Abstract

Objective: To determine the prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients of bronchial asthma. Methods: Two hundred and forty four patients of bronchial asthma, recruited consecutively over a period of three years were analyzed prospectively by clinical evaluation, chest radiography, skin test, sputum culture for fungus and serum precipitin test. Those patients with suspicion of ABPA were further investigated by serum titers of specific IgG and IgE against A. fumigatus. Diagnosis of ABPA was made on pre determined major and minor criteria, where at least five major criteria had to be present. Results: During the study period, 244 patients (150 males; 94 females) with bronchial asthma diagnosed on basis of clinical features and spirometric findings were recruited in the study, with mean age of 27.1 years (9 to 60 years). Mean duration of illness of these patients was 11.2 years (1.5 to 32 years). Immediate cutaneous reactivity to A. fumigatus (Type I) revealed hypersensitivity to the fungus in 30.3% of the patients. On basis of clinical, radiological and immunological criteria, 18 (7.4%) patients (13 males and 5 females) were diagnosed to have ABPA. Their mean age was 33.5 years (17 to 48 years) and mean duration of illness was 11.8 years (1.5 to 28 years). Family history suggestive of atopy was present in 61.5% and history of passage of mucus plugs was present in 66.6% patients. All these patients with ABPA were misdiagnosed as cases of pulmonary tuberculosis, and were given anti tuberculosis treatment. Conclusion: Allergic bronchopulmonary aspergillosis is seen in 7.4% patients with bronchial asthma. Efforts should be made to improve the awareness level about this disease, among general physicians who frequently confuse it with pulmonary tuberculosis, for timely diagnosis and institution of appropriate treatment so as to avoid misuse of antitubercular drugs and prevention of end stage irreversible lung damage.

Introduction

Pulmonary aspergillosis is a clinical spectrum of lung disease caused by the fungus Aspergillus species. The classification of pulmonary aspergillosis includes saprophytic aspergillosis in the form of pulmonary aspergilloma, immune disease in the form of allergic bronchopulmonary aspergillosis (ABPA) and hypersensitivity pneumonitis, and infectious disease in the form of invasive and semi-invasive necrotizing aspergillosis1. ABPA is the best recognized manifestation of Aspergillus-associated hypersensitivity to Aspergillus antigens in patients with long standing atopic asthma and characterized by the presence of asthma, pulmonary infiltrates, peripheral blood eosinophilia, type I skin reactivity and serum precipitin antibodies to aspergillus fumigatus, elevated total serum IgE, increased levels of aspergillus specific IgE and IgG and central bronchiectasis.

The true prevalence of ABPA among asthmatics is not known. This may be attributed to the lack of a uniform diagnostic criterion and standard tests2. Various other Western studies suggest that ABPA complicates 1-6% of all chronic cases of asthma3. This disorder is not uncommon in India4. In a recent study from India, prevalence of ABPA was found to be 27% in patients of asthma5. However, the disease is still underdiagnosed in India, and almost half of the cases are initially misdiagnosed as pulmonary tuberculosis5. The present study was conducted to determine the prevalence of ABPA in asthmatics patients in India.

Material And Methods

Two hundred and forty four patients (150 males and 94 females) with bronchial asthma, diagnosed on basis of clinical history, physical findings and spirometry (reversible airway obstruction to 200 µg of inhaled salbutamol) were recruited for the present study over a period of 3 years (ie, from January 2002 to December 2004).

Patients recruited in the study underwent preliminary evaluation by detailed clinical history, family history of atopic disorder, past treatment, physical examination, routine blood test, spirometry and chest radiograph. All 244 patients also underwent skin test for Type I and Type III cutaneous reactivity to Aspergillus antigen, sputum culture for A. fumigatus on Sabouraud chloromycetin agar and serum precipitin test by immunodiffusion technique for A. fumigatus. Patients with clinical and immunological suspicion were further subjected to serum titers of specific IgG and IgE to A. fumigatus by ELISA technique and value more than two times the control was taken as positive.

