Allergic bronchopulmonary aspergillosis : Indian scenario

Field: Medicine (Health Sciences)

INTRODUCTION Fungus Aspergillus derives its name from its resemblance to a brush called "aspergillum" used by the priests for sprinkling holy water1. Over 150 species of this fungus have been identified, of which A. fumigatus (Af) is responsible for about 95% of Aspergillus - related illnesses in humans. It is a ubiquitous fungus and has been implicated, in a number of airway diseases, ranging from saprophytic colonization to extensive life threatening invasion with a multitude of intermediary conditions2. For the sake of convenience, various Aspergillus - associated respiratory disorders can be broadly classified into three clinical categories, viz allergic aspergillosis, aspergilloma and invasive aspergillosis (Table I)3. Allergic bronchopulmonary aspergillosis (ABPA) is the most frequently recognised presentation of allergic aspergillosis and is world wide in distribution. ABPA is being recognized as an upcoming disease in India also. An attempt has made in this article to review the Indian scenario of ABPA.Table I: Aspergillus associated respiratory disorders3THE MAGNITUDE OF PROBLEM The first three cases of ABPA were reported from England in 19524 and the first case in USA in, 19685. From India, first three cases of ABPA were reported in 19716. Early sporadic case reports67891011 were followed by large series of ABPA from different parts of India12131415161718192021 including the largest one by Agarwal et al21 from North India. All these reports clearly indicate that ABPA is a common entity in our country too. Although majority of ABPA cases occur in adults in age group twenty to forty years, it has been reported in children and infants also6142223242526. Recently, Gaur et al.26 has reported the youngest case of ABPA from the Indian subcontinent, who was only four years old. Majority of ABPA cases occur in patients of bronchial asthma and cystic fibrosis. Rarely it has been described in non-asthmatics also2728. Type I aspergillus cutaneous sensitivity has been reported in 16 to 50 percent patients of bronchial asthma by different workers from abroad293031323334. In India, Chakrabarty et al.20, Maurya et al.35 and Agarwal et al.21 reported Aspergillus cutaneous type I sensitization in as high as 50%, 28.5% and 39.5% of their asthma patients, respectively. Several attempts have been made to estimate the prevalence of ABPA but the lack of uniform diagnostic criteria and standardized tests make it a tough task. Recent review by Novey36 suggested that, keeping these limitations in mind, ABPA may be prevalent in 0.25% to 8% of all asthmatic in USA. Kumar and Gaur from India37 reported 16% ABPA prevalence in asthma patients. Maurya et al, in their study of 105 patients with bronchial asthma reported ABPA prevalence of 7.5%35. Recently, Agarwal et al.21 reported ABPA prevalence 27.2% of in their study of 564 asthmatics from north India. Such high figures do not reflect the exact prevalence of ABPA in general community but probably represent the referral bias of such patients to chest specialists at the tertiary level institutes. WHY ABPA UNDERDIAGNOSED IN INDIA? Despite high prevalence of ABPA reported in different studies, ABPA is still under recognized and under diagnosed in our country. A number of factors may be responsible for this situation. There is high prevalence of tuberculosis (TB) in our country and due to striking radiological similarity between ABPA and TB, a large number of ABPA cases may be misdiagnosed as TB and go on receiving anti-TB drugs for long periods. In some Indian studies, ABPA was misdiagnosed as TB in as high as 17% to 50% cases13171821. Corticosteroids are grossly misused in asthmatics in our country and it may mask the presentation of ABPA. Further, chest skiagrams are not routinely done in asthma patients in our country and there are chances of missing many ABPA cases in the early stages. By and large, there is lack of awareness about ABPA in general practitioners, medical specialists and many chest specialists. The mycoserological tests and investigations like CT Scan required for diagnosing ABPA are not widely available and are rather expensive. DIAGNOSTIC CRITERIA There is no single test that can establish the diagnosis of ABPA and a set of criteria (Table 2) is required for this purpose383940. There is still no consensus on the number of criteria needed to diagnose ABPA and patients in different stages of ABPA may not fulfill all these criteria. Several workers now do not differentiate between major and minor criteria. Eight diagnostic criteria have been laid down by Greenberger in 199741. Lung biopsy is not required for diagnosing ABPA as it can be established on the basis of clinical, radiological and serological features only.Table 2: Diagnostic Criteria for ABPA35 , 36RADIOLOGICAL MANIFESTATIONS A number of radiological features are described in