Methacholine and adenosine 5'-monophosphate challenges in preschool children with cough-variant and classic asthma

Bronchial challenge with different stimuli provides different information and may be used as an adjunct to understand the pathophysiology of cough variant asthma (CVA) in young children in whom the mechanism of disease is still unresolved. This study was designed to investigate the hypothesis that airway hyperresponsiveness (AHR) to methacholine and adenosine 5'-monophosphate (AMP) is similar in preschool children with CVA and classic asthma. We examined airway response to methacholine and AMP in well-defined 3-6-year-old children with CVA (n = 18), classic persistent asthma (n = 31), and healthy controls (n = 10) by transcutaneous oxygen monitorization. The number of AMP responsive children was significantly lower in the group with CVA (38.9%) than classic persistent asthma (67.7%) (P = 0.049). Mean provocative concentration of AMP causing a 15% fall in transcutaneous oxygen tension (PC15PtcO2 AMP) in children with CVA and classic persistent asthma were 234.58 and 36.35 mg/ml, respectively (P = 0.001). None of the healthy children in the control group responded to AMP. The severity of methacholine responsiveness was found similar in CVA and classic persistent asthma groups (P = 0.738). Although both asthma groups showed a similar pattern in methacholine responsiveness, preschool children with CVA were found to differ from children with classic persistent asthma with regard to response profiles to AMP challenge which may point to different pathophysiologic mechanisms of CVA in the young age group.     

Airway inflammation and lung function decline in childhood post-infectious bronchiolitis obliterans

Post-infectious bronchiolitis obliterans (PBO) is a rare form of chronic obstructive lung disease in children with few data on the pulmonary function outcome and underlying inflammatory process. The aim of this study was to determine the change in lung function over time and to investigate by bronchoalveolar lavage (BAL) the inflammatory characteristics of pulmonary involvement. Eleven Caucasian children with PBO were evaluated to estimate the average rate of change in lung function indices using a mixed model. The differential cytology and lymphocyte subsets of BAL fluid were analyzed. The median follow-up was 10.2 (IQR 3.2-12) years. The estimated forced expiratory volume in 1 sec (FEV1) had a baseline intercept of 57% predicted (62% predicted after bronchodilator) at 10 years of age which fell at a rate of 1.01% per year whereas the estimated forced expiratory flow 25-75 (FEF25-75) had a baseline intercept of 36% predicted (42% predicted after bronchodilator) at 10 years of age which fell at a rate of 1.04% per year. The estimated FEV1/FVC ratio had a baseline intercept of 70% (74% after bronchodilator) at 10 years of age which declined with an average slope of 1.02% per year (-1.10% per year after bronchodilator). Although the baseline and post-bronchodilator level of estimated FVC was abnormal (68% and 69% predicted, respectively) it did not change significantly with time. The median disease duration at BAL evaluation was 3.7 (IQR 0.7-8) years. The percentage differential cell counts were characterized by a significant increase in neutrophils (median 50%, IQR 1-66%), and a slight increase of lymphocytes (median 14%, IQR 7.5-15%). In conclusion, pulmonary function in childhood PBO is characterized by significant airway obstruction which deteriorates over time. The presence of an ongoing inflammatory process could explain the decline in lung function over time.     

Exercise, methacholine, and adenosine 5'-monophosphate challenges in children with asthma: relation to severity of the disease

Bronchial hyperreactivity is a characteristic feature of asthma and can be evaluated by different challenges. The aim of this study was to compare exercise, methacholine (MCH), and adenosine 5'-monophosphate (AMP) challenges in 135 children and young adults (mean age +/- SD, 12.4+/-3.9 years) with asthma, and to examine the utility of the different challenges in predicting those children with asthma likely to require prophylactic antiinflammatory treatment. The sensitivity of MCH challenge in detecting bronchial hyperreactivity (at or below 8 mg/mL) was 98%, that of AMP challenge (at or below 200 mg/mL) 95.5%, and that of exercise (more than 8.2% fall in FEV(1)) was 65%. There was a significant difference between mild asthmatic children (85 patients, intermittent asthma, step 1 of NIH guidelines) and moderate asthmatics (50 patients, steps 2 and 3 of guidelines) in relation to the logarithmic mean provocation concentration to elicit a 20% fall in FEV(1) (PC(20)) to MCH (0.49 mg/mL vs. 0.15 mg/mL, P<0.00001), that to AMP (7.67 mg/mL vs. 3.60 mg/mL, P = 0.001), and in relation to the mean percent fall in FEV(1) after exercise (13.9% vs. 22.0%, P = 0.001). Sensitivity and specificity curves between the two severity groups of asthma were constructed, and the intersection point of the two curves for each type of challenge was determined. When mild asthmatics were compared to moderate asthmatics, the intersection points for MCH, AMP, and exercise were 66%, 63%, and 61%, respectively. Logistic regression analysis and receiver operating characteristic (ROC) curves of the three challenges for the two severity groups of asthma showed that methacholine was a better discriminating challenge between the severity groups than the other two challenges. We conclude that the sensitivities of AMP and MCH challenges in the detection of bronchial hyperreactivity in children and young adults with asthma are very similar and higher than that of exercise. There is a significant difference between mild and moderate asthmatics within the three bronchial challenges, with MCH discriminating better than AMP or exercise between groups.     

