1. By Dr.Amit Kumar

2. What is ABPA? ABPA is an idiopathic inflammatory lung disease characterized by an allergic inflammatory response to the colonization of aspergillus fumigatus. In another way “ ABPA is an immunologic pulmonary disorder caused by hypersensitivity to the aspergillus fumigatus. “ It was first described in 1952 by Hinson and coworkers and then again in 1967, when Scadding recognized an association of this disease with proximal bronchiectasis in areas previously affected by infiltrates (predominantly in the upper lobes). The first adult case of ABPA in the United States was described in 1968

3. Aspergillus is an ubiquitous, thermotolerant mold. That reside in decaying organic matter. What is Aspergillus?

5. There are approximately 250 species of Aspergillus, but only a few are human pathogens. Depending on the host immunity and the organism virulence, the respiratory disease caused by aspergillus are aspergilloma, allergic aspergillus sinusitits, ABPA, hypersensitivity pneumonias, airway invasive aspergillosis, chronic necrotizing pulmonary aspergillosis and invasive aspergillosis. The spectrum of disease is broad and can be severe and debilitating, requiring lung transplantation, however if recognized early and managed aggressively, ABPA is treatable can remit indefinitely and progressive lung damage can be avoided.

6. Epidemiology There is no gender predilection and majority of the cases present in the third to fifth decade of life but may also present during childhood. The prevalence of ABPA is about 1-2% in asthma patients and 2-15% in cystic fibrosis patients. In the past two decades, there has been an increase in the number of cases of ABPA due to the heightened physician awareness and the wide spread availability of serologic assays. In a recent meta analysis a prevalence of aspergillus hypersensitivity and ABPA in asthma of 28% and 12.9% respectively.

7. Pathogenesis of ABPA Although the pathogenesis of ABPA is incompletely understood, it is believed to result from a complex immunological reaction to chronic airway colonization by aspergillus. Inhaled spores colonize the airway, proliferate and result in chronic antigenic stimulation of the airway, tissue injury and the clinical features of ABPA.

10. At the microscopic level ABPA is characterized by an intense eosinophilic and mononuclear cell inflammatory response that leads to airway injury and bronchiectasis. A role for type I hypersensitivity reactions is strongly suggested by the elevated serum levels of total and Aspergillus-specific IgE. Type III hypersensitivity is suggested by the presence of Aspergillus,precipitins and circulating immune complexes during disease exacerbations. A type IV cell-mediated immune reaction may also be at work, based on the finding of dual (immediate and delayed) cutaneous reactions and in vitro lymphocyte transformation to Aspergillus antigen stimulation in some patients.

11. CLINICAL PRESENTATION Common signs and symptoms Low grade fever Wheezing Bronchial hyperactivity Haemoptysis Productive cough (often associated with brownish black mucus plugs)

13. PHYSICAL EXAMINATION Can be normal Other possible findings include :  Polyphonic wheezing  Clubbing (16%)  Coarse crackles (15%)  Sign and symptoms of pulmonary HTN and/or respiratory failure. During exacerbations of ABPA, localized findings of consolidation and atelectasis can occur.

14. LABORATORY FINDINGS Aspergillus Skin Test: The Aspergillus skin test is performed using an A fumigatus antigen. An immediate cutaneous hypersensitivity to A fumigatus antigens is a characteristic finding of ABPA and represents the presence A fumigatus specific IgE antibodies, whereas a type III skin reaction probably represents the immune complex hypersensitivity reaction, although its exact significance remains unclear.

15. Total Serum IgE Levels Total Serum IgE Levels : The total IgE level is the most useful test for diagnosis and follow-up of ABPA. A normal serum IgE level excludes ABPA as the cause of the patient’s current symptoms. The only situation where IgE levels can be normal in active ABPA is when the patient is already on glucocorticoid therapy for any reason and investigation for IgE levels has been conducted. After treatment with glucocorticoids, the serum IgE levels decline, and a 35 to 50% decrease is taken as a criteria for remission. The serum IgE determination is also used for follow-up, and a doubling of the patient’s baseline IgE levels indicates relapse of ABPA.

