Mucociliary clearance techniques for treating non-cystic fibrosis bronchiectasis: Is there evidence?

Non-cystic fibrosis bronchiectasis (nCFb) is an acquired condition of variable etiology. An impaired mucociliary clearance seems to be one of the mechanisms behind nCFb, and treatment involves antibiotics, mucoactive agents, and airway clearance techniques (ACTs). Traditional ACTs have four components: postural drainage, percussion, vibration of the chest wall, and coughing. Reviewing the international medical literature on the use of ACTs for patients with nCFb from 1989 to the present day, we retrieved 93 articles, of which 35 met our selection criteria for this analysis. We reviewed active cycle of breathing techniques (ACBT), forced expiration techniques (FET), autogenic drainage, postural drainage, oscillating positive expiratory pressure (OPep), high frequency chest wall oscillation (HFCWO), and exercise or pulmonary rehabilitation. Overall, ACTs appear to be safe for individuals (adults and children) with stable bronchiectasis; where there may be improvements in sputum expectoration, selected measures of lung function, and health-related quality of life. Unfortunately, there is a lack of RCTs in nCFb patients, especially in children. Moreover, none of the studies describes long-term effects of ACTs. It should be noted that a single intervention might not reflect the longer-term outcome and there is no evidence to recommend or contest any type of ACTs in nCFb management. Multicenter RCTs are necessary to evaluate the different techniques of ACTs especially in children with nCFb.

Inhaled mucoactive drugs for treating non-cystic fibrosis bronchiectasis in children.

Non-cystic fibrosis bronchiectasis (nCFb) is an acquired condition of variable etiology. Medical treatment basically involves antibiotics and chest physiotherapy. An impaired mucociliary clearance seems to be one of the mechanisms behind nCFb, and inhaled therapy with mucoactive agents has frequently been used to try to correct it. The most often used mucoactive agents in this setting are N-acetylcysteine, hypertonic saline solution (HS), mannitol powder and recombinant human DNase (rhDNase). Reviewing the international medical literature on the use of these drugs for patients with nCFb from 1992 to the present day, we retrieved 88 articles, only 12 of which met our selection criteria for this analysis. We found only 2 papers and 2 reviews on the use of rhDNase in children, and in adults 3 trials on HS, 5 on mannitol powder and 2 on rhDNase. In conclusion, no observational or randomized controlled trials (RCT) have been published on the use of these drugs in children with nCFb, while the few conducted on adult patients report some evidence of their effects. Further studies are needed on inhaled mucoactive drugs for the treatment of children with nCFb.

Pediatric chronic lower respiratory disorders: microbiological and immunological phenotype.

The role of infectious agents in children with recurrent/chronic lower respiratory disorders (R/CLRDs) is not clear, whereas it has been largely studied in acute respiratory diseases. The purpose of the study was to evaluate the frequency of infections, in particular viral infections, in children with R/CLRDs correlating their presence with clinical/biohumoral parameters. Eighty children affected by R/CLRDs underwent bronchoscopy and analysis of bronchoalveolar lavage (BAL) for cells, mediators (eosinophil cationic protein-ECP, interleukin-IL-8, tumor necrosis factor-TNFα) and pathogens (viruses and bacteria). Viral genomes were detected in 50/80 (62.5%) children. Rhinovirus, the principal detected virus (26/50, 52%), occurred more frequently in male children. Higher percentages of BAL neutrophils and IL-8 values were detected in virus positive than negative children. ECP values resulted significantly higher in the children with rhinovirus than in those with other viruses. No other statistically significant correlation between viral findings and clinical/biohumoral data were found. Respiratory viruses, especially rhinovirus, seem to play an important role in children with R/CLRDs. They are associated with changes in BAL cellularity and inflammatory cytokines. Further studies are needed to confirm the persistence of viruses in these patients and to identify eventual therapeutic strategies.

Temporary impairment of reticulocyte haemoglobin content in subjects with community-acquired pneumonia.