Post-transplant bronchiolitis obliterans.

Over the last decade, improvements in surgical techniques, lung preservation, immunosuppression, and management of ischaemia/reperfusion injury and infections have made intermediate-term survival after lung transplantation an achievable goal. However, chronic allograft dysfunction in the form of bronchiolitis obliterans remains a major hurdle that threatens both the quality of life and long-term survival of the recipients. It affects up to 50-60% of patients who survive 5 yrs after surgery, and it accounts for >30% of all deaths occurring after the third postoperative year. This article discusses the alloimmune-dependent and -independent risk factors for bronchiolitis obliterans, the current understanding of the pathogenesis of bronchiolitis obliterans based on results of animal and human studies, the clinical staging of the complication, strategies that may contribute to the prevention and/or early detection of bronchiolitis obliterans, and suggestions for future research.     

Determinants of airway responsiveness to adenosine 5'-monophosphate in school-age children with asthma

Airway responsiveness to adenosine 5'-monophosphate (AMP) is more specific than that to direct stimuli for asthma diagnosis and response to treatment, but is not detected in all patients with asthma. This study was planned to determine predictive factors for responsiveness to AMP in asthmatic children between 7-16 years old. We performed a retrospective analysis of data from 71 asthmatic children who were challenged by AMP in our department. All children were characterized by skin-prick and lung function tests and bronchial challenge with AMP. Data on simultaneous methacholine challenge tests were available for 46 children, 34 of whom were also challenged with a third stimulus, exercise. Potential demographic factors for responsiveness to AMP were assessed by logistic regression analysis within the study group. The proportion of school-age children with asthma responsive to AMP was 39.4%. The geometric mean provocative concentration of AMP causing a 20% decrease in forced expiratory volume in 1 sec (PC20AMP) was 20.50 mg/ml (range, 0.31-377 mg/ml). There were no significant differences either in response to methacholine below 16 mg/ml (P = 0.66) or in PC20 methacholine level (P = 0.075) when we compared AMP-responsive and -nonresponsive children. These two groups also did not differ with respect to their response to exercise challenge in subgroup analysis (P = 0.34). Among school-age children with asthma, allergic rhinitis (P = 0.004) and sensitizaton to grass mix (P = 0.001), cereal mix (P = 0.003), house dust mite (P = 0.024), and cat (P = 0.043) were found to be more frequent in AMP-responsive children than the others. There was no difference in lung function test parameters between children responsive to AMP and the others. Grass pollen sensitization was found to be the only independent predictive factor for determining AMP responsiveness in school-age children with asthma (odds ratio, 5.65; 95% confidence interval, 1.84-17.45; P = 0.003). In conclusion, atopic sensitization is the most important predictive factor for responsiveness to AMP in school-age children with asthma, as in adults.     

Urinary excretion of adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate in normal children and those with cystic fibrosis.

The urinary excretion of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) was examined in 98 normal children and 46 children with cystic fibrosis between the ages of 9 months and 18 yr. Diurnal variations in cyclic AMP and cyclic GMP excretion were observed in subjects from either group, and peak levels of cyclic nucleotide excretion were generally observed during the period of 0700 to 2100 h. Excretion rates (mumol/day) of cyclic AMP and cyclic GMP increased significantly with age. When cyclic AMP and cyclic GMP excretion rates were normalized for urinary creatine, or body weight, the values declined significantly with age in both groups of patients. Cyclic GMP excretion normalized for body surface area also decreased with age, while the value for cyclic AMP (2.86 plus or minus 0.08 mumol/day/m2, mean plus or minus SE) was constant with age in both normals and cystic fibrosis children. With some comparisons of age groups there were significant differences in cyclic nucleotide excretion between normal subjects and children with cystic fibrosis. The differences noted were dependent upon the methods used to normalize excretion rates (urinary creatine, body weight, surface area, and the ratio of cyclic AMP to cyclic GMP excreated). In general patients with cystic fibrosis excreted greater amounts of cyclic GMP than did normals. The most striking comparison was the ratio of cyclic AMP to cyclic GMP excreted which was 9.09 plus or minus 0.50 in all normal children and 4.41 plus or minus 0.32 in children with cystic fibrosis (P smaller than 0.001).     

