|Year : 2021 | Volume
| Issue : 1 | Page : 3-7
Severe asthma with fungal sensitization
Rajendra Prasad1, Syed Ahmed Hussain Kazmi1, Rishabh Kacker1, Nikhil Gupta2
1 Department of Pulmonary Medicine, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
2 Department of General Medicine, Dr.Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||13-Oct-2020|
|Date of Acceptance||27-Aug-2021|
|Date of Web Publication||07-Dec-2021|
Dr. Rajendra Prasad
A-28, Sector J, Aliganj, Lucknow - 226 024, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Bronchial asthma is an inflammatory disease of the airways, which may be worsened due to many extrinsic factors. The most common trigger is the continuous exposure to allergens, of which fungal agents are important factors. A new phenotype of asthma called severe asthma with fungal sensitization (SAFS) has been described. It is diagnosed by the presence of severe asthma, fungal sensitization, and absence of allergic bronchopulmonary aspergillosis. SAFS is more of a diagnosis of exclusion. Treatment of SAFS initially should be similar to that of severe asthma including humanized anti-IgE monoclonal antibody and other biologics. These patients usually do not have their symptoms relieved with conventional treatment of severe asthma, i.e. high-dose inhaled corticosteroids and long-acting bronchodilators. Prolonged use of oral corticosteroids and pulse high-dose intravenous corticosteroid is effective. There are some evidence implicating the role of antifungal agents including itraconazole, but its use as a specific therapy requires further studies.
Keywords: SAFS, severe asthma, Aspergillus
|How to cite this article:|
Prasad R, Kazmi SA, Kacker R, Gupta N. Severe asthma with fungal sensitization. Indian J Allergy Asthma Immunol 2021;35:3-7
|How to cite this URL:|
Prasad R, Kazmi SA, Kacker R, Gupta N. Severe asthma with fungal sensitization. Indian J Allergy Asthma Immunol [serial online] 2021 [cited 2023 Mar 22];35:3-7. Available from: https://www.ijaai.in/text.asp?2021/35/1/3/331807
| Introduction|| |
Asthma is a heterogenous disease usually characterized by chronic airway inflammation and is defined by the history of respiratory symptoms such as chest tightness, shortness of breath, cough and wheeze that varies over time, and intensity together with variable airflow limitation. It is a serious public health problem affecting people of all ages throughout the world. Asthma can lead to severe limitation of activities in daily life and can even be fatal. Severe asthma is defined as asthma which requires treatment with high-dose inhaled corticosteroids (ICS) plus a second controller and/or systemic corticosteroids to prevent it from becoming uncontrolled or which remains uncontrolled despite adequate therapy. It is estimated that 5%–10% of asthmatics have poorly controlled disease. One-third to one-half of these severe asthmatics have atopic sensitization to filamentous fungi, especially to Aspergillus fumigatus. There are enough evidence that fungal sensitization is associated with more severe asthma phenotypes. Thus, an important subgroup of asthma termed as severe asthma with fungal sensitization (SAFS) has emerged. SAFS mimics allergic bronchopulmonary aspergillosis (ABPA). SAFS and ABPA can be hypothesized as different states of fungal sensitization, which differs in terms of immune response with asthma at one end of the spectrum and ABPA at the other. The term SAFS was introduced in 2006 and is defined as the presence of immediate cutaneous hyperreactivity to fungal antigen or increase in specific IgE antibodies to a particular fungus. Fungal sensitization may or may not be associated with severe asthma. The present study aims to review the current understanding of pathogenesis, diagnosis, and treatment of SAFS.
