see the Airways Group Module for further details). All records in the Specialised Register coded as 'asthma' were searched using the following terms:
Chloroquin* or aralen or arechine or arequin or chingamin or chlorochin or "chloroquine sulfate" or "chloroquine sulphate" or khingamin or nivaquine or "immunosuppresive agent*"
The most recent search was conducted in February 2011.
Searching other resources
Review articles and bibliographies identified from these primary papers were surveyed for additional citations and RCTs. The grey literature database SIGLE (1980‐2001) was also searched. Four authors were contacted to locate further trials and for more information; two responded. No further relevant trials were located.
Data collection and analysis
Selection of studies
The titles and abstracts obtained from the Airways Group were reviewed by two reviewers (Ad and AB) to identify all potential studies for inclusion. If a study was thought to potentially meet the inclusion criteria, or if further details were need to assess the study, then the full text of the publication was obtained for further information.
Data extraction and management
Data were extracted by two authors and entered into RevMan by one author.
Other characteristics of trials have been assessed as follows: i) "Chronic" & "Stable" was assessed operationally in terms of duration of prior oral corticosteroid therapy & variation in dose during that period. (ii) Use of inhaled corticosteroids. This was graded as: A Optimal B Sub optimal C Not stated. (iii) Prior attempts at reduction in oral corticosteroid dose should have been unsuccessful in eliminating chronic use. A "run in " period on a steady dose of oral corticosteroid following an attempt at reduction of corticosteroid dose is an important component of the trial design. the included study has been graded accordingly: A Steroid dose reduction attempted B No steroid dose reduction attempted C Not stated
Assessment of risk of bias in included studies
The methodological quality of each trial was reviewed according to the Cochrane allocation concealment scale:
A adequate concealment B uncertain C clearly inadequate
Trial quality was scored according to the 0‐5 scale of Jadad 1996 and will be assessed by two reviewers acting independently. Data extraction will be performed by two reviewers. Where agreement is not obtained, a third reviewer will check data extraction. Inter‐rater reliability to be assessed by simple agreement. Authors, where possible, will be contacted for missing data
Assessment of heterogeneity
We assessed statistical heterogeneity using the I square measurement (I2). Where heterogeneity was observed (I2 >40%), a Random Effects model was to be used to determine whether this made a difference to the overall pooled effect estimate.
Data synthesis
The planned comparison was a comparison of chloroquine versus placebo. Data were to be pooled with RevMan analyses. For continuous variables a fixed‐effect model was to be used to pool data. For dichotomous variables a fixed‐effect Relative Risk was to be used to pool data.
Subgroup analysis and investigation of heterogeneity
Tests for heterogeneity would have been performed on the data and subgroup comparisons would have been made on the basis of:
Optimal inhaled corticosteroid use Pre trial steroid tapering Disease severity
Results
Description of studies
Results of the search
The original search retrieved eight studies from the Cochrane Airways Group Specialised Register and independent searching of databases. Full text versions were obtained for all references. Two controlled trials were excluded due to lack of randomisation (Isomaki 1968; Stern 1960). Of the remaining five studies, one was a cohort study (Charous 1991), one was a case study (Hiragi 1964), and three were non‐randomised trials (Charous 1990; Spector 1997; Tennenbaum 1966). One study met the inclusion criteria (Roberts 1988).
Update searches have been run on a regular basis from 2003 until 2011 and failed to identify any new references.
Included studies
Study design
Roberts 1988 was a randomised, double‐blind crossover study.
Participants
Nine adult participants were recruited to the study (six males, three females), age range 29‐55. No withdrawals were reported. All participants were described as being steroid‐dependent, and controlled their asthma with one or more of: ß2‐agonists (9/9), high dose inhaled steroid (8/9; low dose steroid: 1/9), oral theophylline (5/9) and ipratropium bromide (2/9). Dose of oral prednisone ranged from 5 mg to 20 mg per day.
No classification of severity was given. FEV1 % predicted ranged from 10 to 94% (median 48). Eight participants were atopic.
Participants' medication was stabilised during a two week run‐in phase.
Interventions
Hydroxychloroquine (400 mg Bid) versus placebo. This was administered in addition to oral steroids. Participants also controlled their asthma with concomitant therapies (see above). The study lasted for 20 weeks.
The tapering protocol was commenced after week one on treatment. Participants were asked to reduce the dose of oral prednisone by 1 mg. If symptoms worsened they were then instructed to increase the dose by 10 mg. If this was necessary for any 3 days during a two week period, they increased the daily dose of prednisone by either 5 mg or to pre‐trial dose (whichever was smaller).
