Pathologic features of allergic bronchopulmonary aspergillosis

We describe the pathologic features in surgically excised lung tissue specimens from 18 cases of allergic bronchopulmonary aspergillosis (ABPA). The main abnormalities involved bronchi and bronchioles. All cases showed bronchocentric granulomatosis (BCG), mucoid impaction of bronchi (MIB), or both. The impacted mucin of MIB contained large numbers of eosinophils and Charcot-Leyden crystals. A distinctive exudative bronchiolitis was present distal to areas of BCG in 13 cases. This lesion was characterized by filling of bronchiolar lumens with necrotic neutrophils and eosinophils in a basophilic mucinous exudate. A peribronchiolar chronic inflammatory infiltrate was seen in 15 cases; eosinophils were prominent in 10 of these cases. Foci of eosinophilic pneumonia were seen in 13 cases, and noninvasive fungal hyphae were identified in 14. We conclude that the finding of BCG or MIB, or a combination of both, especially in conjunction with tissue eosinophilia, should suggest the diagnosis of ABPA. When noninvasive fungal hyphae are also present, the changes are diagnostic of ABPA or a related allergic fungal reaction.     

Immunopathogenesis of allergic bronchopulmonary aspergillosis in cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease mediated by an allergic late-phase inflammatory response to Aspergillus fumigatus antigens. ABPA is characterized by markedly elevated Aspergillus-specific and total IgE levels and eosinophilia, and manifested by wheezing, pulmonary infiltrates, and bronchiectasis and fibrosis, which afflict asthmatic and cystic fibrosis (CF) patients. We propose that ABPA develops in genetically susceptible CF patients due to HLA-DR2 and DR5 restriction, increased sensitivity to IL-4 stimulation, and increased A. fumigatus allergen-specific Th2 CD4+ T-cell-mediated responses. In addition, A. fumigatus proteases play a role in facilitation of antigen transport across the epithelial cell layer by damaging the epithelial integrity and by a direct interaction with epithelial cell surface receptors, resulting in pro-inflammatory cytokine production and corresponding inflammatory responses.     

Successful treatment of allergic bronchopulmonary aspergillosis with recombinant anti-IgE antibody

Allergic bronchopulmonary aspergillosis (ABPA) can cause severe worsening of the respiratory condition in patients with cystic fibrosis. Treatment can result in steroid dependency and serious adverse events. A dramatic and rapid improvement of respiratory symptoms and lung function after a single dose of anti-IgE antibody (omalizumab) in a 12-year-old girl with cystic fibrosis and ABPA is described. This is the first report of this experimental treatment. It suggests an important role for IgE in the pathogenesis of ABPA and offers new therapeutic possibilities.     

Studies in chronic allergic bronchopulmonary aspergillosis. 3. Immunological findings.

Precipitin tests by two different methods, double-diffusion (DD) and counterimmunoelectrophoresis (CIE), and measurements of total and specific IgE against Aspergillus fumigatus were made in 50 patients with chronic allergic bronchopulmonary aspergillosis and in three control groups--atopics with a positive immediate prick test to A. fumigatus but no evidence of allergic aspergillosis, atopics with a negative prick test to A. fumigatus, and non-atopics. Precipitins were found in 84% and 78% of the patients with aspergillosis by the DD and CIE methods respectively. Precipitins were also found in 6 out of 27 (22%) patients with a positive prick test to A. fumigatus but no evidence of aspergillosis and in 1 of 24 patients with a negative prick test to A. fumigatus. The means of specific and total IgE values were significantly higher in the group of patients with aspergillosis than in the three other groups of patients. The increase in specific but not total IgE showed a statistically significant correlation with positive precipitin tests in the patients with aspergillosis. Total IgE but not specific IgE values were significantly higher (0-02 less than P less than 0-05) in patients who had had a transient radiographic shadow in the previous three months. Positive precipitin tests were also significantly correlated with the number of transient shadows in the past and with the interval of time since the last transient shadow.     