Bronchial responsiveness to methacholine and adenosine 5'-monophosphate in preschool children with bronchopulmonary dysplasia

Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, but it is also frequently present in children and adults with chronic obstructive lung diseases. Bronchopulmonary dysplasia (BPD) is a chronic lung disease, most commonly developing after mechanical ventilation and oxygen therapy in premature infants. BHR is usually measured by bronchial challenges, using direct or indirect stimuli. The aim of this study was to evaluate BHR to direct and indirect stimuli in young children with BPD. Methacholine and adenosine 5'-monophosphate (AMP) bronchial challenges were performed on preschool children with BPD (n = 19), using a modified auscultation method. The endpoint was defined as the appearance of wheezing and/or oxygen desaturation. The results obtained were then compared with those of asthmatic (n = 25) and control (n = 23) preschool children. A positive response to methacholine (endpoint concentration, < or = 8 mg/ml) was observed in 89.5% (17/19) of patients with BPD, but a positive response to AMP (endpoint concentration, < or = 200 mg/ml) was observed only in 21.1% (4/19). All patients with asthma responded positively to methacholine, and most (23/25, 92.0%) of them also responded positively to AMP. The majority of controls were unresponsive to both challenges. BHR to methacholine is a frequent finding in preschool-age survivors of BPD, but is usually not accompanied by BHR to AMP. This suggests that most patients with BPD do not have the inflammatory airway response which is characteristic of asthmatic patients.     

Fatal bronchiolitis obliterans associated with chrysotherapy.

We describe a patient who developed fatal bronchiolitis obliterans following gold therapy and review the relationship between rheumatoid arthritis and bronchiolitis.     

Follow-up on the therapeutic effects of a budesonide,azithromycin, montelukast,and acetylcysteine (BAMA) regimen in children with post-infectious bronchiolitis obliterans

BackgroundPost-infectious bronchiolitis obliterans (PIBO) is a rare, severe chronic lung disease without optimal treatment. Currently, treatment in children mainly relies on systemic corticosteroids, but long-term use of these drugs may lead to adverse reactions. This study aimed to evaluate the short-term efficacy of the budesonide, azithromycin, montelukast, and acetylcysteine (BAMA) regimen in paediatric PIBO patients and whether it can reduce systemic corticosteroid use.MethodsThis was a prospective study. From June 2017 to July 2020, patients diagnosed with PIBO at Yuying Children’s Hospital of Wenzhou Medical University were treated with the BAMA regimen for 3 months. Methylprednisolone was added only when the clinical manifestations did not improve or deteriorated. All patients were followed up every 2 to 4 weeks, and changes in clinical symptoms were recorded. Pulmonary function tests and high-resolution computed tomography (HRCT) were performed, and systemic corticosteroid use was recorded after the 3-month follow-up.ResultsA total of 75 patients with PIBO were included; overall, 54 patients completed the course of treatment. After treatment, the respiratory manifestations were improved in 37 patients (68.5%), but 4 patients (7.4%) showed decreased exercise tolerance, and 2 patients (3.7%) were readmitted to the hospital. Additionally, 17 (56.7%) of the 30 patients whose pulmonary function was re-examined showed improvement, and 28 (77.8%) of the 36 patients who underwent HRCT showed marked improvement. Importantly, 20 patients (54.1%) received systemic corticosteroids for 2 weeks or less, while 31.5% of patients used no corticosteroids.ConclusionsThe BAMA regimen effectively relieved clinical symptoms and signs of PIBO in children, improved pulmonary function and HRCT manifestations, and reduced the use of systemic corticosteroids.     

儿童闭塞性细支气管炎的诊治进展

闭塞性细支气管炎在儿童中是一种相对少见而严重的慢性阻塞性肺疾病,与小气道损伤有关,通常病变局限在终末细支气管。起病年龄主要发生于婴幼儿时期,多由感染引起。主要临床特点是反复或持续气促、喘息、咳嗽,运动耐力差,肺部有湿啰音和喘鸣音。对支气管扩张剂无反应。近年随着诊疗技术及临床医师对该病认识水平的提高,该病在儿童中报道发病例数增多。为进一步加强儿科医师对闭塞性细支气管炎的认识,本文就闭塞性细支气管炎的近年诊治进展作一简要综述。     

Constrictive bronchiolitis obliterans and paraneoplastic pemphigus.

