|Year : 2020 | Volume
| Issue : 2 | Page : 98-101
Steroid-sparing effect of omalizumab in stage IV (corticosteroid dependent) allergic bronchopulmonary aspergillosis
PC Kathuria, Manisha Rai, Neelam Kathuria
National Allergy Centre, BLK Super Specialty Hospital, Delhi, India
|Date of Submission||11-Dec-2019|
|Date of Decision||11-Jan-2020|
|Date of Acceptance||26-Jan-2020|
|Date of Web Publication||27-Mar-2020|
Dr. P C Kathuria
National Allergy Centre, 1/3, East Patel Nagar, New Delhi - 110 008
Source of Support: None, Conflict of Interest: None
Allergic bronchopulmonary aspergillosis (ABPA) consists of five stages ranging from the acute stage (pulmonary infiltrate, eosinophilia, and increased total Immunoglobulin-E [IgE]) to pulmonary fibrosis. Our patients were diagnosed as Stage IV (corticosteroid dependent) ABPA, in which treatment with systemic corticosteroids cannot be discontinued as symptoms worsen after discontinuation of oral corticosteroids. Omalizumab is a humanized recombinant, monoclonal antibody that selectively binds to IgE to inhibit the immune response to an allergen. It forms immune complexes which not only lower the level of free IgE antibody, but also serve as an allergen buffer, even in cases of markedly high serum IgE >1000 IU/ml in ABPA. In this article, we report three cases of (Stage IV) corticosteroid-dependent ABPA with poor clinical response even after effective treatment with antifungal therapy and courses of corticosteroids (>3 exacerbations/year). After the start of injection omalizumab, the three patients have experienced significant and sustained clinical improvement and improved quality of life with low-dose prednisolone 5 mg every alternate day. The dose of systemic corticosteroids was reduced by 50% in the 1st year and by 70% in the 2nd year although lung function failed to improve.
Keywords: Aspergillus fumigatus, asthma, corticosteroid-dependent allergic bronchopulmonary aspergillosis Stage IV, Immunoglobulin-E, omalizumab
|How to cite this article:|
Kathuria P C, Rai M, Kathuria N. Steroid-sparing effect of omalizumab in stage IV (corticosteroid dependent) allergic bronchopulmonary aspergillosis. Indian J Med Spec 2020;11:98-101
|How to cite this URL:|
Kathuria P C, Rai M, Kathuria N. Steroid-sparing effect of omalizumab in stage IV (corticosteroid dependent) allergic bronchopulmonary aspergillosis. Indian J Med Spec [serial online] 2020 [cited 2020 Aug 13];11:98-101. Available from: http://www.ijms.in/text.asp?2020/11/2/98/281461
| Introduction|| |
Allergic bronchopulmonary aspergillosis (ABPA) is a condition in which the immune system evokes an exaggerated allergic response to the common soil-dwelling fungus Aspergillus. Aspergillus spores are found regularly in crawl spaces, “unfinished” basements, compost piles, and manure and fertile soil. ABPA is characterized by severe symptoms of asthma or bronchitis associated with chronic airway inflammation and if left untreated, the condition is likely to progress to irreversible airway damage and lung scarring. Patients who already suffer from asthma or cystic fibrosis are more likely to develop this disease, and this condition is characterized by the presence of high levels of Aspergillus-targeted immunoglobulin-E (IgE) antibodies in the blood; these are the key antibodies involved in allergy. Some patients develop acute wheezing, dyspnea, and ABPA exacerbations after inhalation of heavy spore burdens such as moldy, wood chips or after exposure to closed-up cottage homes. This disease results from hypersensitivity to Aspergillus antigens, and afflicted patients may present with airway inflammation, bronchiectasis, and bronchoconstriction. Corticosteroids are the acknowledged first-line therapy for this condition. Itraconazole is often added to therapy if there is a slow or poor response to corticosteroids. Five stages of ABPA have been identified. These stages are acute, remission, exacerbation, corticosteroid-dependent, and fibrotic ABPA. These stages are not necessarily progressive phases of the disease, as patients need not inevitably pass from one stage to the next. Stage I (acute flare) or Stage III (recurrent exacerbation) is treated with 0.5–1.0 mg/kg of prednisolone daily for 14 days and then slowly tapered over 3–6 months. Stage II (remission) and Stage V (fibrotic lung disease) do not warrant oral corticosteroid treatment, whereas Stage IV (corticosteroid-dependent ABPA) is present where patient needs daily dose of oral steroids to keep himself/herself symptom free and cannot discontinue oral corticosteroids. We report three cases of corticosteroid-dependent ABPA (Stage IV) with unsatisfactory clinical progress and multiple acute exacerbations despite antifungal and corticosteroid treatment with unacceptable adverse effects, who responded to omalizumab, and steroid doses could be reduced.
| Case Presentation|| |
A 58-year-old female was diagnosed as allergic bronchial asthma at the age of 14 years; since then, she had frequent exacerbations, even after effective doses of long-acting β2 agonist (LABA), long-acting muscarinic antagonist (LAMA), and inhaled corticosteroid (ICS) of >1200 μg of budesonide. During acute exacerbations, she used to have wheezing and intermittent fever and cough with mucus plugs, and her symptoms improved after a course of methylprednisolone 0.5–1 mg/kg body weight.
