- Open Access
The Difficult-to-Control Asthmatic: A Systematic Approach
© Canadian Society of Allergy and Clinical Immunology 2006
- Published: 15 September 2006
With the judicious use of inhaled corticosteroids, β2 agonists, and leukotriene modifiers, most patients with asthma are easily controlled and managed. However, approximately 5% of asthmatics do not respond to standard therapy and are classified as "difficult to control."  Typically, these are patients who complain of symptoms interfering with daily living despite long-term treatment with inhaled corticosteroids in doses up to 2,000 μg daily. Many factors can contribute to poor response to conventional therapy, and especially for these patients, a systematic approach is needed to identify the underlying causes. First, the diagnosis of asthma and adherence to the medication regimen should be confirmed. Next, potential persisting exacerbating triggers need to be identified and addressed. Concomitant disorders should be discovered and treated. Lastly, the impact and implications of socioeconomic and psychological factors on disease control can be significant and should be acknowledged and discussed with the individual patient. Less conventional and novel strategies for treating corticosteroid-resistant asthma do exist. However, their use is based on small studies that do not meet evidence-based criteria; therefore, it is essential to sort through and address the above issues before reverting to other therapy.
- Chronic Obstructive Pulmonary Disease
- Obstructive Sleep Apnea
- Allergic Rhinitis
Alternate Diagnoses to Consider in Difficult-to-Control Asthmatic Patients
Vocal cord dysfunction
Cardiac asthma/congestive heart failure
Chronic obstructive pulmonary disease
Gastroesophageal/supraesophageal reflux disease
Restrictive lung disease
Symptoms of hyperventilation often go unrecognized and may frequently be attributed to asthma. In a study of 14 "pseudosteroid-resistant" asthmatics, half were found to have hyperventilation as a potential cause of their disease . These patients typically note subjective dyspnea without any provoking triggers. Their difficulty often is with inhaling. They may complain that they "can't get a good breath" or "can't breathe" without any objective signs of respiratory distress. Although a methacholine challenge will invariably be negative, some may note a subjective response to rescue metreddose inhalers (MDIs) as proper inhalation techniques will slow the respiratory rate. For these patients, it may be beneficial to monitor peak expiratory flow rate (PEFR) before and after hyperventilation episodes to make patients aware of their breathing, and to retrain their breathing pattern .
Vocal Cord Dysfunction
Vocal cord dysfunction (VCD) may be seen alone or accompanying asthma and may masquerade as mild or severe asthma. Some patients with VCD may be on aggressive medical regimens, including oral corticosteroids and immunosuppressive therapy, and may even be classified as having corticosteroid-resistant asthma . Typically, patients complain of feeling "tight" but point to their throat, and for them, inhaling is more difficult than exhaling. These patients can quickly and unexpectedly go from well to severely ill, some following an irritant exposure but for most without any obvious trigger . The attack is not necessarily trivial as there can be accompanying oxygen desaturation. On auscultation, wheezing is loudest over the larynx. Although an inspiratory cutoff on the flow volume loop is characteristic of VCD, the diagnosis is best made by direct visualization of the vocal cords, which, during an acute attack, will show paradoxical movement during inspiration . VCD may or may not be a form of conversion disorder but has been found to follow physical or psychological trauma . Physician awareness and patient awareness are keys to successful treatment that involves speech and psychotherapy.
Once the diagnosis of asthma is made, it is important to ensure adherence to the medication regimen and document the correct use of inhalers. For "difficult asthmatics," this is particularly necessary because, although counterintuitive, asthmatics who are more ill are actually less likely to take their medicines . Despite our best efforts, poor adherence is surprisingly still common, and even more so with MDIs compared with oral medications, with some studies documenting between 10 and 46% adherence . The adolescent population in particular is notorious for noncompliance, some of the reasons being forgetfulness, denial, embarrassment, inconvenience, fear of side effects, a lack of efficacy of medicines, and laziness . Even when patients are compliant, use of improper inhaler techniques may prevent appropriate delivery of the drug. Therefore, a patient demonstration of proper techniques should be part of every physician visit.