INTRODUCTION: In the case of inflammation, imbalance of iron homoeostasis is caused by increased retention of iron within cells of the reticuloendothelial system. Iron-restricted erythropoiesis occurs because of decreased availability of iron for haemoglobin (Hb) synthesis in erythroid progenitor cells. Deviations in reticulocyte haemoglobin (Ret-He) content are investigated together with inflammation markers in subjects with community-acquired pneumonia (CAP). Short-term alterations with regard to Ret-He during and after completing antibiotic treatment are investigated. METHODS: A total of 75 patients, classified into three subgroups with CURB-65 scores of ≤1, 2 and ≥3, participated in the study. RESULTS: Within the three subgroups, Hb results demonstrate a decline from the day of admission until day 4. From day 4, an increase towards higher values is observed at day 14. Within 24 h after admission, Ret-He results are situated within the lower quartile region of the reference range interval. Until day 4 of hospital admission, a steady trend towards a decline of 3-8% is established. During antibiotic treatment, an increase in reticulocyte count occurs from 0.039 ± 0.014 × 10(12) /L at day 4 to 0.057 ± 0.020 × 10(12) /L at day 14 (mean ± SD). Recovery of Hb and Ret-He occurs towards values within the reference range. CONCLUSION: In subjects with CAP, acute inflammation results in impairment of Ret-He at an early stage. After onset of pneumonia, decreased results of Ret-He and Ret-He/RBC-He ratio are demonstrated, reflecting acute erythropoietic dysfunction, which are amongst others caused by functional iron depletion.

Noneosinophilic asthma in children: relation with airway remodelling.

Noneosinophilic asthma is increasingly recognised as an important clinical-pathological phenotype in adults. However, this entity has scarcely been investigated in children. In particular, it is unknown whether airway remodelling would develop in children with non-eosinophilic asthma to the same degree as in children with eosinophilic disease. We analysed bronchial biopsies from 80 children undergoing bronchoscopy for appropriate clinical indications: 21 with noneosinophilic asthma, 34 with eosinophilic asthma and 25 control children. Features of airway remodelling - basement membrane thickening, epithelial loss and angiogenesis - and immune activation - inflammatory infiltrate, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-ß, TGF-ß receptor type II - were quantified by histology and immunohistochemistry. The main components of airway remodelling were present in children with noneosinophilic asthma just as in those with eosinophilic disease. Indeed, compared with control children, both noneosinophilic and eosinophilic asthmatic children had thickened basement membrane, increased epithelial loss and higher number of vessels. Moreover, in both groups of asthmatics, expression of IL-4 and IL-5 was increased, while that of TGF-ß receptor type II was reduced, compared with controls. This study demonstrates that structural changes typical of asthma develop in asthmatic children even in the absence of a prominent eosinophilic infiltrate, indicating that other mechanisms, besides eosinophilic inflammation, may promote airway remodelling early in life.

Factors influencing age at diagnosis of primary ciliary dyskinesia in European children.

Primary ciliary dyskinesia (PCD) is a hereditary disorder of mucociliary clearance causing chronic upper and lower airways disease. We determined the number of patients with diagnosed PCD across Europe, described age at diagnosis and determined risk factors for late diagnosis. Centres treating children with PCD in Europe answered questionnaires and provided anonymous patient lists. In total, 223 centres from 26 countries reported 1,009 patients aged < 20 yrs. Reported cases per million children (for 5-14 yr olds) were highest in Cyprus (111), Switzerland (47) and Denmark (46). Overall, 57% were males and 48% had situs inversus. Median age at diagnosis was 5.3 yrs, lower in children with situs inversus (3.5 versus 5.8 yrs; p < 0.001) and in children treated in large centres (4.1 versus 4.8 yrs; p = 0.002). Adjusted age at diagnosis was 5.0 yrs in Western Europe, 4.8 yrs in the British Isles, 5.5 yrs in Northern Europe, 6.8 yrs in Eastern Europe and 6.5 yrs in Southern Europe (p < 0.001). This strongly correlated with general government expenditures on health (p < 0.001). This European survey suggests that PCD in children is under-diagnosed and diagnosed late, particularly in countries with low health expenditures. Prospective studies should assess the impact this delay might have on patient prognosis and on health economic costs across Europe.

Markers of eosinophilic and neutrophilic inflammation in bronchoalveolar lavage of asthmatic and atopic children.

BACKGROUND: Recent studies performing fiberoptic bronchoscopy in children have improved our understanding of asthma pathophysiology. Eosinophilic, but also neutrophilic, inflammation has been described in asthma, but the relationship with atopy was incompletely investigated. The aim of this study is to examine inflammatory cells and mediators in children with asthma compared to the appropriate controls, i.e. atopic children without asthma and children with no atopy or asthma. Moreover, asthmatic children were analysed separately based on the presence of atopy and stratified by age. METHODS: We recruited 191 children undergoing fiberoptic bronchoscopy for appropriate indications: 91 asthmatics (aged 1.4-17 years), 44 atopics without asthma (1.6-17.8 years) and 56 nonasthmatic nonatopic controls (1.4-14 years). In bronchoalveolar lavage, total and differential cell counts and inflammatory mediators, including ECP, eotaxin, IL-8 and TNFalpha, were analysed. RESULTS: Eosinophils and ECP levels were increased in asthmatic children when compared to controls (P = 0.002 and P = 0.01, respectively), but also atopic children without asthma had increased ECP levels compared to controls (P = 0.0001). Among asthmatic children, eosinophils and ECP levels were not different between atopic and nonatopic individuals. Neither neutrophils nor the related mediators (IL-8 and TNFalpha) differed significantly in the three groups. This pattern of inflammation was observed in both preschool and school-aged asthmatic children. CONCLUSIONS: This study suggests that markers of eosinophilic, but not neutrophilic inflammation, are increased in asthmatic children and also in atopic children without asthma. Of interest, in asthmatic children, the activation of the eosinophilic response is not solely because of the presence of atopy.

