Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus, causing severe asthma that may progress to bronchiectasis. Sputum neutrophilia can occur in association with sputum eosinophilia and correlates with the degree of bronchiectasis. The mechanisms of sputum neutrophilia in ABPA are not known. The aim of this study was to investigate the role of the chemokine interleukin (IL)-8 in sputum neutrophilia in ABPA. Induced sputum was obtained from subjects with ABPA (n=29), and compared to nonsensitised asthma (n=9) and healthy controls (n=21). Semiquantitative polymerase chain reaction was used to assess IL-8 gene expression in induced sputum and IL-8 protein was measured by enzyme-linked immunosorbent assay. Sputum IL-8 protein was significantly higher in ABPA compared to asthma and controls. IL-8 messenger ribonucleic acid/glyceraldehyde-3-phosphate dehydrogenase ratio was elevated in ABPA compared to asthma and controls. Sputum IL-8 correlated with sputum neutrophils, matrix metalloproteinase-9 levels and forced expiratory volume in one second. Interleukin-8 gene expression and protein release were increased in allergic bronchopulmonary aspergillosis and correlated with airway neutrophilia and airway obstruction. The interleukin-8-mediated neutrophil influx in allergic bronchopulmonary aspergillosis may induce lung damage via release of matrix metalloproteinase-9, potentially leading to bronchiectasis.

Heterogeneity of airway inflammation in persistent asthma : evidence of neutrophilic inflammation and increased sputum interleukin-8.

STUDY OBJECTIVES: To identify the characteristics of airway inflammation in persistent asthma and to examine the role of neutrophilic inflammation in noneosinophilic persistent asthma. METHODS: Nonsmoking adults (n = 56) with persistent asthma and healthy control subjects (n = 8) underwent hypertonic saline solution challenge and sputum induction. Selected sputum portions were dispersed with dithiothreitol and assayed for total cell count, cellular differential, supernatant eosinophil cationic protein (ECP), myeloperoxidase, and interleukin (IL)-8. RESULTS: We identified two distinct inflammatory patterns. Typical eosinophilic inflammation occurred in 41% of subjects, whereas the remainder exhibited noneosinophilic asthma (59%). Both neutrophil percentage and absolute neutrophil counts were increased in subjects with noneosinophilic asthma (64%, 283 x 10(6)/mL) compared to eosinophilic asthma (14%, 41 x 10(6)/mL) and control subjects (34%, 49 x 10(6)/mL; p = 0.0001). Myeloperoxidase was elevated in both noneosinophilic (280 ng/mL) and eosinophilic groups (254 ng/mL) compared with control subjects (82 ng/mL; p = 0.002). Sputum IL-8 levels were highest in subjects with noneosinophilic asthma (45 ng/mL) compared to eosinophilic asthma (9.6 ng/mL) and control subjects (3.5 ng/mL; p = 0.0001). Neutrophils correlated with IL-8 levels (r = 0.72). ECP was highest in subjects with eosinophilic asthma (2,685 ng/mL) compared with noneosinophilic asthma (1,081 ng/mL) and control subjects (110 ng/mL; p = 0.0001). CONCLUSION: Induced-sputum analysis in persistent asthma identifies two different inflammatory patterns. The most common pattern is noneosinophilic, associated with a neutrophil influx and activation, which may be mediated by IL-8 secretion. There is heterogeneity of airway inflammation in persistent asthma, which indicates differing mechanisms and may impact on treatment responses.

Acute anti-inflammatory effects of inhaled budesonide in asthma: a randomized controlled trial.

Corticosteroids can have acute effects on airway function and methacholine airway responsiveness in asthma as early as 6 h after dosing, suggesting there may be an acute anti-inflammatory effect of inhaled corticosteroid in asthma. This study aimed to determine the effects of a single dose of inhaled budesonide on sputum eosinophils and mast cells in adults with asthma, and to examine whether the mechanism of clearance of eosinophils was by apoptosis. A randomized, double-blind, placebo-controlled, crossover study was conducted. At the screening visit, adults with stable asthma (n = 41) ceased inhaled corticosteroid therapy for 4 d and those with significant sputum eosinophilia (> or = 7%) were randomized (n = 26) to a single dose of budesonide 2,400 microg or placebo via Turbuhaler, on two separate study days. Symptoms and lung function were followed for 6 h, then sputum was induced and airway responsiveness to hypertonic saline determined. Sputum eosinophils (mean, SE) were significantly lower 6 h after budesonide (25%, 4.5), compared with placebo (37%, 6.2, p < 0.05). There was a 2.2-fold (95% CI 1.45 to 3.33) improvement in airway responsiveness with budesonide. No significant difference was seen on mast cells, apoptotic eosinophils, symptoms, or lung function. In conclusion, a single dose of inhaled corticosteroids has beneficial effects on airway inflammation and airway hyperresponsiveness as early as 6 h after dosing. This may be clinically useful as therapy during mild exacerbations of asthma.