Studies in chronic allergic bronchopulmonary aspergillosis. 2. Radiological findings.

The characteristics and the incidence of changes in plain chest radiographs were analysed in detail in 50 asthmatic patients with chronic allergic bronchopulmonary aspergillosis in whom the diagnosis had been made from 2 to 25 years previously (mean duration 10-9 years). One thousand two hundred and forty-two chest radiographs, an average of about two per year per patient, were reviewed. Two hundred and sixty-seven acute episodes of transient shadows (a mean of 5-3 per patient), mostly homogeneous consolidations and band-like shadows, were recorded throughout the period of follow-up. Features of overinflation were present in 21 patients in the first radiograph and in 17 in the last, the decrease being attributed to the effects of permanent lung damage due to the allergic aspergillosis. Permanent changes, such as tubular and ring shadows, loss of vascular shadows, and lobar shrinkage were recorded in 41 patients at the start and in 49 at the end of the follow-up. The tubular shadows were found in 28 patients in the first radiograph and in 45 in the last, whereas ring shadows were seen in 18 and 30 patients respectively. Half of the episodes of consolidation and atelectasis left permanent changes, mainly ring shadows, as seen in the last radiograph. Of the band-like shadows, 32% were found to be followed by the subsequent appearance of tubular shadows. Statistically significant correlations were found between the duration of aspergillosis, the number of transient shadows throughout the period of follow-up, the extent of the permanent shadows, and the reduction of gas transfer factor at the time of the final follow-up.     

Studies in chronic allergic bronchopulmonary aspergillosis. 1. Clinical and physiological findings.

This report outlines the clinical and physiological features in 50 asthmatic patients with chronic allergic bronchopulmonary aspergillosis in whom the diagnosis was made from 2 to 25 years ago (mean duration 10-9 years). From a questionnaire and analysis of the peak expiratory flow rate measurements it was found that they were worse in the winter months, corresponding to the maximal concentrations of Aspergillus fumigatus in the atmosphere. Nineteen patients reported daily sputum production of up to an eggcupful or more, and 24 had noticed sputum 'plugs' in the previous year. Reduction of vital capacity (VC) was found in 20 patients, of forced expiratory volume in one second (FEV1) in 38 patients, and of maximal expiratory flow at 50% VC breathing air (V50air) in 47 patients. Nine patients had significantly reduced gas transfer factor (DLCO). Significant improvement (more than 15%) in FEV1 after inhaled bronchodilator was shown by only 17 patients. There were statistically significant correlations between the degree of reduction in the physiological measurements of VC, FEV1, and V50air with the age of the patient at the time of the study and the later in life the diagnosis of aspergillosis was made, whereas the reduction in DLCO was also significantly related to the duration of aspergillosis. Prospective studies are needed for a proper assessment of any protective effect of treatment on the pathophysiological changes due to the disease over many years.     

Omalizumab for asthma and allergic bronchopulmonary aspergillosis in adults with cystic fibrosis

BackgroundIn cystic fibrosis (CF), omalizumab has been used for difficult-to-treat asthma and allergic bronchopulmonary aspergillosis (ABPA) but safety and efficacy data are limited for this population.MethodsWe assessed patients receiving omalizumab for asthma or ABPA in the Toronto adult CF center between 2005 and 2017. We evaluated treatment safety and efficacy by analyzing changes in FEV₁% predicted (FEV₁pp) max value, slope and variability captured by the area under the curve (AUC), the cumulative dose of systemic corticosteroids (SCS), use of intravenous (IV) antibiotics and hospitalization days before omalizumab and up to 1 year after treatment initiation. Linear mixed effects model was used for FEV₁pp slope and the trapezoidal rule for FEV₁pp AUC.ResultsTwenty-seven CF patients received omalizumab, 16 (59.3%) for asthma and 11 (40.7%) for ABPA. No significant omalizumab-related adverse effects were observed. In the asthmatic group, the max value of FEV₁pp improved on omalizumab and the cumulative dose of SCS decreased. In the ABPA group, the rate of FEV₁pp decline (slope) and the variability of FEV₁pp (AUC) improved on omalizumab. In ABPA patients, the cumulative SCS dose was not significantly different but 4 (36%) patients decreased their SCS dose by >50% compared to baseline. Days on IV antibiotics and hospital days did not differ significantly before and while on omalizumab therapy.ConclusionsIn adult CF patients with difficult-to-treat asthma or ABPA, omalizumab should be considered. Larger studies are needed to identify patient characteristics that may predict response to omalizumab.     

