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clinical course and less severe immunologic findings when compared to ABPA-CB based on the inference of three studies (total of 124 patients). 12,139,140 In the largest of these three studies (76 patients), only the A fumigatus-specific IgG levels were higher in patients with ABPA-CB compared to ABPA-S. Other immunologic parameters were not significantly different between the two groups. 12 In our study of 126 patients, the clinical, spirometric, and immunologic findings were not significantly different when classifying ABPA into ABPA-S and ABPA-CB or as ABPA-S, ABPA-CB, and ABPA-CB-ORF. 22 However, the course of patients with ABPA-S is likely to be less severe when compared to those with ABPA-CB. In a multivariate analysis of 155 patients with ABPA, we demonstrated that the severity of bronchiectasis and presence of hyperattenuating mucoid impaction on HRCT-predicted relapses of ABPA and the severity of bronchiectasis was an independent predictor of failure to achieve longterm remission. 23 Thus it may not be important to stage the severity of ABPA based on the presence or absence of CB, but it remains prudent to diagnose and treat ABPA early to prevent the development of bronchiectasis because it in- Table 6—Stages of ABPA 8,22 Stage Description Clinical Picture Radiologic Findings Immunologic Features I Acute phase Usually symptomatic, fever, weight loss, wheeze Normal or presence of radiologic opacities II Remission Asymptomatic Generally normal or significant resolution of radiologic opacities from the acute phase III Exacerbation Symptomatic as in acute Transient or fixed pulmonary phase opacities IV Glucocorticoid-dependent Symptomatic Transient or fixed pulmonary ABPA opacities 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 IgE 1,000 IU/mL, raised specific IgG/IgE and precipitins to A fumigatus 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 Doubling of IgE levels from baseline Two groups can be identified: one in whom IgE levels do not rise but require steroids for asthma control (glucocorticoiddependent asthma); the other in whom steroids are required to continually suppress the disease activity (glucocorticoiddependent ABPA) Serum IgE levels and specific immunoglobulins do not become normal in most patients, and even these patients can have frequent exacerbations creases the probability of a smoother course of this relapsing-remitting disorder. Management The management of ABPA includes two important aspects: institution of glucocorticoids to control the immunologic activity and close monitoring for detection of relapses. Another possible target is the use of antifungal agents to attenuate the fungal burden secondary to the fungal colonization in the airways. Systemic Glucocorticoid Therapy: Oral corticosteroids are the treatment of choice for ABPA. They not only suppress the immune hyperfunction but are also antiinflammatory. There are no data to guide the dose and duration of glucocorticoids, and different regimens of glucocorticoids have been used (Table 8). The use of lower doses of glucocorticoids was associated with frequent relapses or corticosteroid dependence (45%). 9 We use a higher dosage of glucocorticoids for a longer duration and observed higher remission rates and a lower prevalence of glucocorticoid-dependent ABPA (13.5%). 22 This raises the possibility of a higher dose and prolonged duration of corticosteroid therapy being associated 814 Global Medicine Downloaded From: http://jupcvss.chestpubs.org/ on 08/01/2013
Table 7—Radiologic Classification of ABPA* Classification Features Greenberger et al12 classification ABPA-S All the diagnostic features of ABPA but no evidence of central bronchiectasis on HRCT. Patients with ABPA-S may be classified as Patterson stages I to IV. These patients may have recurrent exacerbations and may also be classified as stage III (ABPA-CB) All findings of ABPA including CB on HRCT. Patients with ABPA- CB may belong to any of the Patterson stages Kumar140 classification ABPA-S ABPA without CB ABPA-CB ABPA with CB ABPA-CB-ORF ABPA with CB other radiologic features such as pulmonary fibrosis, bleb, bullae, pneumothorax, parenchymal scarring, emphysematous change, multiple cyst, fibrocavitary lesions, aspergilloma, groundglass