Airway mast cells and eosinophils correlate with clinical severity and airway hyperresponsiveness in corticosteroid-treated asthma.

BACKGROUND: The relationship between airway inflammation and asthma severity in corticosteroid-treated asthma is unclear. OBJECTIVES: Our purpose was to characterize the inflammatory cell profile of the airway lumen and epithelium in corticosteroid-treated asthma and to relate these findings to clinical and physiologic markers of asthma severity. METHODS: Adults (n = 20) with asthma received standardized high-dose inhaled corticosteroid therapy with beclomethasone 2000 microgram per day for 8 weeks. Airway responsiveness to methacholine and hypertonic (4.5%) saline solution was then assessed, followed by sputum induction and, 1 week later, bronchoscopy with bronchoalveolar lavage and bronchial brush biopsy to assess inflammatory cells. RESULTS: Clinical asthma severity was associated with airway hyperresponsiveness. Metachromatic cells were the main granulocyte present in bronchial brush biopsy specimens and correlated with airway responsiveness to saline solution (r = -0.75), methacholine (r = -0.74), peak flow variability (r = 0.59), and clinical asthma severity (r = 0.57). Eosinophils were the main granulocyte present in sputum and correlated with airway responsiveness to saline solution (r = -0.63) but not with other clinical markers of asthma severity. Bronchoalveolar lavage cell counts were not related to clinical asthma severity. CONCLUSIONS: In asthmatic patients treated with cortico-steroids, the dominant inflammatory effector cell in the epithelium is the metachromatic cell, and in sputum it is the eosinophil. These cells correlate with the degree of airway hyperresponsiveness. Clinical asthma severity correlates with airway responsiveness and epithelial metachromatic cells. Induced sputum eosinophils and airway responsiveness to hypertonic saline solution may be useful markers of airway inflammation for clinical practice.

Induced sputum eosinophils and neutrophils and bronchiectasis severity in allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus that may progress to bronchiectasis. The aim of the present study was to characterize airway inflammation in patients with clinically stable ABPA and asthma, and to correlate this with bronchiectasis severity. Subjects with ABPA and central bronchiectasis (ABPA-CB; n=16) and ABPA with serological evidence alone (ABPA-S; n=10) were studied. Comparison groups were A. fumigatus-sensitized asthma (n=19), non-A. fumigatus-sensitized asthma (n=15) and healthy controls (n=8). Hypertonic saline challenge, sputum induction and high-resolution computed tomography (HRCT) of the chest were performed. Sputum eosinophil numbers were markedly elevated in ABPA-CB (median 8.4%) compared to ABPA-S (2.4%), A. fumigatus-sensitized asthma (1.8%), asthma (1.8%) and controls (0.3%) (p<0.01); sputum eosinophil cationic protein levels were higher in ABPA-CB (median 13,706 ng.mL(-1)), compared to ABPA-S (1,633.5 ng.mL(-1)), A. fumigatus-sensitized asthma (1,550.7 ng.mL(-1)), asthma (309.2 ng.mL(-1)), and controls (110 ng.mL(-1)) (p<0.001). ABPA-CB also showed increased sputum neutrophil number (median 60.3%) compared to the other groups (controls 29.3%) (p=0.01). The severity of bronchiectasis on HRCT correlated with sputum neutrophil (r=0.6) and eosinophil number (r=0.5) but not serum immunoglobulin-E levels. In conclusion, clinically stable allergic bronchopulmonary aspergillosis with bronchiectasis is characterized by an intense heterogenous inflammatory infiltrate consisting of eosinophils and neutrophils, which correlates closely with the severity of bronchiectasis on high-resolution computed tomography. Sputum analysis may be useful in monitoring the course of allergic bronchopulmonary aspergillosis.

Induced sputum eosinophil cationic protein (ECP) measurement in asthma and chronic obstructive airway disease (COAD)