ABPA. Broadly, they are divided into transient and permanent shadows424344. Transient lesions are due to parenchymal infiltrates, mucoid impaction or secretions in the damaged bronchi and usually clear with or without glucocorticoid therapy. These are not considered pathognomonic of ABPA. The changes can occur in any part of the lung, but upper lobes are predominently involved. Various transient changes include perihilar infiltrates simulating hilar lymphadenopathy45, air-fluid levels due to dilated central bronchi filled with secretions and massive unilateral or bilateral consolidation. These patchy infiltrates go on shifting from one place to other in serial skiagrams ′fleeting-shadows". There can be ′tooth-paste′ transient shadows, which are band like shadows due to mucoid impaction in the damaged bronchi. When these secretions fill the distally occluded bronchi, a ′gloved-finger′ shadow is produced. The ′tram-line′ shadows are two parallel hair lines, extending out from the hilum and are due to oedema of the bronchial wall. There can be transient shadows due to segmental or lobar collapse. Menon and Das have also given description of ′wine glass′, ′gossamer′ and ′lotus-like′ shadows, but such shadows were seen only in small percentage of their patients14. Permanent radiological lesions are due to fibrotic changes in the bronchial walls or lung parenchyma and persist even when the patient is asymptomatic. These include central bronchiectasis with normal peripheral airways and parallel line or ring shadows due to dilated bronchi. In late stages of ABPA, cavitation46, upper lobe fibrosis, localized emphysema or bullae have been described. In addition to transient and permanent radiological changes, some uncommon radiological manifestatisons like true lymphadenopathy,4748 and ipsilateral pleural effusion49 have also been reported in ABPA. HRCT and Bronchography in ABPA Till a few years ago, bronchography was the ′gold-standard′ investigation for detecting bronchiectasis in ABPA. As bronchography is risky in asthma patients, is difficult to carry out in children and the dye is not widely available now, it is rarely performed in ABPA cases these days. High-resolution CT scan (HRCT) has emerged as the investigation of choice for this purpose. An Indian study compared HRCT with bronchography in ABPA cases and found that HRCT was 83 percent sensitive and 92 percent specific when compared with bronchography50. A few Indian studies215051 have reported HRCT findings in ABPA. HRCT may be normal in ABPA seropositive (ABPA-S) cases. Central bronchiectasis with normal peripheral bronchi is the most characteristic feature of ABPA, though at times, it can extend to periphery also. Bronchiectasis on HRCT have been described as the 'string of pearls′ or 'signet ring′ appearance. Other CT findings include ′centrilobular nodules′, consolidation, fibrosis, collapse and bullae. A high-attenuation mucus has been described as most characteristic finding of ABPA2152, but is found in small percentage of cases only. Such mucus plugs are usually denser than the normal sketal muscle or its density measurements are of 72 to 102 HU52. The hyperdense mucous plugs seen on CT scans are thought to be due to high content of calcium salts, metals (iron and manganese) and/or haemorrhagic products52. ATYPICAL PRESENTATIONS OF ABPA Although different categories of aspergillus-related respiratory disorders usually present separately, these can coexist also. Coexistence of ABPA with allergic aspergillus sinusitis (AAS) has been described as case reports in literature535455 but a recent review55 showed that such co-existence may not be that uncommon. Some Indian reports have also described co-existence of ABPA with aspergilloma5657585960. TB is widely prevalent in our country, but its coexistence with ABPA is rare136162. It has been suggested that fungus Aspergillus and Mycobacteria are unable to grow simultaneously in the human lungs, which may partly explain their uncommon co-existence61. STAGES OF ABPA Patterson63 and Greenberger64 have described five stages of ABPA i.e. acute stage, stage of remission, stage of exacerbation, stage of steroid-dependent asthma and fibrotic stage (Table 3). In acute stage, patients present with acute symptoms, raised total serum IgE, peripheral blood eosinophilia and skiagram abnormalities suggestive of ABPA. Treatment with corticosteroids lead to clinico-radiological improvement and decline in serum IgE and blood eosinophilia. When this improvement persists for over six months, patient is said to be in stage of remission. If there is recurrence of symptoms, and fresh shadows appear in chest X-ray along with rise in total IgE levels and blood eosinophil counts, patient is in stage of exacerbation. If one does not know previous record of patient, it is very difficult to differentiate between stage I and III. In one third of cases, exacerbations are entirely asymptomatic and may only be