| Fungi and Severe Asthma|| |
Worsening asthma control with inhalation of fungal spores is similar as a foreign particle is being inhaled into the lung. Fungi interact directly with the human host in many ways. Many fungi have been associated with SAFS. The first evidence of the link between fungal sensitization and asthma was published in 1978, when Aspergillus sensitization was found to be involved in the severity of airway obstruction in 193 asthmatics. Relation between Alternaria species sensitivity and increased risk of respiratory disease was shown in 11 asthmatics. Subsequently, a correlation between sensitization to various fungi (e.g. Alternaria, Aspergillus, Aureobasidium, Cladosporium, Helminthosporium, and Trichophyton species) and severe asthma has been noticed.,,,,,,,,, The Respiratory Health Survey in European Community was conducted, which showed that asthma severity was associated with Alternaria or Cladosporium species sensitivity in 1132 adult asthmatics. It is a matter of inquisitiveness that whether all the fungi really cause SAFS or it is just a random association, as most of these fungi are rarely capable of growing in the human host to cause infection in the lung. The fungi have to grow at body temperature and this property is restricted to narrow range of fungi, particularly yeasts and member of Aspergillus and Penicillium. Only Aspergillus species can grow at 37°C. Small fungal spores of the mold A. fumigatus, which is abundant in environment, can easily reach the lower airways and alveoli through inhalation. Only with A. fumigatus, two extreme types of immune phenomenon, the Aspergillus-sensitized asthma and ABPA, are reported.,,,
| Prevalence of SAFS|| |
The prevalence of SAFS remains highly variable because it is a newly described entity. The World Health Organization estimated worldwide asthma prevalence to be roughly around 339 million cases with the possibility of up to 33.9 million of these falling into the SAFS category. Many studies have evaluated the prevalence of Aspergillus sensitization in bronchial asthma, which can be used to determine the prevalence of SAFS. In a systematic review and meta-analysis of 20 observational studies that included more than 5000 asthmatics, it was demonstrated the prevalence of Aspergillus sensitization in bronchial asthma to be ranging from 15% to 48%, with a pooled prevalence of 28%. Similar frequency of Aspergillus sensitization has been documented even in other studies., In a study conducted by Prasad et al., the prevalence of Aspergillus sensitization was found out to be 30.3% in 244 patients of bronchial asthma.
| Pathogenesis of SAFS|| |
The mechanism by which fungal allergens induce the hypersensitivity reaction is still an area of research. Fungal allergens are implicated in severe asthma compared with other aeroallergens because many allergens cause only a limited airway inflammation on inhalation., However, fungi such as Aspergillus species can elicit a profound immune response even without prior exposure. Fungal spores are ubiquitous in the environment and, thus, gain access to the respiratory tract via the inhalational route. SAFS is proposed as the occurrence of fungal sensitization with no and/or low levels of colonization. ABPA occurs in asthmatics who are genetically predisposed and SAFS being closely related to ABPA has the same genetic predisposition. The polymorphic major histocompatibility complex Class II molecules on antigen-presenting cells plays an important role in restricting antigen-specific T-cell activation. Fungi are known to produce a wide range of allergens that can be broadly classified into cell wall components such as β (1 → 3)-glucans, secreted products such as proteinases and glycosidases, and enzymes. Of these, the proteinases are presumed to be the most important agents. It may well be hypothesized that SAFS occurs due to an immune response against larger amounts of fungal proteinases. The antigens are further processed by the antigen-presenting cells and presented to T cells, which are then in turn activated. This immune-mediated inflammatory response leads to airway inflammation and worsening asthma control.
| Diagnosis of SAFS|| |
Fungal sensitization is defined as the presence of immediate cutaneous hyperreactivity to fungal antigen(s) or an increase in specific IgE antibodies to a particular fungus. Skin tests employ crude antigens and thus are more sensitive but less specific than fungus-specific serum IgE tests to diagnose fungal sensitization. Studies have compared skin testing with specific IgE levels, with conflicting results. The specific IgE levels were found to be better than skin prick test (SPT), which is in contrast to the findings of another study in which intradermal skin testing was superior to the measurement of specific IgE levels., Although theoretically both intradermal tests and SPT should perform in an identical manner, intradermal tests generally have been found to be more sensitive than SPT. SAFS is currently more of a diagnosis of exclusion. Criteria for the diagnosis of severe asthma with fungal sensitivity (SAFS) include history of poorly controlled asthma with the use of >500 μg/day of fluticasone or the equivalent, near continuous oral corticosteroids (OCS) use for >6 months, or >2 oral steroid tapers per year, total serum IgE <1000 IU/mL, positive immediate skin test reactivity to A. fumigatus or elevated specific serum IgE to A. fumigatus, absence of serum precipitins by gel diffusion or elevated specific serum IgG to A. fumigatus, and no radiographic evidence of bronchiectasis or infiltrates.