Diagnosis of ABPA was made on major and minor criteria laid down by Rosenberg et al.6 Major criteria used for diagnosis of ABPA were (1) history of asthma; (2) peripheral blood eosinophilia; (3) Type I cutaneous reactivity to A. fumigatus antigen; (4) precipitating antibody against A. fumigatus; (5) fleeting or fixed radiological opacities; (6) raised specific serum IgG against A. fumigatus; (7) raised specific serum IgE against A. fumigatus; (8) HRCT thorax showing proximal bronchiectasis. Other minor criteria included (1) Type III cutaneous reactivity to A. fumigatus antigen; (2) sputum culture positive for A. fumigatus; (3) passage of mucus plugs in sputum. In present study, at least five major criteria had to be present for diagnosis of ABPA.

Results

Among 244 patients with bronchial asthma recruited in the present study (Table 1), 150 (61.5%) were males and 94 (38.5%) were females. Their mean age was 27.1 years (9 to 60 years) with 155 (63.5%) patients between 20 to 39 years of age. Mean duration of illness was 11.2 years (1.5 to 32 years), with 216 (88.5%) patients having duration less than 19 years. Clinical profile of these patients showed that episodic breathlessness, was predominant symptom in all patients, followed by cough in 155 (63.5%); expectoration in 67 (27.5%); chest pain in 19 (7.8%); haemoptysis in 12 (4.9%); fever in 7 (2.9%) and mucus plugs in 7 (2.9%) patients. Apart from bronchial symptoms, some patients had other disorders like, allergic rhinitis in 123 (50.4%) and atopic dermatitis in 45 (18.4%) patients. Among these patients of bronchial asthma, 50.7% had family history suggestive of atopic disorders. In past treatment they took bronchodilators, with or without oral or inhaled steroids. Those patients with radiological shadows were also prescribed anti tubercular drugs, sometimes in the course of their illness. Absolute eosinophil count (AEC) above 500cells/µl was found in 75.3% cases. Chest radiographs were normal in 221 (90.5%) patients of bronchial asthma. Among 23 abnormal radiographs, 15 (6.1%) patients had fleeting shadows, predominantly in upper zone; 5 (2%) had soft infiltrates; 2 (0.8%) had ring shadows; 1 (0.4%) had tram track appearance and 4 (1.6%) had prominent broncho vascular markings. On skin testing by A. fumigatus antigen, 74 (30.3%) patients showed Type I reactivity and 28 (11.5%) patients showed Type III reactivity. Sputum culture with growth of A. fumigatus was positive in 71 (29.9%) patients. Other serological tests were done in 144 patients only due to financial constraints, which showed specific IgE to A. fumigatus positive in 49 (34.0%) patients, specific IgG to A. fumigatus positive in 41 (28.5%) patients and both of them were positive in 26 (18.1%) patients.

Table 1: Characteristics of patients of Bronchial Asthma

Diagnosed on basis of presence of at least five major criteria described above, 18 (7.4%) patients of bronchial asthma had ABPA (13 males, 5 females) (Table 2). Their mean age was 33.5 years (17 to 48 years) and mean duration of illness was 11.8 years (1.5 to 28 years), with 12 (66.7%) patients having duration between 5 to 15 years. Breathlessness was main complaint in all of them, followed by cough with expectoration in 9 (50%); mucus plugs in 2 (11.1%); fever in 4 (22.2%); chest pain in 2 (11.1%) and haemoptysis in 2 (11.1%) patients. Family history of atopy was present in 11 (61.5%) patients. All these patient were initially misdiagnosed as pulmonary tuberculosis and were prescribed antitubercular treatment. Peripheral blood absolute eosinophil count was more than 1000 cells / µl in 17 (94.4%) patients. On chest radiographic examination, 1 patient (5.6%) had normal radiograph, while rest of 17 patients with abnormal radiograph had predominantly unilateral, upper zone abnormality, with fleeting pulmonary infiltrates as the most common finding in 15 (88.2%) patients, followed by prominent broncho vascular markings in 4 (22.2%); ring shadows in 2 (11.1%) and tram track appearance in 1 (5.9%) patient. Skin reactivity to Aspergillus antigens showed Type I reaction in all patients (100%) and Type III reaction in 16 (88.9%) patients. Sputum culture for A. fumigatus and serum precipitin against A. fumigatus was positive in all patients. Aspergillus specific IgE and IgG antibodies were positive in all 13 patients of ABPA, who underwent these specific serologic tests.