identified by doubling of serum IgE levels or fresh radiological shadows65. Stage IV ABPA is usually indistinguishable from corticosteroid-dependent asthma without ABPA as steroids may mask the features of ABPA66. Fibrotic lung stage in ABPA may, at time be, difficult to differentiate from tuberculous fibrocavitary lesions.Table 3: Features of fi ve stages of ABPA,60Patterson et al67 described two stages of ABPA i.e. ABPA-S (serological positive) and ABPA-CB (with central bronchiectasis). ABPA-S cases are only seropositive and have no pulmonary damage and probably represent the earliest stages of ABPA. Based on radiological, serological and clinical severity, Kumar68 categorized ABPA into three tages as ABPA-S, ABPA-CB and ABPA-CB-ORF(with central bronchiectasis and other radiological features) and labelled them as mild, moderate and severe forms of ABPA. Patients with ABPA-CB or ABPA-CB-ORF had more signs and symptoms and higher serological values compared to ABPA-S patients. WHEN TO SUSPECT ABPA? A high index of suspicion is required to establish the diagnosis of ABPA. All asthmatics who have type I cutaneous reaction positive to Af antigen, should be investigated for ABPA. Bronchial asthma patients having systemic complaints and/or history of expectorating golden- brownish plugs, should be investigated for ABPA. ABPA should also be excluded in asthmatics having radiological infiltrates or central bronchiectasis and blood eosinophilia. Patients with history of repeated anti-tubercular therapy without improvement and having associated dyspnoea and wheezing should also be evaluated to exclude ABPA. MANAGEMENT The goals of treatment of ABPA are (a) to detect and treat exacerbations promptly so as to prevent or minimize bronchiectasis that may develop at the site of infiltrates (b) to manage associated asthma or irreversible lung disease (c) to exclude ABPA in family members and (d) to identify potential fungal source in the environment37. Oral glucocorticoids are currently the treatment of choice, as they suppress both the immune function and inflammation6070. Different studies and reviews have recommended different dosages and durations of therapy. In one schedule, prednisolone was recommended in dose of 0.5 mg/kg/d for two weeks and then changed to alternate day for three month. This dose was gradually tapered off by decreasing 2.5 mg fortnightly. Stage 4 and 5 cases usually require daily or alternate prednisolone for several years along with symptomatic treatment. In another review71, a starting dose of 0.75 mg/kg/d of prednisolone was given for initial four weeks. It was the gradually tapered off over next 5-6 months. With such dose schedules, high relapse rates and steroid dependence was reported21. Recently Agarwal et al21 treated their 126 ABPA cases with higher dosage of prednisolone given for longer duration. In this study, 0.75 mg/kg prednisolone was given for 6 weeks and then reduced to 0.5 mg/kg for next 6 weeks. This dose was then tapered by 5 mg. every 6 weeks and therapy was continued for a total duration of atleast 6 to 12 months. In this study, higher remisson rates and lower prevalence of steroid-dependent ABPA was reported. In view of this, there is a need for further randomized controlled studies to settle the issue. The role of various antifungal agents is being explored. Initially a number of antifungal agents were tried and discarded, because of poor effectiveness or adverse effects. Newer antifungal agents like ketoconazole, fluconazole and itraconazole have been studied by number of workers abroad72 and few from India7374. Rai et al74 have shown encouraging results with itraconazole and fluconazole. It has been suggested that antifungal agents decreased fungal load and thus reduced antigenic stimulation and inflammatory response. A recent Cochrane review75 has concluded that azole antifungal drugs may be of some benefit in treating ABPA, if added to the standard therapy of high dose of oral corticosteroids. However, long term trials are required before a final recommendation can be made for their use as an adjunctive therapy for patients with ABPA. Till such time agents like itraconazole should be tried only in situations where corticosteroids are absolutely contraindicated3. CONCLUSIONS An attempt has been made to review ABPA scenario in our country. ABPA is not uncommon in India, but is under recognized and under diagnosed. Possible reasons for this situation have been explored. A high index of suspicion is required to diagnose ABPA early as this along with aggressive treatment may prevent further lung damage and end-stage fibrosis. All asthmatics should be skin tested with Af antigen for type I cutaneous sensitivity and ABPA should be excluded in those found positive. Oral glucocorticoids are currently the treatment of choice for ABPA. Further trials are needed to optimize the dose and duration of steroid therapy. Role of antifungal agents is being explored.