| Treatment of SAFS|| |
The important clinical question is whether patients with SAFS should be managed differently from other patients with severe asthma without fungal sensitization. The initial management of asthma with fungal sensitization should be on the same basis as those without fungal sensitization. The combination of long-acting beta-2 agonist (LABA) and ICS delivered using the SMART approach achieves better control of asthma than a high dose of ICS or ICS-LABA combination in poorly controlled asthmatics. Additional controller medications such as theophylline and leukotriene receptor antagonists should be added routinely. Omalizumab and itraconazole should be considered when the response is partial or lacking.
Omalizumab is a monoclonal antibody to IgE that prevents allergen-induced IgE-mediated signaling of the classic allergic inflammatory cascade. In a study where 205 patients who received omalizumab were analyzed to see change in 5-item Asthma Control Questionnaire (ACQ-5) score, the exacerbation frequency, and OCS dosage over a 24 month period revealed that omalizumab is an effective therapy in SAFS, leading to sustained improvements in symptoms and exacerbations.
| Corticosteroids|| |
A conventional high-dose ICS is insufficient to control SAFS. ICS useful for asthma management in patients with SAFS do not control the pathophysiology or clinical manifestations of SAFS.,,,, Use of chronic recurrent OCS carries a troublesome toxicity profile. Pulse steroid therapy 10–20 mg/kg/day, i.v. methylprednisolone infused on three consecutive days every 3–4 weeks have been found to be safe and effective in two open-labelled series of 13 steroid-dependent ABPA patients selected for this treatment because they were either not well controlled or had severe corticosteroid side effects on conventional oral prednisone treatment. Pulse i.v. steroid therapy was well tolerated, with disease control allowing discontinuation of pulse therapy after 6–12 months.,
The alternatives to long-term oral steroids are the use of antifungal agents as a primary treatment of SAFS. Antifungal treatment of SAFS rests upon an assumption that allergic inflammatory responses arise in part from noninvasive airway fungal infection. Antifungal therapy for SAFS has been directed against the main fungal pathogen, A. fumigatus. Pacheco et al. showed that itraconazole reduced specific IgG titers in patients. Germaud and Tuchais showed effectiveness of itraconazole in 11 out of 12 treated patients, including prevention of exacerbations in six patients who were successfully weaned off oral steroids. An antifungal agent, itraconazole, has also been used in SAFS in Fungal Asthma Sensitization Trial study. It was a randomized, placebo-controlled investigation assessing the effects of itraconazole, 200 mg twice daily till 8 months. The primary endpoint was change in the Asthma Quality of Life Questionnaire (AQLQ) score. The secondary endpoints were rhinitis score, decline in total IgE levels, and pulmonary function. The study enrolled 58 patients, only 41 of whom completed 32 weeks of therapy. At the end of 32 weeks, there was an improvement in the AQLQ. Modest degrees of improvement were also noted in the secondary endpoints. The apparent benefit of itraconazole is also confounded by the fact that itraconazole can increase the levels of certain inhaled steroids, thereby potentiating the effect of steroids.,, However, the optimal dose and therapy of antifungal remains unknown. Finally, azoles themselves have direct and profound immunologic effects.,,,,,, Hence, it is not definite that was it the antifungal action of azoles or the anti-inflammatory property of the drug that led to improvement in patients with SAFS. Newer oral triazoles with excellent anti-Aspergillus activity have also been reported as beneficial in the treatment of SAFS. Voriconazole has the advantage of excellent oral bioavailability. Amphotericin deoxycholate has been frequently used via inhalational route in the treatment of pulmonary fungal infection, primarily in the setting of cancer treatment and lung transplantation. There have been no published reports of inhaled amphotericin use in SAFS. The role of itraconazole and other antifungal agents in the treatment of SAFS requires further studies.
| Conclusion|| |
Fungal sensitization has been associated with increased asthma severity and mortality.