16. Serum IgE and IgG Antibodies Specific to A fumigates : An elevated level of A fumigatus-specific antibodies measured by fluorescent enzyme immunoassay is considered the hallmark of ABPA. A cutoff value of IgG/IgE more than twice the pooled serum samples from patients with AH can greatly help in the differentiation of ABPA from other conditions

17. Radiologic Investigations: A wide spectrum of radiographic appearances can occur in ABPA. The chest radiographic findings of ABPA include transient or fixed pulmonary opacities, tramline shadows, finger-in-glove opacities, and toothpaste shadows. Findings noted on high-resolution CT (HRCT) include central bronchiectasis, mucoid impaction, mosaic attenuation, presence of centrilobular nodules, and tree-in- bud opacities

19. Serum Precipitins Against A fumigatus: They can also be present in other pulmonary disorders and thus represent supportive not diagnostic evidence for ABPA. Peripheral Eosinophilia: A blood absolute eosinophil count > 1,000 cells/  L is also a major criterion for the diagnosis of ABPA. A low eosinophil count does not exclude the diagnosis of ABPA. Sputum Cultures for A fumigatus: Culture of A fumigatus in the sputum is supportive but not diagnostic of ABPA.

20. Pulmonary Function Tests: These tests help categorize the severity of the lung disease but have no diagnostic value in ABPA Role of Specific Aspergillus Antigens: The recombinant allergens Asp f1, Asp f2, Asp f3, Asp f4, and Asp f6 have been evaluated for their diagnostic performance in serologic studies in asthmatic patients and in patients with CF Preliminary data suggest a promising role of these antigens in the diagnosis of ABPA. Further studies are required before they can be implemented in routine clinical practice.

21. Diagnosis and Diagnostic Criteria Criteria Used for the Diagnosis of ABPA Rosenberg-Patterson criteria Major criteria (mnemonic ARTEPICS) A = Asthma R = Roentgenographic fleeting pulmonary opacities T = Skin test positive for Aspergillus (type I reaction, immediate cutaneous hyperreactivity) E = Eosinophilia P =Precipitating antibodies (IgG) in serum I =IgE in serum elevated (>1,000 IU/mL) C =Central bronchiectasis S =Serums A fumigatus-specific IgG and IgE (more than twice the value of pooled serum samples from patients with asthma who have Aspergillus hypersensitivity)

22. 1.Presence of Aspergillus in sputum 2.Expectoration of brownish black mucus plugs 3.Delayed skin reaction to Aspergillus antigen (type III reaction) The presence of six of eight major criteria makes the diagnosis almost certain. The disease is further classified as ABPA-S or ABPA-CB on the absence or presence of central bronchiectasis, respectively Minor criteria

23. Minimal ABPA-CB ( Central Bronchiectasis) 1.Asthma 2.Immediate cutaneous hyperreactivity to Aspergillus antigens 3.Central bronchiectasis 4.Elevated IgE 5.Raised A fumigatus-specific IgG and IgE Minimal ABPA-S (Serum) 1.Asthma 2.Immediate cutaneous hyperreactivity to Aspergillus antigens 3.Transient pulmonary infiltrates on chest radiograph 4.Elevated IgE 5.Raised A fumigatus-specific IgG and IgE Minimal diagnostic criteria for ABPA

24. STAGING OF ABPA: ABPA has been classified into five stages, but a patient does not necessarily progress from one stage to the other sequentially. Stage - I : Acute phase Acute asthma symptoms, fever, weight loss. Elevated serum IgE (>1000 IU/ml) Peripheral blood eosinophilia (may be absent in patients treated with oral coricosteroids) Fleeting infiltrates on chest x-ray (may be absent in patients treated with oral coricosteroids) Positive specific IgE, IgG, skin test reactivity, and precipitins to A. fumigatus Responds to steroids/antifungal therapy

25. Stage – II : Remission Asymptomatic Generally normal or significant resolution of radiologic opacities from the acute phase Usually 35–50% decline in IgE levels by 6 wk to 3 mo; we give additional label of “complete remission” if the patient did not have any additional ABPA exacerbations over the next 3 mo after stopping steroid therapy

26. Stage III: Exacerbation/recurrence Recurrence/worsenning of clinical symptoms Recurrent pulmonary infiltrates Rising IgE levels Disease is characterized by the development of new pulmonary infiltrates or by a >100 percent increase in total IgE. Elevation of IgE may precede clinical or radiological worsening during this stage, and an isolated increase in severity of bronchospasm does not constitute an exacerbation. Although a majority of disease exacerbations are associated with a concomitant increase in symptoms, exacerbations may occur in the absence of any increase in symptoms.