For difficult-to-control asthmatics who have ongoing exposure to allergens or other triggers, identifying and eliminating these may help with asthma management. Microbial volatile organic compounds released from excess indoor mould growth and water-intruded areas are increasingly being recognized as important irritants triggering asthma . Although dust mite control measures are relatively easy to implement for those with dust mite allergy, noncompliance remains an important obstacle. Cost may become an issue for some families as environmental control measures are not covered by insurance companies . Removing or just keeping the house cat away from the bedroom is easy advice, but, apparently, too often it is not followed. Patients with a history of asthma that improves on weekends or holidays should raise the concern for exposure to occupational allergens or irritants. For these, serial PEFR measurements and specific challenge testing may need to be performed to institute appropriate avoidance measures or, when necessary, removal from the workplace. A drug history is always important to gather in a difficult asthmatic as such well-known and extensively used drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) and β-blockers can be significant unidentified precipitators of life-threatening asthma . One should keep in mind that aspirin and NSAIDS are in many over-the-counter cold remedies and are often overlooked. A simple question such as "What do you think causes your asthma?" may tease this out. Furthermore, identifying the aspirin-sensitive individual with aspirin-exacerbated respiratory disease or aspirin triad will help guide therapy (ie, aspirin desensitization) . Dietary additives have been reported to cause wheezing, although this is still subject to debate .
Concomitant Disorders that May Be Present in Asthmatic Patients
Gastroesophageal/supraesophageal reflux disease
Endocrinopathies (eg, hyperthyroidism, carcinoid syndrome)
Allergic bronchopulmonary aspergillosis
Aspirin-exacerbated respiratory disease
Churg-Strauss syndrome/other vasculitides
Gastroesophageal Reflux Disease/Supraesophageal Reflux Disease
Gastroesophageal reflux disease (GERD) is more common in patients with asthma, with an estimated prevalence of 34 to 80% . However, the diagnosis of GERD/supraesophageal reflux disease (SERD) is not always clear-cut. In one study, 40 to 60% of asthmatics, 57 to 94% of those with otolarynogologic symptoms and 43 to 75% with cough were shown to have SERD without classic reflux symptoms . To make the diagnosis, a 24-hour pH monitoring dual-probe study can correlate episodes of reflux with cough or other symptoms of asthma. Although a negative study can exclude acid-related symptoms, a positive study does not necessarily guarantee the success of acid suppression therapy. Often a therapeutic trial of medical therapy for GERD may be both diagnostic and therapeutic, with testing reserved for more uncertain or recalcitrant cases. Twice-daily proton pump inhibitors have been shown to have some therapeutic success, but it may take several weeks before an improvement in symptoms is noted . Furthermore, lifestyle changes consisting of elevating the head of the bed, waiting at least 2 hours between dinner and bedtime, and eating smaller and more frequent meals with reduction or elimination of substances that can exacerbate reflux (eg, alcohol, caffeine, nicotine), in addition to weight loss, are strongly recommended.
It is important to mention that hyperventilation and other forms of dysfunctional breathing may exist concomitantly with asthma, although the prevalence for this is unclear . Teasing this out can be a challenge, and tailoring therapy will likely be even more difficult. Recognizing the coexistence of dysfunctional breathing, however, can help prevent unnecessary step-up of asthma therapy.
There is increasing evidence that the upper and lower airways represent "one continuous airway," in which a pathologic process affecting one can affect the other. Therefore, uncontrolled allergic rhinitis or chronic rhinosinusitis can affect asthma control. Treatment of allergic rhinitis with nasal corticosteroids, for example, has been shown to improve symptoms of asthma and airway hyperresponsiveness . Identifying and managing upper respiratory inflammation is therefore important, especially in the group of difficult-to-control asthmatics. Endocrinopathies such as hyperthyroidism or hypocorticalism and carcinoid syndrome may lead to exacerbations and will need to be concomitantly treated. An elevated immunoglobulin E level in a persistent asthmatic with evidence of centrilobular bronchiectasis should lead to a full evaluation for allergic bronchopulmonary aspergillosis. Patients with Churg-Strauss vasculitis may also have particularly severe and difficult-to-manage asthma, the presence of which should be suspected in the setting of serum eosinophilia or a mononeuritis multiplex.