Studies in chronic allergic bronchopulmonary aspergillosis. 4. Comparison with a group of asthmatics.

A comparison is made of lung function tests and radiographic findings in 20 asthmatic patients with allergic bronchopulmonary aspergillosis paired in terms of sex, age, and duration of asthma with 20 other asthmatics in whom the diagnosis of aspergillosis was excluded in order to see if the aspergillosis causes more lung damage. One hundred per cent of the patients with aspergillosis and 75% of the patients with asthma alone showed a significantly reduced forced expiratory volume in one second (FEV1) before bronchodilator. All the patients in the two groups had a significantly reduced maximal expiratory flow at 50% vital capacity breathing air (V50air) but the severity of the reduction was statistically greater in the aspergillosis group. Reversibility in FEV1 of 15% and more was found in 50% of patients with asthma alone as against 31% of patients with aspergillosis. The degree of reversibility of FEV1 was also statistically greater in patients with asthma alone. Improvement of less than 20% of V50 after helium-oxygen breathing was found in 33% of the patients with asthma alone and in 75% of the patients with aspergillosis. Patients with aspergillosis also showed significantly (0-001 less than P less than 0-01) more reduced gas transfer factor. Radiological features of overinflation were as common in the two groups. Tubular and ring shadows were found in 95% and 60% respectively of patients with aspergillosis as against 45% and 15% of patients with asthma alone.     

Controlled trial of natamycin in the treatment of allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis often requires treatment with oral corticosteroids to control the host response to Aspergillus fumigatus. In a double blind study 25 patients with allergic bronchopulmonary aspergillosis taking maintenance oral corticosteroids were randomly allocated to receive 5 mg natamycin or placebo by nebuliser twice daily for one year. The primary aim of the study was to assess the steroid sparing potential of natamycin. Standardised reductions in corticosteroid dosage were therefore undertaken every five weeks, unless clinically contraindicated. Five patients were withdrawn in the first four months: two (1 natamycin, 1 placebo) died, two (1 natamycin, 1 placebo) had suspected drug reactions, and one (natamycin) was non-compliant. The pretreatment characteristics of the 20 patients (10 in each group) who completed the study were similar, 17 (9 natamycin, 8 placebo) having evidence of recent disease activity. At the end of the study prednisolone dose had been reduced by a similar amount in each group (median natamycin 2.25 mg, placebo 2.5 mg). Evidence of disease activity during the study year (transient shadowing on the chest radiograph, blood eosinophilia, or increases in antibodies to A fumigatus, or any combination of these) was observed in similar numbers of patients in each group (5 natamycin, 7 placebo). There was no evidence that natamycin conferred benefit on these patients with allergic bronchopulmonary aspergillosis.     

Rise in total IgE as an indicator of allergic bronchopulmonary aspergillosis in cystic fibrosis.