27. Stage - IV : Glucocorticoid-dependent ABPA Symptomatic  Transient or fixed pulmonary opacities o Two groups can be identified: one in whom IgE levels do not rise but require steroids for asthma control (glucocorticoid dependent asthma); the other in whom steroids are required to continually suppress the disease activity (glucocorticoid dependent ABPA)

28. Stage - V : End-stage (fibrotic) ABPA Symptomatic, findings of fixed airway obstruction, severe pulmonary dysfunction, type II respiratory failure, cor pulmonale Evidence of bronchiectasis, pulmonary fibrosis, pulmonary hypertension Serum IgE levels and specific immunoglobulins do not become normal in most patients, and even these patients can have frequent exacerbations

30. Differential Diagnosis and Complication The disorder needs to be differentiated from the following conditions: Aspergillus hypersensitive bronchial asthma, Pulmonary tuberculosis in endemic areas, Community-acquired pneumonia (especially acute presentations), and other inflammatory pulmonary disorders such as eosinophilic pneumonia,Bronchocentric Granulomatosis, and Churg-Strauss syndrome. The complications of ABPA include recurrent asthma exacerbations and, if untreated, the development of bronchiectasis with subsequent pulmonary hypertension and respiratory failure. In fact, this is the reason why routine screening is recommended in bronchial asthma to prevent the complications just described.

33. ABPA IN SPECIAL SITUATIONS ABPA Complicating CF: The association of ABPA and CF was first reported in 1965. The occurrence of ABPA in CF is associated with deterioration of lung function, higher rates of microbial colonization, pneumothorax, massive hemoptysis, and poorer nutritional status. Screening for ABPA in CF 1.Maintain a high level of suspicion for ABPA in patients with CF. 2.Determine the total serum IgE levels annually. If the total serum IgE levels is > 500 IU/mL, perform A fumigatus skin test or use an IgE antibody to A fumigatus. If results are positive, consider diagnosis on the basis of minimal criteria. 3. If the total serum IgE levels is 200–500 IU/mL, repeat the measurement if there is increased suspicion for ABPA and perform further diagnostic tests (immediate skin test reactivity to A fumigatus, IgE antibody to A fumigatus, A fumigatus precipitins, or serum IgG antibody to A fumigatus, and chest radiography).

34. ABPA Complicating Other Conditions: Occasionally ABPA has been reported to complicate other lung diseases like idiopathic bronchiectasis, post-tubercular bronchiectasis, bronchiectasis secondary to Kartagener syndrome, COPD, and in patients with chronic granulomatous disease and hyper IgE syndrome. Coexistence of ABPA and Aspergilloma: The serologic findings of ABPA have also been reported in patients with aspergilloma and chronic necrotizing pulmonary aspergillosis. ABPA without Bronchial Asthma: ABPA may occasionaly develop in an individual without pre existing asthma.

35. Allergic Bronchopulmonary Mycosis: Allergic bronchopulmonary mycosis is the occurrence of an ABPA- like syndrome due to non-A fumigatus fungal organisms. ABPA and Allergic Aspergillus Sinusitis: Allergic Aspergillus sinusitis (AAS) is a clinical entity in which mucoid impaction akin to that of ABPA occurs in the paranasal sinuses.

36. PROGNOSIS: With appropriate treatment long-term control of ABPA is feasible, and durable remissions are common. Treatment of stage I disease with corticosteroids typically results in decreased sputum production, improved control of bronchospasm,> 35 percent reduction in total IgE within 8weeks, clearing of precipitating antibodies, and resolution of radiographic infiltrates. IgE levels typically do not completely normalize but rather decrease by approximately one-half of peak levels seen in the acute stage. Progression of stage IV disease to pulmonary fibrosis can be prevented if patients are maintained on low-dose steroids, and most patients with stage V disease have a stable course over several years. Persons with an FEV1 persistently <0.8 L have a worse prognosis. In addition to severe airflow obstruction and pulmonary fibrosis, longterm complications of ABPA occasionally include the development of an aspergilloma, chronic or recurrent lobar atelectasis, allergic Aspergillus sinusitis, or Aspergillus tissue invasion and semi-invasive Aspergillosis. Transplantation has been undertaken successfully among patients with ABPA, however, post-transplant recurrence ofABPA has beenreported.

37. CONCLUSIONS A high index of suspicion for ABPA should be maintained while managing any patient with bronchial asthma whatever the severity or the level of control. Host immunologic responses are central to the pathogenesis, and they are the primary determinants of the clinical, biologic, pathologic, and radiologic features of this disorder. ABPA may precede the clinical recognition of the disorder for many years or even decades, and it is often misdiagnosed as a variety of pulmonary diseases. Because a patient with ABPA can be minimally symptomatic or asymptomatic, all patients with bronchial asthma should be routinely screened with an Aspergillus skin test. In patients with Aspergillus hypersensitivity, further immunologic studies are warranted to diagnose ABPA before the development of bronchiectasis because bronchiectasis is a poor prognostic marker in the natural history of this disease.