In 2013, she was receiving corticosteroid (methylprednisolone) every other day. Her total IgE was 1300 IU/ml with eosinophilia (18%). Intradermal skin tests (IDSTs) were positive to Aspergillus fumigatus (9 mm wheal size) and other fungi also. X-ray chest revealed an infiltrate in the middle lobe of the right lung, computed tomography (CT) chest was suggestive of central bronchiectasis characteristic of ABPA [Figure 1], specific IgE to A. fumigatus was 7.8 kU/L, serum cortisol was 2.6 mg/dL (normal = 8–22 μg/dL), and specific IgG to A. fumigatus was positive. She was diagnosed as Stage IV ABPA. In order to reduce the oral steroids (methylprednisolone 16 mg), she was started with itraconazole 200 mg twice a day, but she experienced adverse drug reaction and was switched to fluconazole 150 mg daily for 6 weeks but without any benefits. However, while decreasing the dose of methylprednisolone from 16 to 8 mg, there was worsening of symptoms with drop in peak expiratory flow rate (PEFR) from 270 to 230 L/min. She could not be weaned off oral corticosteroids and so was initiated on injection omalizumab 300 mg every 4 weeks for 6 months and continued at 150 mg every month for 2 years. Improvement with omalizumab was decided clinically: responder (Grade I – complete and Grade II – marked improvement) or nonresponder (no appreciable change, or worsening of symptoms). She responded as Grade II, so injection omalizumab was continued for 2 years. During this period, she showed marked improvement in terms of symptom scoring (reduced 70%) by visual analog scale, reduced the amount of steroid intake to 50% in the 1st year (16 mg to 8 mg) and 70% in the 2nd year (4 mg every alternate day), and had no exacerbations during this period. Her lung function remained stable (PEFR variability and reversibility <10% and forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC] 71%–73%). Follow-up was done for 3 years with no exacerbations.
A 59-year-old male had a history of nonproductive cough without fever at the age of 12 years, which later became progressive with repetitive episodes of cough and wheezing. He had a history of repeated episodes of pneumonia for which bronchodilators and antibiotics were prescribed. He was diagnosed with pulmonary tuberculosis at the age of 30 years and took anti-tubercular treatment for 1½ years. He had a history of sensitivity to dust/dampness/smoke, etc., and was on regular intake of LABA + LAMA + ICS with doxophylline and montelukast along with corticosteroid intake (20 mg of prednisolone) for the last 12 years.
CT chest revealed central bronchiectasis [Figure 2]a and [Figure 2]b. The total IgE was 990 IU/mL, specific IgE to A. fumigatus was 2.6 kU/ml, serum cortisol was 3.2 μg/ml, specific IgG to A. fumigatus was positive, and skin test was 3+, IDST 10-mm wheal size. A spirometry determined FVC of 51% and FEV1 of 40% predicted, and he was diagnosed as (Stage IV) ABPA steroid dependent with hypothalamic–pituitary–adrenal suppression. He was given voriconazole 200 mg/day, but was discontinued after 6 weeks because of adverse effects. In July 2013, injection omalizumab was started for 6 months at 300 mg once a month and then continued at a dose of 150 mg/month for 1.5 years. The dose of prednisolone was reduced to 50% (10 mg) after 6 months and, after 12 months, reduced to a maintenance dose of 5 mg/day. During the follow-up period of 3 years, his respiratory status remained stable, with no exacerbations. Thus, omalizumab has the potential as an adjuvant therapy in corticosteroid-dependent ABPA (Stage IV).
|Figure 2: (a and b) Computed tomography of case 2 showing central bronchiectasis|
Click here to view
A 57-year-old male, a long-standing case of severe persistent bronchial asthma (Step V) with ABPA (Stage IV) with diabetes mellitus for the last 5 years, on regular intake of maintenance dose of 16-mg methylprednisolone on alternate days with high dose of ICS (1200 μg of budesonide); LABA and LAMA; and montelukast, theophylline, and oral β2 agonist along with conventional treatment for diabetic mellitus (insulin and oral hypoglycemic agents [OHAs]). His total IgE was 1015 kIU/L, skin prick test was positive to A. fumigatus, specific IgE to Aspergillus was 8.5 KU/L, serum was positive for precipitating antibody to Aspergillus (IgG), and serum cortisol was 3.7 μg/dL, and he had persistent and diffuse airway obstruction (FEV1– 30%, FVC – 52%, and FEV1/FVC – 44%). CT chest revealed central bronchiectasis [Figure 3]. He remained symptomatic and required frequent courses of oral/parenteral corticosteroid during exacerbations and was prescribed a maintenance dose of 15-mg oral prednisolone on alternate days, but on tapering prednisolone, his symptoms got worse and PEFR readings dropped. He was started on injection omalizumab at 300 mg every month for 6 months and then at 150 mg every month for 1.5 years. The dose was well tolerated and after 4 months, prednisolone was slowly weaned off to 50%. Then, after 1 year, the dose was reduced to 5 mg on alternate days and PEFR reading stabilized (300 L/min to 320 L/min). The dose of OHA and insulin was also reduced. Since the start of injection omalizumab and on follow-up for 3 years, he remained on 5 mg of prednisolone, on alternate days with no exacerbations.