Potential Contributing Socioeconomic and Psychological Factors in the Difficult-to-Control Asthmatic
Socioeconomic risk factors
Access to medical care
Psychosocial issues (eg, crime, violence, unemployment)
Environment (indoor and outdoor allergens and irritants, eg, tobacco smoke, NO2)
Differing cultural practices
The psychosocial risk factors that exist in certain neighbourhoods can have a large impact on asthma care. Stresses arising from crime, violence, drugs, gangs, and unemployment take time, energy, and focus away from appropriately caring for a child with asthma. Families are often headed by single women who balance work, child care, and other issues of daily living. Multiple caretakers may exist for these children, making effective communication and education particularly difficult and challenging. Furthermore, aggression, anxiety, and depression can be important issues in difficult living conditions and have been found to be risk factors for childhood asthma mortality . Differing cultural practices can also represent barriers to effective care as certain individuals may choose to follow folk remedies for cures or to search other "healers" instead of seeking or complying with standard Western medical care.
Adherence can be a problem in any population, but additional barriers can exist for socioeconomically disadvantaged asthmatics. A lack of education or understanding of English, low household income, racial or ethnic minority status, and poor patient/physician communication are all factors associated with poor adherence . Besides adherence to medications, avoidance of triggers in this population also proves to be difficult. A study of inner-city children showed that only one-third were able to avoid known asthma triggers most of the time and about two-thirds could not prevent exposure to cigarette smoke .
Lastly, among socioeconomic factors, environmental exposure is also a major risk. The substandard housing that many of these patients live in contains high levels of indoor allergens, such as dust mite, mold, cockroach, and rodents, that are difficult to avoid and exterminate. Additionally, there can be exposure to tobacco smoke, volatile organic compounds, and nitrogen dioxide in the home. In highly polluted and industrial environments, limiting outdoor exposure to chemicals such as sulphur dioxide and ozone can be particularly difficult .
Although the barriers against effective asthma care appear to be insurmountable in the socioeconomically disadvantaged population, it appears that, especially in this group, education is an important step in achieving better asthma control. A recent review of programs that have attempted to reduce the number of emergency department visits and hospitalizations in African American and Hispanic patients found that successful programs have incorporated intensive and repetitive patient education regarding asthma as an inflammatory airway disease, environmental control, controller versus "quick relievers," prevention of exercise-induced asthma, written action plans for acute exacerbations, and demonstrating proper techniques for using inhaler devices . In addition, education by a nurse or pharmacist advocate, with time allotted for individual instruction, can be especially effective.
Existing psychological issues in a patient may make asthma particularly difficult to treat (see Table 3). Negative emotions, for whatever reason, even in normal patients, can influence the symptoms and management of asthma and should be recognized and addressed. When patients present with atypical symptoms or do not respond properly to medications, functional symptoms should be suspected. Psychiatric analysis may help determine this. In patients with comorbid asthma and anxiety disorders, treatment should be geared at controlling the asthma as asthma and sudden exacerbations are likely to cause anxiety and panic-like symptoms in the first place. Asthmatics with comorbid depression are especially difficult to treat. For this population, it is important and necessary to address and treat the depression before there can be any success with asthma therapy .
A few other categories of difficult-to-control asthma deserve brief mention. Premenstrual worsening of asthma can occur in some females and is typically poorly responsive to glucocorticoids but may respond to aggressive hormonal therapy . Nocturnal worsening of asthma may persist in some individuals despite maximal doses of corticosteroids, necessitating more aggressive interventions. Brittle asthma can be extremely unstable, may be related to a lack of perception of symptoms and disease severity, may involve unidentified triggers, and therefore may respond only to individualized therapy . Patients with "steroid-dependent asthma" can often be found on a "roller-coaster" pattern of recurring bursts of corticosteroid therapy, and for these, treating exacerbations long enough and with high-enough doses of steroids may be needed to achieve long-lasting effects. Steroid-resistant asthmatics are defined as those patients with persistent obstruction (<15% improvement in forced expiratory volume in 1 second) and inflammation despite treatment with 40 mg prednisone per day for more than 14 days. This "resistance" may be relative as some patients may respond to higher doses of steroids . On a molecular level, there appear to be two types of steroid resistance. The first type is less common and is believed to result from a reduction in the number of existing and functioning glucocorticoid receptors. Patients with this type do not experience improvement in their asthma, nor do they experience any side effects from the steroids. The second type is more common and involves a reversible binding defect of the steroid to its receptor. A third type may result from an increase in the catabolism of steroids and is seen most commonly in patients on mitochondrial enzyme oxidizing system stimulators, such as phenobarbital . Finally, there are patients with prolonged severe asthma who develop remodelling of their airways and irreversible obstruction for whom early recognition can be essential to effective management .