BACKGROUND: Induced sputum is a useful way to monitor airway inflammation in asthma, but cell counts are time-consuming and labour intensive. OBJECTIVE: The aim of this study was to evaluate a novel processing method using eosinophil cationic protein (ECP) as a biochemical marker of sputum eosinophil number and activation in subjects with asthma and other airway diseases. METHODS: Sputum was dispersed with dithiothreitol and centrifuged to yield cell free supernatant and a cell pellet. The pellet was treated with a cellular lysis buffer to release cell-associated ECP. ECP was measured in sputum supernatant and in the lysed cell pellet and was compared with sputum eosinophil counts in 31 adults with asthma, chronic obstructive airway disease (COAD), bronchiectasis and healthy controls. The ratio of supernatant to pellet ECP was evaluated as an index of eosinophil degranulation. The effect of sputum processing reagents and storage time on ECP measurement was also evaluated. RESULTS: ECP measured in the cell pellet lysate correlated closely with sputum absolute eosinophil counts across a range of subject groups (r = 0.72, P = 0.004). Sputum eosinophil counts were less well correlated with supernatant ECP levels (r = 0.54, P < 0.05). Incubation with dithiothreitol or lysis buffer did not influence ECP measurement and sputum ECP levels were stable over a 6-9 month period. Sputum supernatant and pellet lysate ECP concentrations were increased in stable asthma, asthma exacerbations and COAD/bronchiectasis (P < 0.05). The ratio of supernatant to pellet ECP was used as an index of eosinophil degranulation and found to be elevated in asthma exacerbations, COAD and bronchiectasis, but not in stable asthma. CONCLUSION: The measurement of ECP in the sputum cell pellet provides a reliable and efficient estimate of sputum eosinophil counts which can potentially be used in clinical trials and epidemiological surveys. The ECP ratio may be a useful marker of eosinophil activation, and was increased in asthma exacerbation and COAD. The increased ECP in COAD reflects a non-selective accumulation of eosinophils in this condition.

Chronic cough resembles asthma with IL-5 and granulocyte-macrophage colony-stimulating factor gene expression in bronchoalveolar cells.

BACKGROUND: Chronic cough is a multifactorial condition, which, like asthma, can be associated with eosinophilic airway inflammation. In asthma, airway eosinophilia is believed to be mediated by cytokines such as interleukin-5 and granulocyte-macrophage colony stimulating factor (GM-CSF). The role of these cytokines in chronic cough is unclear. OBJECTIVE: The aim of this study was to examine gene expression for IL-5 and GM-CSF in chronic cough and compare the results with those found in asthma. METHODS: We studied adults with asthma (n = 12), chronic cough responsive to inhaled corticosteroid (ICS-responsive cough) (n = 9), and chronic cough not responsive to inhaled corticosteroid (non-ICS-responsive cough) (n = 4). Bronchoalveolar lavage (BAL) was performed, and cytokine gene expression was assessed by using a semiquantitative reverse transcriptase polymerase chain reaction. RESULTS: IL-5 mRNA was expressed by BAL cells from nine of 12 asthmatic subjects and six of nine subjects with ICS-responsive chronic cough. IL-5 mRNA was not detected in subjects with non-ICS-responsive chronic cough (zero of four subjects, p < 0.05). GM-CSF mRNA was expressed in BAL cells from seven of 12 asthmatic subjects and six of nine subjects with ICS-responsive cough. GM-CSF mRNA was not detected in non-ICS responsive cough subjects (zero of four subjects, p < 0.05). GM-CSF gene expression was related to the degree of methacholine airway responsiveness in asthmatic subjects (r = -0.59). CONCLUSION: We conclude that chronic cough, like asthma, is associated with airway inflammation and gene expression for IL-5 and GM-CSF. Ongoing expression of these cytokines is likely to be related to the persistence of airway inflammation and chronic cough.

A systematic evaluation of mechanisms in chronic cough.

We tested the hypothesis that hyperresponsiveness of the upper airway (UAHR) is present in patients with chronic cough of diverse etiology. We determined the frequency of bronchial hyperresponsiveness (BHR), hyperresponsiveness of the upper airway, sputum eosinophilia, pulmonary aspiration, and psychological symptoms in adults with chronic cough. Consecutive adults (n = 30) presenting to a tertiary referral clinic with chronic cough were compared with a group of 20 asymptomatic adults. Measurements included histamine provocation testing with measurement of flow volume curves to determine inspiratory and expiratory airflow obstruction; hypertonic saline induced sputum for analysis of eosinophils, mast cells and lipid-laden macrophages; and a validated psychological symptom questionnaire. Symptomatic rhinitis and gastroesophageal reflux were common causes of chronic cough. BHR occurred in seven patients (23%) and in no control subjects (p < 0.05). UAHR occurred in 40% of patients with cough and in four (20%) control subjects (p > 0.05). Eosinophils were present in the sputum of more patients with cough than control subjects (50% versus 19%; p < 0.05). High degrees of eosinophilia were present in six patients with cough, including three without BHR. No subject had significant lipid-laden macrophages. There was greater somatization in patients with chronic cough; ten subjects scored in the clinically significant range (p < 0.05). Abnormalities in one or more of these tests were 7.67-fold (95% CI 1.83-34.52) more likely to occur in cough patients than control subjects. We conclude that chronic cough is a nonspecific symptom that is associated with several apparently unrelated mechanisms. These include UAHR, somatization, BHR, and eosinophilic bronchitis. UAHR cannot be implicated as a single unifying mechanism. These findings emphasize the need to systematically evaluate several different causes of cough in patients who present with chronic cough.