After treatment period 1, there was two week wash‐out during which time they reverted to the pre‐trial dose of prednisone.
Outcomes
Roberts 1988 measured consumption of steroids (absolute scores), symptoms (visual analogue scale), peak flow (L/min) and FEV1 (L/min). Side‐effects were noted.
Risk of bias in included studies
The included study was described as randomised and double‐blind. It received a Jadad score/allocation concealment rating of 3/B. These scores reflect under‐reporting of methods of randomisation, allocation and blinding rather than poor methods per se. All participants were accounted for in the results. However, no exclusion criteria were reported explicitly, and the diagnosis of asthma was not confirmed by consensus guidelines. The small sample size does not give the trial generalisability.
There was a two week washout between treatment periods but no carry‐over effect was measured.
Effects of interventions
Data are presented by comparison and then by outcome. As only one study could be used, data are presented from the published paper. No unpublished data were forthcoming from the trialists. Published data were presented as means and SEMs. We converted the SEMs to SDs and entered them in to RevMan.
Hydroxychloroquine + oral steroid versus plus + oral steroid
Primary outcome: Reduction in oral steroid
Roberts 1988 reported that there was no significant difference between placebo and hydroxychlorquine in terms of absolute dose of prednisone consumption (absolute scores: hydroxy: 12.4 mg (SEM 12.2) versus placebo 9.9 mg (SEM 8.1). No significant difference was reported in terms of change in consumption (no values presented. AD and TJL imputed baseline and absolute scores from raw data presented in a graphical format. These data have been entered as change scores.
Six participants in both groups were able to reduce steroid consumption (NS).
Secondary outcomes:
Peak flow (AM)
Roberts 1988 reported no significant difference between hydroxychlorquine and placebo (hydroxy: 196 L/min (SEM 94); placebo: 164 (SEM 98)).
Peak flow (PM)
Roberts 1988 reported no significant difference between hydroxychlorquine and placebo (hydroxy: 225 L/min (SEM 76); placebo: 204 (SEM 52)).
Pre‐dose FEV1
Roberts 1988 reported no significant difference in FEV1 between hydroxychlorquine and placebo (hydroxy: 1.34 (SEM 0.58); placebo: 1.28 (SEM 0.59).
Symptoms
Roberts 1988 reported no significant difference on symptoms between hydroxychlorquine and placebo (hydroxy: 4.8 (SEM 1.8); placebo: 5.5 (SEM 2.0).
Side effects
Roberts 1988 reported no significant side‐effects were noted between the two groups (no values presented).
Discussion
The findings of this review are limited by the paucity of data available from randomised studies. One small study (N = 9) met the inclusion criteria of the review. Whilst the population recruited to the study were not well‐defined by the trialists in terms of severity or diagnosis, the concomitant therapies, baseline lung function and their need for oral steroids, indicated that they represented the target population of this review.
The steroid‐sparing effects of gold have been assessed elsewhere in order to see whether they confer similar or improved asthma control whilst avoiding the serious side‐effects associated with oral steroids (Evans 2000). There has been very little recent interest in whether chloroquine offers such a role, as all the references identified were published before 1998. However, new inhaled steroids have been shown to be effective in terms of their oral steroid tapering efficacy, although the side‐effect profile of inhaled fluticasone remains unclear in the long‐term (Adams 2008). Equally, the assembled evidence in this review does not indicate whether long‐term use of chloroquine is associated with side‐effects, as they were not extensively reported in the non‐randomised studies (see Table 1). There have been concerns that chloroquine is associated with ocular disturbances, and steps were taken in both the included and excluded trials to ascertain whether this was so (Roberts 1988; Tennenbaum 1966).
1. Side‐effects noted in non‐randomised studies.
| Trials | N | Duration | SEs noted |
| Isomaki 1968 | 19 (no withdrawals) | 28 weeks | Nausea (n = 1). No other SEs related to treatment were noted. No participants withdrew as a result of SEs. |
| Stern 1960 | 13 completed out of 25 | Described as 'long‐term'. Treatment given ranged from 9 weeks to 1 year | No serious toxic effect noted. Chloroquine: Nausea n = 1. Three participants switched from chloroquine to placebo due to adverse effects |
| Tennenbaum 1966 | 4 (all completed) | 6 months | Early keratopathy in one patient. No other SEs reported. Mild nausea (n = 1) |
| Charous 1991 | 14 | 12 months | Non reported. |
In order for Chloroquine to be considered as an additional treatment to oral steroids, it must be shown to be effective over placebo in terms of steroid‐tapering. Furthermore the side‐effect profile of the drug should be established before its use as a possible adjuvant treatment can be recommended. Whilst further trials could be done to better establish the efficacy and safety of chloroquine, it is possible that more recent developments of potent inhaled steroids, such as inhaled fluticasone, or novel antibody treatment such as anti‐immunoglobulin E (Walker 2006) may have superceded the need for agents such as chloroquine in a steroid tapering capacity. However, for those who do not respond to any other steroid tapering agents, further trials could be warranted.