A few medical regimens, although nonstandard therapy, have been shown to have some clinical benefit in refractory asthma. The use of a single dose of intramuscular triamcinolone for difficult adult and pediatric asthmatics has been shown to reduce objective measures of inflammation and the number of asthma exacerbations, respectively [39, 40]. The reasons for these may be a combination of improved compliance, improved anti-inflammatory profile of parenteral steroids, and overcoming a relative steroid resistance. Omalizumab has also shown good clinical benefit for those moderate to severe persistent allergic asthmatics who have failed other therapy and should be considered for this group of patients . Anti-inflammatory therapies such as tumour necrosis factor-α inhibitors that target other aspects of the immune system have shown some benefits in early clinical trials of selected asthmatics with a specific immune profile, although their safety and efficacy will need to be more fully determined . Immunosuppressive agents such as cyclosporin A have been shown to have beneficial effects in some studies, but one must always weigh the potential side effects with the actual benefits . Lastly, therapies in both preclinical and early clinical stages, particularly immunomodulating agents such as deoxyribonucleic acid (DNA) vaccines, hold promise for high therapeutic potential and may become future options for these patients .
When confronted with a patient in whom asthma appears to be refractory to inhaled β2 agonists, leukotriene modifiers, and high-dose inhaled corticosteroids, a systematic and logical approach should be adopted. The first step is to confirm the diagnosis and to exclude potential masquerades of asthma, such as hyperventilation, VCD, or COPD. Next, assess compliance by direct questioning or monitoring inhaler use or prescription filling. Have the patient demonstrate the correct inhaler technique in the office. Once these are confirmed, the presence or persistence of exacerbating factors should be vigorously sought. Have all provoking stimuli in the forms of allergens or irritants been removed from the daily environment of the patient? Are there any potential aggravating factors or concomitant disorders, such as GERD or upper airway disease, that have not been treated? Is the patient taking any other medicines that can affect the asthma? Finally, acknowledge any underlying socioeconomic or psychological factors and, when possible, address these with the patient. Are there any barriers to communication, and should the treatment regimen be simplified for the sake of adherence? Perhaps the patient fits into a special category of particularly unstable asthma or exhibits a particular asthma phenotype for which tailoring and individualizing therapy will be beneficial. Approaching and addressing these issues in a systematic manner will help prevent unnecessary and inefficient therapy and will lead to the improved management of the difficult asthmatic patient.
- Barnes PJ, Woolcock AJ: Difficult asthma. Eur Respir J. 1998, 12: 1209-18. 10.1183/09031936.98.12051209.View ArticlePubMedGoogle Scholar
- Sutherland ER, Martin RJ: Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma. J Allergy Clin Immunol. 2003, 112: 819-27. 10.1016/S0091-6749(03)02011-6.View ArticlePubMedGoogle Scholar
- Sutherland EF: Outpatient treatment of chronic obstructive pulmonary disease: comparisons with asthma. J Allergy Clin Immunol. 2004, 114: 715-24. 10.1016/j.jaci.2004.07.044.View ArticlePubMedGoogle Scholar
- Thomas PS, Duncan MG, Barnes PJ: Pseudosteroid resistant asthma. Thorax. 1999, 54: 352-6. 10.1136/thx.54.4.352.PubMed CentralView ArticlePubMedGoogle Scholar