Using quality-control analysis of peak expiratory flow recordings to guide therapy for asthma.

OBJECTIVE: To compare the action points in published asthma management plans with those derived from quality-control analysis of peak expiratory flow recordings. DESIGN: Longitudinal observational study. SETTING: An ambulatory asthma education and management program in a tertiary care hospital. PATIENTS: 35 adults with asthma and exacerbation of asthma. MEASUREMENTS: Peak expiratory flow diaries and symptom recordings. RESULTS: Asthma action points from published asthma management guidelines had poor operating characteristics. The success rate was 35% when the action point was a peak expiratory flow rate less than 60% of the patient's best peak flow. The success rate improved to 88% when the action point was a peak expiratory flow rate less than 80% of the patient's best peak flow. Published action points had a high failure rate. Peak flow decreased to below the published action points during a stable period of asthma in 7% to 51% of patients studied. Action points defined using quality-control analysis did significantly better. A peak flow value less than 3 standard deviations below the patient's mean peak flow detected 84% of exacerbations and had a low failure rate (19%). Other quality-control tests had sensitivities of 91% and 71%. Quality-control action points could detect exacerbations up to 4.5 days earlier than conventional methods. CONCLUSIONS: Individualized action points can be derived for patients with asthma by applying quality-control analysis to peak flow recordings. These action points are more sensitive in detecting exacerbations of asthma and have fewer false-positive results. Action plans developed in this manner should be more useful for the early detection of deteriorating asthma.

A case of Actinomyces meyeri pneumonia in a child.

Pulmonary actinomycosis is an uncommon infection whose diagnosis is often delayed as clinically the disease may mimic tuberculosis or cancer. It is rare in children. We present the first report from Australasia of a case of Actinomyces meyeri pneumonitis in a 13-year-old boy.

Occult ruptured spleen--two unusual clinical presentations.

Case reports of two patients with occult rupture of the spleen are presented. In one, blunt trauma appeared to involve only the neck and upper chest, resulting in two distinct tracheal injuries and no clinical indication of abdominal injury. On the 5th day after injury this patient strangulated an indirect inguinal hernia. At subsequent surgery, a ruptured spleen was also found. The second patient gave no history of trauma and presented in cardiac and respiratory failure after a 2-month illness characterized by abdominal pain. On clinical and biochemical assessments, he was considered to have pancreatitis complicated by pseudocyst formation. Laparotomy revealed intra-abdominal haemorrhage and a ruptured spleen. The diagnosis and complications of occult ruptured spleen are discussed.

Hypersensitivity pneumonitis in a mouldy house.

Two cases of hypersensitivity pneumonitis, one confirmed by histopatholgy, are described. The patients were members of different families and developed the disease as occupants, at separate times, of the same inner-city dwelling. We believe the disorder resulted from exposure to thermophilic microorganisms prevalent in their domestic environment. Both patients recovered after moving from this place of residence. The need for greater awareness of this variety of hypersensitivity pneumonitis is stressed.

Fat embolism syndrome: incidence, significance and early features.

During the period 1968 to 1978 a total of 447 patients were treated in the Royal Newcastle Hospital for acute respiratory failure after injury. In 321 patients respiratory failure occurred after thoracic and/or long bone injury. In only 17 of these could a diagnosis of fat embolism syndrome (FES) as a sole cause of respiratory failure be substantiated when strict diagnostic criteria were applied. In a further 15 patients FES may have coexisted with other causes of respiratory failure. The outstanding features of patients with FES were: (I) all were in the younger age groups; (II) all developed respiratory symptoms within 48 hours of admission to hospital; (III) most had multiple limb fractures; (IV) more than half had been transferred from other hospitals; and (V) three were pregnant and had sustained in comparison with the others, less severe long bone injuries.

Terminal exacerbation of chronic melioidosis in New South Wales.

A fatal case of melioidosis, thought to be the third recorded from New South Wales, is presented. Infection probably occurred in Queensland. The patients presented with a subcutaneous abscess complicated by pyaemia, extensive lung involvement and septicaemic shock. The diagnosis was bacteriologically confirmed shortly before death, by isolation of Pseudomonas pseudomallei from blood, pus swabs and tracheal aspirates. There is a need for greater awareness of this disease in persons who have resided in South-East Asia and in North-Eastern Australia.

Eosinophilic meningitis (angiostrongylosis): a probable case.

A probable case of eosinophilic meningitis is described. This report is thought to be the first of a case of this disorder diagnosed in New South Wales, although infection probably occurred in Queensland. The life cycle of the parasite Angiostrongylus cantonensis is outlined briefly and the clinical manifestations of this disease are discussed. Treatment with thiabendazole seems to have been beneficial to this patient.