appearance, collapse, mediastinal lymph node, pleural effusion, and pleural thickening *Both the classification schemes believe that patients without CB and ORF have serologically milder disease, but it has been shown that there is no difference in clinical, spirometric, and serological severity between patients with and without bronchiectasis (see text for details). with better outcomes. However, there are no direct comparisons between the two regimens, and the selection is a matter of personal preference. The clinical effectiveness of steroid therapy is reflected by marked decreases in the patient’s total serum IgE levels (there seems to be no correlation between serum levels of A fumigatus-specific IgE levels and disease activity 141 ) along with symptom and radiographic improvements. The goal of therapy is not to attempt normalization of IgE levels but to decrease the IgE levels by 35 to 50%, which leads to clinical and radiographic improvement. One should also establish a stable serum level of total IgE to serve as a guide to future detection of relapse. Inhaled Corticosteroids: Although small case studies suggest some benefit of inhaled corticosteroids in the management of ABPA, 142–145 a double-blind multicenter placebo-controlled trial in 32 patients suggested no superiority over placebo. 146 We use inhaled corticosteroids only for the control of asthma once the oral prednisolone dose is reduced to 10 mg/day. Oral Itraconazole: Ketoconazole has been tried in the past 147 and has been replaced by the less toxic Table 8—Treatment Protocols for the Management of ABPA Oral glucocorticoids Regime 1 5 Prednisolone, 0.5 mg/kg/d, for 1–2 wk, then on alternate days for 6–8 wk. Then taper by 5–10 mg every 2 wk and discontinue Repeat the total serum IgE concentration and chest radiograph in 6 to 8 wk Regime 2 22,113 Prednisolone, 0.75 mg/kg, for 6 wk, 0.5 mg/kg for 6 wk, then tapered by 5 mg every 6 wk to continue for a total duration of at least 6 to 12 mo. The total IgE levels are repeated every 6 to 8 wk for 1 yr to determine the baseline IgE concentrations Follow-up and monitoring The patients are followed up with a medical history and physical examination, chest radiograph, and measurement of total IgE levels every 6 wk to demonstrate decline in IgE levels and clearing of the chest radiograph A 35% decline in IgE level signifies satisfactory response to therapy. Doubling of the baseline IgE value can signify a silent ABPA exacerbation If the patient cannot be tapered off prednisolone, the disease has evolved into stage IV. Management should be attempted with alternate-day prednisone with the least possible dose Monitor for adverse effects (eg, hypertension, secondary diabetes) Prophylaxis for osteoporosis: oral calcium and bisphosphonates Oral itraconazole Dose: 200 mg bid for 16 wk then once a day for 16 wk Indication: First relapse of ABPA or glucocorticoid-dependent ABPA Follow-up and monitoring Monitor for adverse effects (eg, nausea, vomiting, diarrhea, and elevated liver enzymes) Monitor for drug–drug interactions Monitor clinical response based on clinical course, radiography, and total IgE levels agent, itraconazole. 130,141,148–160 Only two randomized controlled studies (84 patients) have evaluated the role of itraconazole in ABPA. 130,156 Pooled analysis showed that itraconazole could significantly decrease the IgE levels by 25% when compared to placebo but did not cause significant improvement in lung function. 161 A major limitation was that neither of the studies reported long-term outcomes in ABPA. Thus longer term trials are required before a firm recommendation can be made for the use of itraconazole in ABPA. We currently use itraconazole only after the first relapse of ABPA despite glucocorticoid therapy or in patients with glucocorticoiddependent ABPA (Table 8). In the limited numbers of patients in whom we have used the drug, there was no observable advantage. 22 Itraconazole not only has numerous adverse effects, 162 but it also inhibits the metabolism of methylprednisolone (but not prednisolone) with resultant increased frequency of www.chestjournal.org <strong>CHEST</strong> / 135 /3/MARCH, 2009 815 Downloaded From: http://jupcvss.chestpubs.org/ on 08/01/2013
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