A variety of fungi are related to SAFS; however, this association has been more extensively studied for Aspergillus species. Diagnosis of SAFS should carefully be made as there is a significant overlap with ABPA, especially ABPA-S. Patients with SAFS should be initially managed on a similar line as those with severe asthma. Corticosteroids remain the validated mainstay pharmacological treatment in SAFS. The role of itraconazole and other antifungal agents in the treatment of SAFS requires further study. Further studies are required to define the exact place of SAFS as a separate subtype of asthma.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, et al
. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588. doi: 10.1183/13993003.00588-2019. PMID: 31558662.
Reddy RC. Severe asthma: Approach and management. Postgrad Med J 2008;84:115-20.
Schwartz HJ, Citron KM, Chester EH, Kaimal J, Barlow PB, Baum GL, et al
. A comparison of the prevalence of sensitization to Aspergillus
antigens among asthmatics in Cleveland and London. J Allergy Clin Immunol 1978;62:9-14.
O'Hollaren MT, Yunginger JW, Offord KP, Somers MJ, O'Connell EJ, Ballard DJ, et al.
Exposure to an aeroallergen as a possible precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med 1991;324:359-63.
Peat JK, Tovey E, Mellis CM, Leeder SR, Woolcock AJ. Importance of house dust mite and Alternaria
allergens in childhood asthma: An epidemiological study in two climatic regions of Australia. Clin Exp Allergy 1993;23:812-20.
Nelson HS, Szefler SJ, Jacobs J, Huss K, Shapiro G, Sternberg AL. The relationships among environmental allergen sensitization, allergen exposure, pulmonary function, and bronchial hyperresponsiveness in the Childhood Asthma Management Program. J Allergy Clin Immunol 1999;104:775-85.
Neukirch C, Henry C, Leynaert B, Liard R, Bousquet J, Neukirch F. Is sensitization to Alternaria
alternata a risk factor for severe asthma? A population-based study. J Allergy Clin Immunol 1999;103:709-11.
Roux P, Smit M, Weinberg EG. Seasonal and recurrent intensive care unit admissions for acute severe asthma in children. S Afr Med J 1993;83:177-9.
Niedoszytko M, Chełmińska M, Jassem E, Czestochowska E. Association between sensitization to Aureobasidium pullulans
(Pullularia sp) and severity of asthma. Ann Allergy Asthma Immunol 2007;98:153-6.
Matsuoka H, Niimi A, Matsumoto H, Ueda T, Takemura M, Yamaguchi M, et al.
Specific IgE response to trichophyton and asthma severity. Chest 2009;135:898-903.
Fairs A, Agbetile J, Hargadon B, Bourne M, Monteriro WR, Brightling CE, et al
. IgE sensitisation to Aspergillus fumigatus
is associated with reduced lung function in asthma. Am J Respir Crit Care Med 2010;182:1362-8.
Agarwal R, Noel V, Aggarwal AN, Gupta D, Chakrabarti A. Clinical significance of Aspergillus
sensitisation in bronchial asthma. Mycoses 2011;54:e531-8.
Menzies D, Holmes L, McCumesky G, Prys-Picard C, Niven R. Aspergillus
sensitization is associated with airflow limitation and bronchiectasis in severe asthma. Allergy 2011;66:679-85.
Maurya V, Gugnani HC, Sarma PU, Madan T, Shah A. Sensitization to Aspergillus
antigens and occurrence of allergic bronchopulmonary aspergillosis in patients with asthma. Chest 2005;127:1252-9.
Zureik M, Neukirch C, Leynaert B, Liard R, Bousquet J, Neukirch F, et al.