Authors' conclusions
Implications for practice.
The current evidence base does not lend support for the use of chloroquine as an oral steroid‐sparing agent.
Implications for research.
Further trials are necessary to establish whether chloroquine is a safe and effective steroid‐sparing agent. Such trials should be adequately powered, and should take account of new, potent inhaled steroids and active concomitant treatments such as ß2‐agonists, which may also have a steroid‐sparing effect. Run‐in phases should look to optimise steroid dosage rather than to stabilise it, in order to ensure that any steroid‐sparing effects may be more readily attributable to the addition of chloroquine. Entry criteria should then look to exclude those patients adequately controlled without the need for additional steroid‐sparing treatment. Side‐effects should also be carefully monitored.
What's new
| Date | Event | Description |
|---|---|---|
| 9 March 2011 | New search has been performed | Literature search run. No studies identified. |
History
Protocol first published: Issue 2, 2001 Review first published: Issue 4, 2003
| Date | Event | Description |
|---|---|---|
| 13 February 2009 | New search has been performed | Literature search run: no new studies found. |
| 22 July 2008 | Amended | Converted to new review format. |
| 24 July 2003 | New citation required and conclusions have changed | Substantive amendment |
Acknowledgements
We would like to thank the editorial base staff of the Cochrane Airways Group for assistance with searching, logistics and location of studies, namely Sarah Tracy, Karen Blackhall and Jo Picot. We would like to thank Makiko Meguro for translating papers from Japanese.
Data and analyses
Comparison 1. Chloroquine + steroid versus placebo + steroid.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Oral steroid consumption (change from baseline) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2 Symptoms | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3 Peak flow (am) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4 Peak flow (pm) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5 FEV1 | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected |
1.1. Analysis.
Comparison 1 Chloroquine + steroid versus placebo + steroid, Outcome 1 Oral steroid consumption (change from baseline).
1.2. Analysis.
Comparison 1 Chloroquine + steroid versus placebo + steroid, Outcome 2 Symptoms.
1.3. Analysis.
Comparison 1 Chloroquine + steroid versus placebo + steroid, Outcome 3 Peak flow (am).
1.4. Analysis.
Comparison 1 Chloroquine + steroid versus placebo + steroid, Outcome 4 Peak flow (pm).
1.5. Analysis.
Comparison 1 Chloroquine + steroid versus placebo + steroid, Outcome 5 FEV1.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Roberts 1988.
| Methods | DESIGN Randomised controlled cross‐over trial METHOD OF RANDOMISATION: Not stated CONCEALMENT OF RANDOMISATON: Not stated BLINDING: Double‐blind DESCRIPTION OF WITHDRAWALS/ DROPOUTS: all completed JADAD SCORE: 3 | |
| Participants | Enrolled into study N = 9
Withdrawals/dropouts: N =0
Completing trial: N = 9 Age: Mean (SD) 44 (10.3) range 29‐58 Sex: (M/F) 3/6 Severity: chronic steroid dependent Patient selection: Source Unspecified Inclus. criteria: None stated, but minimum one year use of oral steroids Excl. criteria: None stated |
|
| Interventions | Hydroxychloroquine = 400 mg/day Control treatment = Placebo Duration of study = 20 weeks 12 weeks run in 8 weeks = treatment/placebo 2 weeks washout 8 weeks ‐ treatment/placebo Original dose of prednisolone used during the washout period. | |
| Outcomes | Reduction in oral prednisolone Visual analogue symptom scores Beta 2 agonist FEV1 PFR (am & pm | |
| Notes | TAPERING OF STEROID USE: Classified B Run‐in period, but no tapering of oral steroids attempted PRIOR INHALED STEROID USE: Classified as A All but one patient on high dose inhaled beclomethasone (A) REGIME FOR REDUCING ORAL STEROID USE ON TRIAL: After 1st week patients asked to reduce steroid dose by 1 mg per week. If asthma symptoms worsened, extra 10 mgs on that day. If this was necessary on any 3 days in 2 weeks period then patient increased steroid dose by 5 mgs/pre‐trial dose | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Charous 1990 | Open trial |
| Charous 1991 | Cohort study |
| Hiragi 1964 | Case study. |
| Isomaki 1968 | Double‐blind, parallel group study. Randomisation not mention. Authors contacted, but no response forthcoming |
| Spector 1997 | Review article. |
| Stern 1960 | Double‐blind quasi experiment (alternate allocation) investigating the efficacy of Aralen versus placebo rather than as a steroid sparing agent for non‐steroid dependent asthmatics. |
| Tennenbaum 1966 | Open trial |
Contributions of authors
Taraneh Dean: Protocol initiation, analysis, lead author Ann Dewey: Protocol development, data extraction, analysis, interpretation Anna Bara: Protocol development and data extraction Toby Lasserson: Data extraction, analysis and interpretation Haydn Walters: Protocol development, interpretation, editorial input
Sources of support
Internal sources
No sources of support supplied
External sources
Garfield Weston Foundation, UK.