BACKGROUND--Allergic bronchopulmonary aspergillosis is a serious complication of cystic fibrosis and may be difficult to diagnose. The aim of this study was to define the usefulness of measuring total IgE compared with other major criteria in the diagnosis of allergic bronchopulmonary aspergillosis in children with cystic fibrosis. METHODS--A retrospective analysis was carried out of the case records of 160 children attending a tertiary referral paediatric cystic fibrosis clinic. RESULTS--Sixteen children had a total IgE level above 500 IU/ml. Eleven children had six or more other major criteria and were considered to have allergic bronchopulmonary aspergillosis. These 11 children had a fourfold rise in IgE in association with clinical deterioration. A further child had a fourfold rise in IgE to 341 IU/l, and was also thought to have allergic bronchopulmonary aspergillosis. Eleven had a fall in IgE with successful treatment; one patient died with uncontrolled disease. Only one of these 12 children had negative precipitins to Aspergillus fumigatus. The five children with a raised IgE not thought to have bronchopulmonary aspergillosis had four or fewer major criteria and were not treated; none had positive precipitins. CONCLUSIONS--A fourfold rise in total IgE, particularly to above 500 IU/ml, is strongly suggestive of the diagnosis of allergic bronchopulmonary aspergillosis in children with cystic fibrosis. The measurement of total IgE has the merit of being simple to perform and objective. Positive aspergillus precipitins provide useful confirmatory evidence. These two criteria, taken in conjunction with clinical deterioration and new radiological shadowing, allow simplification of the diagnosis of allergic bronchopulmonary aspergillosis in cystic fibrosis.     

Pulmonary sequestration associated with aspergillosis.

Pulmonary sequestration involves an abnormal pulmonary tissue separated from the normal pulmonary parenchyma, not connected to the tracheobronchial tree and supplied by a systemic artery. A case of intralobar pulmonary sequestration is presented. Case; a 49-year-old male was admitted to our hospital complaining of fever, cough and sputum production. Sputum culture resulted in a large growth of Aspergillus niger. Angiography showed an abnormal blood supply from the abdominal aorta to the right lower lobe. Right lower lobectomy was performed. The postoperative courses are uneventful.     

Pulmonary sequestration and aspergillosis.

OBJECTIVE: Pulmonary sequestration (PS) is an uncommon congenital disease. Symptoms when present are usually secondary to pyogenic infection. Our objective was to draw attention on superimposed fungal infection. METHODS: During the last 20 years, we operated upon 19 intralobar PS. Four of six patients operated during the last decade proved to have intralobar PS containing Aspergillus. RESULTS: In one patient aspergillosis presented as an aspergilloma and communications between the sequestration and small bronchi were present. In another patient diagnosis was made before operation because of positive precipitins test. In two patients aspegillosis was discovered by the pathologist. CONCLUSIONS: Review of literature demonstrates PS fungal colonization to be a rare but recently reported entity (14 cases reported). The observation of four consecutive patients leads us to suggest that PS aspergillosis must be considered in order to evaluate its incidence.     

Pulmonary sequestration associated with asymptomatic aspergillosis.

Intralobar pulmonary sequestration associated with asymptomatic aspergillosis is a rare case. We describe the case of a 65-year-old woman with intrapulmonary sequestration, anomalous systemic arterial supply to the left lower lobe and aspergillosis who underwent left lower lobectomy and ligation of an anomalous artery by Video-Assisted Thoracoscopic surgery (VATS). Pathological examination showed the parenchymal distortion and chronic inflammation. Aspergillus were found in the cyst. VATS lobectomy for intralobar pulmonary sequestration is a safe and valid procedure.     

Pulmonary eosinophilia associated with montelukast

Antileukotriene drugs are new therapeutic agents that have recently been approved for the treatment of asthma. Several cases of eosinophilic conditions including Churg-Strauss syndrome have been reported to be associated with zafirlukast, a cysteinyl leukotriene type 1 receptor antagonist. So far no other leukotriene modifier has been associated with the syndrome. The case history is presented of a man with allergic rhinitis and asthma who had received intermittent pulse therapy with oral corticosteroids. Pulmonary eosinophilia developed while he was receiving treatment with montelukast, a chemically distinct cysteinyl leukotriene type 1 receptor antagonist. After discontinuation of montelukast therapy and administration of systemic corticosteroids the patient's symptoms reversed rapidly and there was prompt resolution of the pulmonary infiltrates. We believe that cysteinyl leukotriene type 1 receptor antagonists are safe and effective drugs for most patients with asthma but caution is needed for those with more severe disease who require systemic corticosteroids, especially if they show characteristics of the atypical allergic diathesis seen in the prodromal phase of Churg-Strauss syndrome.