Sputum colour reported by patients is not a reliable marker of the presence of bacteria in acute exacerbations of chronic obstructive pulmonary disease.

Sputum colour is regarded as a good marker of bacterial involvement in acute exacerbations of chronic obstructive pulmonary disease (COPD) and guides many physicians in deciding on antibiotic treatment. Although most doctors rely on the sputum colour that is reported by patients, it can also be assessed using a validated colour chart. In this study, reported sputum colour and assessed sputum colour were compared as markers of the presence of bacteria, bacterial load, and systemic inflammation. Data on 257 exacerbations in 216 patients hospitalized with an acute exacerbation were analysed (mean age, 72 years; mean forced expiratory volume in 1 s, 44.8% + or - 17.8% (+ or - standard deviation)). Sputum colour was reported by the patients and assessed at the laboratory with a colour chart. Subsequently, quantitative sputum cultures were performed. C-reactive protein was measured as a marker of systemic inflammation. A sputum sample was obtained in 216 exacerbations (84%), of which 177 (82%) were representative. A pathogen was identified in 155 patients (60%). Assessed sputum colour was a better marker of the presence of bacteria (OR 9.8; 95% CI 4.7-20.4; p <0.001) than reported sputum colour (OR 1.7; 95% CI 1.0-3.0; p 0.041). The sensitivity and specificity were 73% and 39% for reported sputum colour, and 90% and 52% for assessed sputum colour. Assessed sputum colour was clearly related to sputum bacterial load and C-reactive protein levels, whereas reported sputum colour was not. It is concluded that sputum colour reported by patients is an unreliable marker of the presence of bacteria in acute exacerbations of COPD. Assessed sputum colour is clearly superior and is also related to bacterial load and systemic inflammation.

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children.

Primary ciliary dyskinesia (PCD) is associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease, situs abnormalities and abnormal sperm motility. The diagnosis of PCD requires the presence of the characteristic clinical phenotype and either specific ultrastructural ciliary defects identified by transmission electron microscopy or evidence of abnormal ciliary function. Although the management of children affected with PCD remains uncertain and evidence is limited, it remains important to follow-up these patients with an adequate and shared care system in order to prevent future lung damage. This European Respiratory Society consensus statement on the management of children with PCD formulates recommendations regarding diagnostic and therapeutic approaches in order to permit a more accurate approach in these patients. Large well-designed randomised controlled trials, with clear description of patients, are required in order to improve these recommendations on diagnostic and treatment approaches in this disease.

Clinical evaluation and treatment of acute asthma exacerbations in children.

This update on treatment of asthma exacerbations in children is the result of an Italian Pediatric Society Task-force, made up of a panel of experts working in 2007-2008. The aim is to give clear indications on the use of the drugs most employed in children, grading the quality of evidence and the strength of recommendations. Suggestions on their limits due to unlicensed and off-label use are reported. The level of evidence and the strength of recommendations for different therapeutic approaches demonstrate that frequently the use of drugs in children is extrapolated from the experience in adults and that more studies are required to endorse the correct use of different drugs in asthmatic children.

Unilateral laryngeal paralysis in a newborn with congenital varicella syndrome.

We report a case of a newborn with unilateral laryngeal paralysis due to congenital varicella syndrome. The patient needed neonatal resuscitation with positive pressure ventilation for severe respiratory failure. Fiberoptic bronchoscopy showed left unilateral laryngeal paralysis. From the first week of life he presented left Horner's syndrome and difficult swallowing. He was hospitalised during the first 3 months of life for recurrent aspiration pneumonia and failure to thrive. At 11 months an ophthalmic evaluation with Ret-Cam showed a chorioretinal scar in the macular region that allowed the final diagnosis.

Procoagulant activity in children with community acquired pneumonia, pleural effusion and empyema.