Declarations of interest
None known.
New search for studies and content updated (no change to conclusions)
References
References to studies included in this review
Roberts 1988 {published data only}
- Roberts JA, Gunneberg A, Elliott JA, Thomson NC. Hydroxychloroquine in steroid dependent asthma. Pulmonary Pharmacology 1988;1:59‐61. [DOI] [PubMed] [Google Scholar]
References to studies excluded from this review
Charous 1990 {published data only}
- Charous BL. Open study of hydroxychloroquine in the treatment of severe symptomatic or corticosteroid‐dependent asthma. Annals of Allergy 1990;65:53‐8. [PubMed] [Google Scholar]
Charous 1991 {published data only}
- Charous BL. Effectiveness of long‐term treatment of severe asthma with hydroxychloroquine (HCQ). Annals of NY Academy of Sciences 1991;629:432‐3. [DOI] [PubMed] [Google Scholar]
Hiragi 1964 {published data only}
- Hiragi. Novel treatment for bronchial asthma. Sego Rynsko 1964;13(1):152‐7. [Google Scholar]
Isomaki 1968 {published data only}
- Isomaki H, Kreus KE. Chloroquine in the treatment of bronchial asthma. Annals of Allergy 1968;26:61‐5. [PubMed] [Google Scholar]
Spector 1997 {published data only}
- Spector SL. Alternative treatments in the patient with intractable asthma. Pulmonary Medicine 1997;3:23‐9. [DOI] [PubMed] [Google Scholar]
Stern 1960 {published data only}
- Stern A, Zucker A, Sherman W, Florio A. An investigation into the use of aralen in bronchial asthma. Annals of Allergy 1960;18:980‐2. [Google Scholar]
Tennenbaum 1966 {published data only}
- Tennenbaum JI, Smith RE. Antimalarial therapy for resistant asthma. Annals of Allergy 1966;24:37‐40. [PubMed] [Google Scholar]
Additional references
Adams 2008
- Adams NP, Bestall JC, Lasserson TJ, Jones P, Cates CJ. Fluticasone versus placebo for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD003135.pub4] [DOI] [PubMed] [Google Scholar]
Charous 1998
- Charous BL, Halpern EF, Stevens GC. Hydroxychloroquine improves airflow and lowers circulating IgE levels in subjects with moderate symptomatic asthma. Journal of Allergy & Clnical Immunology 1998;102:198‐203. [DOI] [PubMed] [Google Scholar]
Evans 2000
- Evans DJ, Cullinan P, Geddes DM, Walters EH, Jones PW. Gold as an oral steroid sparing agent for asthma. Cochrane Database of Systematic Reviews 2000, Issue 4. [DOI: 10.1002/14651858.CD002985] [DOI] [Google Scholar]
Goldstein 1983
- Goldstein JA. Hydroxychloroquine for asthma (letter). American Review of Respiratory Disease 1983;128:1100‐1. [DOI] [PubMed] [Google Scholar]
Jadad 1996
- Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary?. Controlled Clinical Trials 1996;17:1‐12. [DOI] [PubMed] [Google Scholar]
Ruhl 1993
- Ruhl R, Halpern GM, Gershwin ME. Unconventional approaches to drug therapy in severe asthma. Allergologia et Immunopathologia 1993;21(2):53‐60. [PubMed] [Google Scholar]
Walker 2006
- Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH. Anti‐IgE for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD003559.pub3] [DOI] [PubMed] [Google Scholar]