Constrictive bronchiolitis obliterans is rare, and the pathogenesis of the disease often remains unknown. This study reports on the case of a 38 yr-old female with constrictive bronchiolitis obliterans and paraneoplastic pemphigus associated with malignant lymphoma. The patient developed progressive obstructive lung disease. The chest radiograph showed almost normal lungs. Paraneoplastic pemphigus is a newly described syndrome in which patients have autoantibodies binding to some epithelia, including in the respiratory tract. The disease develops in association with non-Hodgkin's lymphomas or other malignant neoplasms. The case presented here suggests that constrictive bronchiolitis obliterans associated with paraneoplastic pemphigus may be one of the facets of autoimmune responses in this context.     

Bronchoconstriction induced by inhaled adenosine 5'-monophosphate in subjects with allergic rhinitis.

Adenosine and its related nucleotide, adenosine 5'-monophosphate (AMP) induce bronchoconstriction in asthmatics, probably caused by histamine release from airway mast cells. The objective of this study was to determine the effect of inhaled AMP on lung function in subjects with allergic rhinitis. A total of 52 adults (28 subjects with allergic rhinitis, 14 asthmatics and 10 healthy subjects) were challenged with increasing concentrations of AMP and methacholine. Airflow was assessed after each concentration and the response to each bronchoconstrictor agent was measured by the provocative concentration required to produce a 20% fall (PC20) in forced expired volume in one second (FEV1). All 14 asthmatics, 10 subjects with allergic rhinitis and none of the healthy controls were hyperresponsive to AMP. Subjects with allergic rhinitis had higher prevalence of hyperresponsiveness to AMP than healthy controls (p=0.038). Although the prevalence of hyperresponsiveness for methacholine and for AMP in subjects with allergic rhinitis was similar (39% and 36%, respectively), four subjects had hyperresponsiveness to methacholine but not to AMP, whereas three subjects had hyperresponsiveness to AMP but not to methacholine. To conclude, inhaled adenosine 5'-monophosphate causes airway narrowing in a significantly higher proportion of subjects with allergic rhinitis than healthy volunteers. Furthermore, methacholine and adenosine 5'-monophosphate hyperresponsiveness are not detected in the same individuals with allergic rhinitis, thus suggesting that responsiveness to the two bronchoconstrictor stimuli is not reflecting the same abnormalities of the airways.     

Urinary excretion of cyclic adenosine 3',5'-monophosphate in children of different ages.

The urinary excretion of cyclic AMP was investigated in 97 healthy children, 3 months to 16 years old. When the excretion was expressed as mumol/24 h an increase with age (r = 0.693, P less than 0.001) and an increase with body weight (r = 0.700, P less than 0.001) were found to be quite similar. In relation to surface area, the average excretion for children up to 91/2 years old was 4.45 +/- 1.71 mumol/m2 in constrast with 2.22 +/- 0.66 mumol/m2 in older children (P less than 0.001). The decline appears to be associated with approaching puberty. When cAMP excretion was related to urinary creatinine, an inverse correlation with age was found (r = -0.772, P less than 0.001). In the youngest category, 3 months to 4 years old, the ratio was 9.26 +/- 1.49 mumol/g creatinine vs 4.67 +/- 1.05 mumol/g creatinine in the age group 12 to 16 years old (P less than 0.001), which compares closely with the normal adult average of 4.34 +/- 1.25 mumol/g creatinine found in our previous study. Throughout there was no evidence of sex differentiation.     

Paraneoplastic pemphigus associated with bronchiolitis obliterans

Paraneoplastic pemphigus (PNP) is an autoantibody-mediated mucocutaneous blistering disease associated with underlying neoplasms. Autoantibodies of PNP bind to the plakin family of cytoplasmic proteins and desmogleins of cell-surface target antigens. We describe a 36-year-old female patient with PNP who had non-Hodgkin's lymphoma, and who developed bronchiolitis obliterans and died of respiratory failure. Autopsy findings confirmed luminal narrowing of bronchioles by scarring, which is a histopathologic features of bronchiolitis obliterans. After the onset of respiratory failure, the reaction of autoantibodies against the plakins detected by immunoprecipitation at the onset of PNP disappeared with negative immunofluorescence within the bronchial epithelium. It is thought that autoantibodies against some of these antigens play a role in causing acute inflammation of the respiratory epithelium. In treating PNP, the possibility of the patient developing the lethal complication bronchiolitis obliterans should be kept in mind. Furthermore, prevention of the initial autoantibody-mediated injury to the respiratory epithelium should be an important treatment goal.