Table 2: Characteristics of patients of Allergic Bronchopulmonary Aspergillosis

Discussion

ABPA is the best recognized manifestation of Aspergillus associated hypersensitivity to Aspergillus antigens in patients with long standing atopic asthma. The true prevalence of ABPA in patients of bronchial asthma is still not known. This may be due to the lack of a uniform diagnostic criterion and standardized tests7. This study, which is carried out to determine the prevalence of ABPA in asthmatic patients, showed a prevalence rate of 7.4%. This is in correlation with the previous studies in which, the prevalence of ABPA varies from 1 to 11% in patients with asthma8,9,10,11,12,13,14,15,16. Whereas other Indian studies reported the prevalence of ABPA as 27.2% and 16%5,17. This discrepancy may be due to difference in sample size, constitution of study population and local prevalence of the disease. Several Western studies showed that ABPA affects people of all age groups without any sex predilection18,19. In our study, it was predominantly found in people with age less than 40 years and with male predilection which is in correlation with the recent Indian study5. This discrepancy may be due to gender bias in seeking medical help, in this part of India, where social structure is comparatively less favorable for females. In correlation with an earlier study17, which showed family history of suggestive of atopic disorder in 63% patients of ABPA, our study found it in 11 (61.5%) patients of ABPA. Previous studies reported that almost half of ABPA patients were misdiagnosed and treated as pulmonary tuberculosis5,20, but all of our patients were prescribed anti tubercular drugs some times in the course of their illness, which reflects the lower level of awareness among general physicians for ABPA.

The present study found radiographic shadows in 23 patients, but only 18 had ABPA. Thus radiographic shadows neither establish nor exclude the diagnosis of ABPA, as one of our patients with ABPA had normal radiograph. Radiographic infiltrates in patients of ABPA lay in correspondence with bronchial distribution, usually involving the upper lobes21 and are mainly fleeting in character, which is evident in our study also. Peripheral blood absolute eosinophil count above 1000cells/ l was found in 17 (94.4%) patients. Previous study17 found Type I reactivity to A. fumigatus in 87% cases and Type III reactivity in 36% cases of bronchial asthma, but present study found Type I reactivity in 30.3% and Type III reactivity in 11.5% cases, which is in close correlation to a Western study which showed Type I reaction positive in 23 to 28% patients of bronchial asthma22. Out of 74 patients with positive Type I skin test, only 18 (24.3%) were found to have ABPA. This observation in light of a previous study, which found prevalence of positive Type I skin test in 20% of general population23, says that positive skin test, is not confirmatory of ABPA. Wide variation in prevalence of positive Type I skin test among patients of bronchial asthma, may be due to difference in local prevalence of skin reactivity in areas, where these studies are conducted. Sputum culture for A. fumigatus, showed positive growth in 71 patients, but only 18 (25.4%) had ABPA.

Elevated serum titers of specific IgE24 or IgG25 antibody to A. fumigatus are strong indicator of ABPA, but in our study, out of 49 patients with positive specific IgE to A. fumigatus, and 41 patients with positive specific IgG to A. fumigatus, only 13 (26.5% and 31.7% respectively) were found to have ABPA, which again highlights the fact that, like skin test and chest radiograph, these serologic tests also lack reliability for diagnosis of ABPA if performed alone. Present study found 16.9% patients of bronchial asthma having serum precipitins to A. fumigatus, which is close to 10% found in another previous study, 26 but in our study, out of 27 patients with positive serum precipitins, only 18 had ABPA, which again demonstrates its low reliability, and like skin test it may also be detected in general population to the extent of 1%.27

Thus in conclusion it could be said that among patients with bronchial asthma, prevalence of ABPA is 7.4%. Any particular test lacks reliability for establishing or excluding the diagnosis of ABPA if performed alone, due to which diagnosis of ABPA should be considered, in presence of at least five tests with positive results. Any patient of long standing bronchial asthma, with high levels of peripheral blood absolute eosinophil count, fleeting pulmonary infiltrates on serial chest radiographs, and persistently corticosteroid requirement for control of asthma, should always be investigated for ABPA. Efforts need to be intensified to improve the awareness level about this disease, among general physicians who frequently confuse it with pulmonary tuberculosis, for timely diagnosis and institution of appropriate treatment so as to avoid misuse of antitubercular drugs and prevention of end stage irreversible lung damage.

References