- De Peuter S, Van Diest I, Lemaigre V: Can subjective asthma symptoms be learned?. Psychosom Med. 2005, 67: 454-61. 10.1097/01.psy.0000160470.43167.e2.View ArticlePubMedGoogle Scholar
- O'Connell MA, Sklarew PR, Goodman DL: Spectrum of presentation of paradoxical vocal cord motion in ambulatory patients. Ann Allergy. 1995, 74: 341-4.Google Scholar
- Christopher KL, Wood RP, Eckert RC: Vocal-cord dysfunction presenting as asthma. N Engl J Med. 1983, 308: 1566-70. 10.1056/NEJM198306303082605.View ArticlePubMedGoogle Scholar
- Newman KB, Mason UG, Schmaling KB: Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med. 1995, 152: 1382-6.View ArticlePubMedGoogle Scholar
- Gavin LA, Wamboldt M, Brugman S: Psychological and family characteristics of adolescents with vocal cord dysfunction. J Asthma. 1998, 35: 409-17. 10.3109/02770909809048949.View ArticlePubMedGoogle Scholar
- Spector S: Noncompliance with asthma therapy--are theresolutions?. J Asthma. 2000, 37: 381-8. 10.3109/02770900009055463.View ArticlePubMedGoogle Scholar
- Celano M, Geller RJ, Philips KM: Treatment adherence among low-income children with asthma. J Pediatr Psychol. 1998, 23: 345-8. 10.1093/jpepsy/23.6.345.View ArticlePubMedGoogle Scholar
- Buston KM, Wood SF: Non-compliance amongst adolescents with asthma: listening to what they tell us about self-management. Fam Pract. 2000, 17: 134-8. 10.1093/fampra/17.2.134.View ArticlePubMedGoogle Scholar
- Daisey JM, Angell WJ, Apte MG: Indoor air quality, ventilation and health symptoms in schools: an analysis of existing information. Indoor Air. 2003, 13: 53-64. 10.1034/j.1600-0668.2003.00153.x.View ArticlePubMedGoogle Scholar
- Denson-Lino JM, Willies-Jacobo LJ, Rosas A: Effect of economic status on the use of house dust mite avoidance measures in asthmatic children. Ann Allergy. 1993, 71: 130-2.PubMedGoogle Scholar
- Ind PW, Dixon CMS, Fuller RW: Anticholinergic blockade of β blocker induced bronchoconstriction. Am Rev Respir Dis. 1989, 139: 1390-4.View ArticlePubMedGoogle Scholar
- Szczeklik A, Stevenson DD: Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol. 2003, 111: 913-21. 10.1067/mai.2003.1487.View ArticlePubMedGoogle Scholar
- Peroni DG, Boner AL: Sulfite sensitivity. Clin Exp Allergy. 1995, 25: 680-1. 10.1111/j.1365-2222.1995.tb00003.x.View ArticlePubMedGoogle Scholar
- Simpson WG: Gastroesophageal reflux disease and asthma: diagnosis and management. Arch Intern Med. 1995, 155: 798-804. 10.1001/archinte.155.8.798.View ArticlePubMedGoogle Scholar
- Richter JE: Extraesophageal presentations of gastroesophageal reflux disease. Semin Gastroenterol Dis. 1997, 8: 75-89.Google Scholar
- Park W, Hicks DM, Khandwala F: Laryngopharyngeal reflux: prospective cohort study evaluating optimal dose of proton pump inhibitor therapy and pretherapy predictors of response. Laryngoscope. 2005, 115: 1230-8. 10.1097/01.MLG.0000163746.81766.45.View ArticlePubMedGoogle Scholar
- Morgan MDL: Dysfunctional breathing in asthma: is it common, identifiable and correctable?. Thorax. 2002, 57: ii31-5.PubMed CentralPubMedGoogle Scholar
- Aubier M, Levy J, Cleici C: Different effects of nasal and bronchial glucocorticoid administration on bronchial hyperresponsiveness in patients with allergic rhinitis. Am Rev Respir Dis. 1992, 146: 122-6.View ArticlePubMedGoogle Scholar
- Pongracic J, Evans R: Environmental and socioeconomic risk factors in asthma. Immunol Allergy Clin North Am. 2001, 21: 413-26. 10.1016/S0889-8561(05)70218-6.View ArticleGoogle Scholar
- Bindman A, Grumbach K, Osmond D: Preventable hospitalizations and access to health care. JAMA. 1995, 274: 305-11. 10.1001/jama.274.4.305.View ArticlePubMedGoogle Scholar