Sensitisation to airborne moulds and severity of asthma: Cross sectional study from European Community respiratory health survey. BMJ 2002;325:411-4.
Agarwal R, Gupta D, Aggarwal AN, Behera D, Jindal SK. Allergic bronchopulmonary aspergillosis: Lessons from 126 patients attending a chest clinic in north India. Chest 2006;130:442-8.
Agarwal R, Gupta D, Aggarwal AN, Saxena AK, Chakrabarti A, Jindal SK. Clinical significance of hyperattenuating mucoid impaction in allergic bronchopulmonary aspergillosis: An analysis of 155 patients. Chest 2007;132:1183-90.
Agarwal R, Gupta D, Aggarwal AN, Saxena AK, Saikia B, Chakrabarti A, et al.
Clinical significance of decline in serum IgE levels in allergic bronchopulmonary aspergillosis. Respir Med 2010;104:204-10.
Agarwal R, Khan A, Gupta D, Aggarwal AN, Saxena AK, Chakrabarti A. An alternate method of classifying allergic bronchopulmonary aspergillosis based on high-attenuation mucus. PLoS One 2010;5:e15346.
Agarwal R, Chakrabarti A. Epidemiology of allergic bronchopulmonary aspergillosis. In: Pasqualotto AC, editor. Aspergillosis: From Diagnosis to Prevention. New York: Springer; 2009. p. 671-88.
Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Aspergillus
hypersensitivity and allergic bronchopulmonary aspergillosis in patients with bronchial asthma: Systematic review and meta-analysis. Int J Tuberc Lung Dis 2009;13:936-44.
Prasad R, Garg R, Sanjay, Dixit R. A study on prevalence of allergic bronchopulmonary aspergillosis in patients of bronchial asthma. Internet J Pulm Med 2008;9:2.
Renz H, Smith HR, Henson JE, Ray BS, Irvin CG, Gelfand EW. Aerosolized antigen exposure without adjuvant causes increased IgE production and increased airway responsiveness in the mouse. J Allergy Clin Immunol 1992;89:1127-38.
Gulbenkian AR, Egan RW, Fernandez X, Jones H, Kreutner W, Kung T, et al.
Interleukin-5 modulates eosinophil accumulation in allergic guinea pig lung. Am Rev Respir Dis 1992;146:263-6.
Corry DB, Grünig G, Hadeiba H, Kurup VP, Warnock ML, Sheppard D, et al.
Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice. Mol Med 1998;4:344-55.
Agarwal R. Allergic bronchopulmonary aspergillosis: Lessons learnt from genetics. Indian J Chest Dis Allied Sci 2011;53:137-40.
28Horner WE, Helbling A, Salvaggio JE, Lehrer SB. Fungal allergens. Clin Microbiol Rev 1995;8:161-79.
Liang KL, Su MC, Jiang RS. Comparison of the skin test and ImmunoCAP system in the evaluation of mold allergy. J Chin Med Assoc 2006;69:3-6.
O'Driscoll BR, Powell G, Chew F, Niven RM, Miles JF, Vyas A, et al.
Comparison of skin prick tests with specific serum immunoglobulin E in the diagnosis of fungal sensitization in patients with severe asthma. Clin Exp Allergy 2009;39:1677-83.
Malo JL, Paquin R. Incidence of immediate sensitivity to Aspergillus fumigatus
in a North American asthmatic population. Clin Allergy 1979;9:377-84.
Agarwal R, Khan A, Aggarwal AN, Gupta D. Is the SMART approach better than other treatment approaches for prevention of asthma exacerbations? A meta-analysis. Monaldi Arch Chest Dis 2009;71:161-9.
Wark P, Hussaini S, Holder C, Powell H, Gibson P, Oldmeadow C. Omalizumab Is an Effective Intervention in Severe Asthma with Fungal Sensitization. J Allergy Clin Immunol Pract 2020;8:3428-33.