UNLABELLED: In patients with community-acquired pneumonia (CAP), bacterial-cell-wall-derived fragments may induce the coagulation cascade. To contribute to the knowledge of underlying mechanisms, we have studied the fibrinolytic activity in children with CAP and parapneumonic effusions. PATIENTS AND METHODS: Twenty previously healthy children admitted to our Department with CAP were studied; with (n = 11) or without (n = 9) pleural effusion (PPE). We also investigated 10 children with empyema. In all children we analyzed coagulation and fibrinolytic parameters and compared the results to nine controls. RESULTS: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were not significantly modified in the three groups as compared to controls (P = 0.975, P = 0.535, respectively). The fibrinogen levels were significantly increased in respect to the control group (P < 0.0001). The median values of D-dimer showed an increasing trend that was statistically significant: children with pneumonia 244 microg/L, with pneumonia and PPE 751 microg/L and with empyema 2003 microg/L, in respect to values (48 microg/L) of our control group (P < 0.0001). CONCLUSION: The results suggest that plasma level of D-dimer can give an additional contribution for the evaluation of the severity of CAP and its complications in children.

Case for diagnosis: 4-month-old infant with increasing cough, hemoptysis, and anemia.

A 4-month-old caucasian infant presented non-productive cough, fever associated with hemoptysis, and increasing anemia. He had mild tachypnoea; routine lab tests were normal. The thoracic HRCT scan showed a very large mass in the right lung adherent to the thorax wall, well defined and limiting the medium and upper lobe; the mass was well vascularized, and with central hypodensic areas. Fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) cytology were normal. The definitive histology of the mass showed the presence of inflammatory cells admixed with fibroblasts and rare Touton giant cells in the lesion suggestive of a juvenile xanthogranuloma (JXG) of the lung.

Biochemical markers for the prediction of spontaneous pre-term birth.

OBJECTIVES: The aim of this study was to identify predictive biochemical markers for preterm labor. METHODS: In this prospective study we included 225 asymptomatic Caucasian women consecutively enrolled at 24 weeks of gestation. The following data were collected only once at 24 weeks of gestation: vaginal pH, vaginal fFN, cervical and serum concentration of IL-6, IL-8 and TNFalpha, maternal blood serum, ferritin. Student's t-test, the chi(2)-test and multiple linear regression were used as statistical methods. RESULTS: There were no differences between the age of patients, parity and gestational age at sampling between women who delivered at term and those who delivered pre-term (<37 weeks' gestation). There was a significant increase of cervical IL-6 (pre-term 608+/-1595 pg/l vs. at term 58.9+/-112 pg/l) and serum ferritin (pre-term microg/l 74.4+/-1.1 vs. at term 26.3+/-56.5 microg/l) in pregnant women who delivered pre-term (P<0.05). No differences in cervical IL-8 and cervical TNFalpha between pre-term and term deliveries were found. Multiple linear regression confirmed that the vaginal pH value and cervical fFN test were the best predictive biochemical markers of pre-term birth (standardized coefficient Beta=0.33 and 0.22, respectively). CONCLUSIONS: In order to evaluate pregnancies for pre-term labor, the presence of pH>4.5 and a positive fFN test seems to be predictive of subsequent pre-term delivery.

Activated protein C resistance in normal and pre-eclamptic pregnancies.

OBJECTIVES: A lower ratio in the classic activated protein C resistance (APC-R) test has been reported during pregnancy, which has been called 'acquired' APC-R. However, little is known about the cause of the lowered ratio, and whether or not there is a correlation with blood coagulation activation. The primary objective of our study was to determine changes in APC-R levels in each of the trimesters of normal pregnancy. The secondary objective was to confirm whether APC-R levels were lower in pregnancies complicated by pre-eclampsia than in a control group. Finally, this prospective study was performed to investigate the prevalence of APC-R among pregnant women and to elucidate its obstetric consequences. METHODS: We enrolled 35 healthy pregnant women and 47 pregnant women affected by pre-eclampsia in our study. The following laboratory tests were performed: prothrombin time, partial thromboplastin time, fibrinogen levels, antithrombin III, plasmatic fibronectin (as a marker of endothelial damage), haptoglobin (as a marker of intravascular haemolysis), a functional test for APC-R and analysis of factor V Leiden mutation by polymerase chain reaction. RESULTS: The activated protein C sensitivity ratio was lower in the pathological group than in the control group (p = 0.008 and p = 0.02, respectively). Plasmatic fibronectin was found to be higher in the pathological group than in the control group (p = 0.05). Finally, the overall prevalence of factor V Leiden mutation was 5.4%, i.e. 2/35 women (5.7%) in the control group and 3/47 women in the pathological group (6.38%). CONCLUSIONS: The APC ratio decreased after 20 weeks of gestation until week 42. This decrease was most pronounced in the third trimester, in which resistance was demonstrated in 34.2% of control group patients. In pre-eclampsia, we found a greater reduction of the APC ratio than in controls. We hypothesise that this is due to a decrease in the plasmatic levels of coagulation inhibitors and an increase in coagulatory factors.