- Evans R: Prevalence, morbidity, and mortality of asthma in the inner city. Pediatr Asthma Allergy Immunol. 1994, 8: 171-7. 10.1089/pai.1994.8.171.View ArticleGoogle Scholar
- Togias A, Horowitz E, Joyner D: Evaluating the factors that relate to asthma severity in adolescents. Int Arch Allergy Immunol. 1997, 113: 87-95. 10.1159/000237515.View ArticlePubMedGoogle Scholar
- Leickly FE, Wade SL, Crain E: Self-reported adherence, management behavior, and barriers to care after an emergency department visit by inner city children with asthma. Pediatrics. 1998, 101: E8-10.1542/peds.101.5.e8.View ArticlePubMedGoogle Scholar
- Strunk R, Mrazek D: Deaths from asthma in childhood: can they be predicted?. N Engl Regional Allergy Proc. 1986, 7: 454-61. 10.2500/108854186778984691.View ArticleGoogle Scholar
- Kattan M, Mitchell H, Eggleston P: Characteristics of inner-city children with asthma: the National Cooperative Inner-City Asthma Study. Pediatr Pulmonol. 1997, 24: 253-62. 10.1002/(SICI)1099-0496(199710)24:4<253::AID-PPUL4>3.0.CO;2-L.View ArticlePubMedGoogle Scholar
- Malveaux F, Fletcher-Vincent S: Environmental risk factors of childhood asthma in urban centers. Environ Health Perspect. 1995, 59-62. 10.2307/3432347. 103 SupplGoogle Scholar
- Peden D: The effect of air pollution in asthma and respiratory allergy--the American experience. Allergy Clin Immunol News. 1995, 7: 1-5.Google Scholar
- Self TH, Chrisman CR, Mason DL, Rumbak MJ: Reducing emergency department visits and hospitalizations in African American and Hispanic patients with asthma: a 15-year review. J Asthma. 2005, 42: 807-12. 10.1080/02770900500369835.View ArticlePubMedGoogle Scholar
- Rietveld S, Creer TL: Psychiatric factors in asthma: implications for diagnosis and therapy. Am J Respir Med. 2003, 2: 1-10.View ArticlePubMedGoogle Scholar
- Beynon HLC, Garbett ND, Barnes PJ: Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet. 1998, ii: 370-2.Google Scholar
- Ayres JG, Miles JF, Barnes PJ: Brittle asthma. Thorax. 1998, 53: 315-21. 10.1136/thx.53.4.315.PubMed CentralView ArticlePubMedGoogle Scholar
- Woolcock AJ: Steroid resistant asthma: what is the definition?. Eur Respir J. 1993, 6: 743-7.PubMedGoogle Scholar
- Leung DY, Spahn JD, Szefler SJ: Steroid-unresponsive asthma. Semin Respir Crit Care Med. 2002, 23: 387-98. 10.1055/s-2002-34353.View ArticlePubMedGoogle Scholar
- Ward C, Walters H: Airway wall remodeling: the influence of corticosteroids. Curr Opin Allergy Clin Immunol. 2005, 5: 43-8. 10.1097/00130832-200502000-00009.View ArticlePubMedGoogle Scholar
- ten Brinke A, Zqinderman A, Sterk PJ: "Refractory" eosinophilic airway inflammation in severe asthma. Am J Respir Crit Care Med. 2004, 170: 601-5. 10.1164/rccm.200404-440OC.View ArticlePubMedGoogle Scholar
- Panickar JR, Kenia P, Silverman M: Intramuscular triamcinolone for difficult asthma. Pediatr Pulmonol. 2005, 39: 421-5. 10.1002/ppul.20176.View ArticlePubMedGoogle Scholar
- Humbert M, Beasley R, Ayres J: Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy. Allergy. 2005, 60: 309-16. 10.1111/j.1398-9995.2004.00772.x.View ArticlePubMedGoogle Scholar
- Berry MA, Hargadon B, Shelley M: Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006, 354: 697-708. 10.1056/NEJMoa050580.View ArticlePubMedGoogle Scholar
- Niven AS, Argyros G: Alternate treatments in asthma. Chest. 2003, 123: 1254-65. 10.1378/chest.123.4.1254.View ArticlePubMedGoogle Scholar
- Varga EM, Nouri-Aria K, Till SJ: Immunomodulatory treatment strategies for allergic diseases. Curr Drugs Targets Inflamm Allergy. 2003, 2: 31-46. 10.2174/1568010033344507.View ArticleGoogle Scholar