Citron M, Crompton GK, Berry G, Milne LJR, Pines A, Clark RA et al.
Beclomethasone dipropionate in allergic bronchopulmonary aspergillosis. Report to the Research Committee of the British Thoracic Association. Br J Dis Chest. 1979;73:349-56. doi: 10.1016/s0007-0971(79)80172-2. PMID: 400108.
Heinig JH, Weeke ER, Groth S, Schwartz B. High-dose local steroid treatment in bronchopulmonary aspergillosis. A pilot study. Allergy 1988;43:24-31.
Imbeault B, Cormier Y. Usefulness of inhaled high-dose corticosteroids in allergic bronchopulmonary aspergillosis. Chest 1993;103:1614-7.
Seaton A, Seaton RA, Wightman AJ. Management of allergic bronchopulmonary aspergillosis without maintenance oral corticosteroids: A fifteen-year follow-up. QJM 1994;87:529-37.
Agarwal R, Khan A, Aggarwal AN, Saikia B, Gupta D, Chakrabarti A. Role of inhaled corticosteroids in the management of serological allergic bronchopulmonary aspergillosis (ABPA). Intern Med 2011;50:855-60.
Thomson JM, Wesley A, Byrnes CA, Nixon GM. Pulse intravenous methylprednisolone for resistant allergic bronchopulmonary aspergillosis in cystic fibrosis. Pediatr Pulmonol 2006;41:164-70.
Cohen-Cymberknoh M, Blau H, Shoseyov D, Mei-Zahav M, Efrati O, Armoni S, et al.
Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros 2009;8:253-7.
Pacheco A, Martin JA, Cuevas M. Serologic response to itraconazole in allergic bronchopulmonary aspergillosis. Chest 1993;103:980-1.
Germaud P, Tuchais E. Allergic bronchopulmonary aspergillosis treated with itraconazole. Chest 1995;107:883.
Denning DW, O'Driscoll BR, Powell G, Chew F, Atherton GT, Vyas A, et al.
Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: The Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med 2009;179:11-8.
Skov M, Main KM, Sillesen IB, Müller J, Koch C, Lanng S. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J 2002;20:127-33.
Varis T, Kaukonen KM, Kivistö KT, Neuvonen PJ. Plasma concentrations and effects of oral methylprednisolone are considerably increased by itraconazole. Clin Pharmacol Ther 1998;64:363-8.
Varis T, Kivistö KT, Neuvonen PJ. The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone. Eur J Clin Pharmacol 2000;56:57-60.
Kim JH, Ahn YK. The effects of itraconazole on the immune responses in ICR mice. J Toxicol Sci 1994;19:7-15.
Abruzzo GK, Fromtling RA, Turnbull TA, Giltinan DM. Effects of bifonazole, fluconazole, itraconazole, and terbinafine on the chemiluminescence response of immune cells. J Antimicrob Chemother 1987;20:61-8.
Pawelec G, Jaschonek K, Ehninger G. The anti-fungal agent itraconazole exerts immunosuppressive effects on alloreactivity but not on natural immunity in vitro
. Int J Immunopharmacol 1991;13:875-9.
Pawelec G, Ehninger G, Rehbein A, Schaudt K, Jaschonek K. Comparison of the immunosuppressive activities of the antimycotic agents itraconazole, fluconazole, ketoconazole and miconazole on human T-cells. Int J Immunopharmacol 1991;13:299-304.
Kanda N, Enomoto U, Watanabe S. Anti-mycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis. J Invest Dermatol 2001;117:1635-46.
Ausaneya U, Kawada A, Aragane Y. Itraconazole suppresses an elicitation phase of a contact hypersensitivity reaction. J Invest Dermatol 2006;126:1028-35.
Simitsopoulou M, Roilides E, Likartsis C, Ioannidis J, Orfanou A, Paliogianni F, et al.
Expression of immunomodulatory genes in human monocytes induced by voriconazole in the presence of Aspergillus fumigatus
. Antimicrob Agents Chemother 2007;51:1048-54.