| Discussion|| |
Aspergillus is a genus of fungi with worldwide distribution, found in decomposing organic ceiling walls with water contamination. Aspergillus spores can penetrate deep into the respiratory system to the alveolar level. These spores once present in the pulmonary tissues, germinate and lead to hyphae growing in the mucus plugs. There are two types of hypersensitivity reaction – Type I response (IgE mediated) and Type III hypersensitivity response (IgG mediated). IgE-mediated response results in mast cell degranulation with bronchoconstriction and increased capillary permeability. Type III reaction involves immune complex with inflammatory cells deposited within the mucus membranes of the airways, leading to necrosis and neutrophilic infiltration. This necrosis is further facilitated by proteolytic enzymes by both fungus and neutrophils, leading to wide-scale damage of pulmonary parenchyma and irreversible lung remodeling. The diagnosis of ABPA is a combination of clinical, radiological, and laboratory criteria. Now, recombinant antigens of A. fumigatus (rAspf4 and f6) represent specific markers for ABPA and allow differentiation from Aspergillus-sensitized asthma.
Treatment is decided by the severity and the intensity of symptoms and lung functions, with the aim to reduce immunological activity and inflammatory cells. Oral corticosteroid remains the mainstay of therapy along with antifungal treatment to prevent and eradicate the growth of fungal hyphae within the pulmonary tissue. Our three cases were diagnosed as (Stage IV) ABPA on the basis of clinicoradiological and immunological tests, with progressively worsening symptoms, with severe exacerbations (>3/year), that required hospitalization and high dose of corticosteroids. It was decided to treat them with injection omalizumab. Omalizumab is a humanized monoclonal antibody directed against IgE. Clinical response by the end of 4 months of injection omalizumab treatment was very satisfactory, which led to the decision of further continuing therapy. Similar benefit with omalizumab for the treatment of ABPA with severe bronchial asthma, refractory to high doses of ICS with intolerance to antifungal treatment, has been reported, and it can supposedly prevent progress to irreversible damage (fibrotic Stage V).,,,, None of our three cases experienced any side effect due to omalizumab during the treatment period except nasopharyngitis, headache, injection-site pain, injection-site reaction, and arthralgia, which were well controlled with symptomatic treatment. These cases illustrate that injection omalizumab given over 2 years can result in sustained clinical improvement, and long-lasting effect over a follow-up period of 3 years can be seen with no exacerbations. Added benefits include reduction in steroid dosing, suggesting that omalizumab has a steroid-sparing effect, which has also been reported by other authors., However, long-term efficacy and safety data may be warranted in well-planned studies.
| Conclusion|| |
In this case series study, all patients had positive clinical response to therapy with omalizumab, showing a good safety profile. Omalizumab has the potential to be an effective alternative or as an additional therapy option for ABPA in asthma patients who fail to respond to corticosteroids, providing a steroid-sparing effect.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Patel AR, Patel AR, Singh S, Singh S, Khawaja I. Diagnosing allergic bronchopulmonary aspergillosis: A review. Cureus 2019;11:e4550.
Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al
. Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46:327-60.
Agarwal R, Nath A, Aggarwal AN, Gupta D, Chakrabarti A. Aspergillus
hypersensitivity and allergic bronchopulmonary aspergillosis in patients with acute severe asthma in a respiratory intensive care unit in North India. Mycoses 2010;53:138-43.
Li JX, Fan LC, Li MH, Cao WJ, Xu JF. Beneficial effects of Omalizumab therapy in allergic bronchopulmonary aspergillosis: A synthesis review of published literature. Respir Med 2017;122:33-42.
Evans MO 2nd
, Morris MJ, Coop CA, Evans SE. Omalizumab, an additional therapy for allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol 2015;115:250-1.
Tracy MC, Okorie CU, Foley EA, Moss RB. A case of allergic bronchopulmonary aspergillosis treated with omalizumab. J Investig Allergol Clin Immunol 2012;22:145-7.
Tillie-Leblond I, Germaud P, Leroyer C, Tétu L, Girard F, Devouassoux G, et al
. Allergic bronchopulmonary aspergillosis and omalizumab. Allergy 2011;66:1254-56.
van der Ent CK, Hoekstra H, Rijkers GT. Successful treatment of allergic bronchopulmonary aspergillosis with recombinant anti-IgE antibody. Thorax 2007;62:276-7.
Zirbes JM, Milla CE. Steroid-sparing effect of omalizumab for allergic bronchopulmonary aspergillosis and cystic fibrosis. Pediatr Pulmonol 2008;43:607-10.
Beam KT, Coop CA. Steroid sparing effect of omalizumab in seropositive allergic bronchopulmonary aspergillosis. Allergy Rhinol (Providence) 2015;6:143-5.
[Figure 1], [Figure 2], [Figure 3]