Irmgard Eichler

High levels of eosinophil cationic protein in wheezing infants predict the development of asthma

BACKGROUND In association with respiratory tract infections, infants may have episodes of wheezing, which represent the onset of asthma in some of them. Activated eosinophils play a central part in asthmatic inflammation. OBJECTIVE We investigated whether, in infants experiencing their first episode of wheezing, eosinophil activation is present and can predict the development of asthma. METHODS In a prospective trial, eosinophil activation was measured by eosinophil cationic protein (ECP) concentrations in serum from 33 nonatopic infants with their first episode of wheezing, 15 nonatopic infants with upper respiratory tract infection without wheezing, and 18 healthy nonatopic infants. One year later, the children were re-evaluated for a diagnosis of infantile asthma. RESULTS Wheezing infants had higher median serum ECP levels (13.4 micrograms/L) than children with nonwheezy respiratory tract infection (7.6 micrograms/L, p < 0.005) or healthy subjects (7.1 micrograms/L, p < 0.005). In addition, wheezing infants (n = 13) with serum ECP concentrations greater than 20 micrograms/L were more likely to have asthma within 1 year than patients with ECP levels less than 20 micrograms/L (odds ratio = 12.4; confidence interval, 4.6-33.5). CONCLUSION Eosinophil activation measured by serum ECP is present in infants with their first episode of wheezing illness, especially in those infants in whom asthma subsequently develops within 1 year. These data may indicate a predictive value of serum ECP measurements in children with wheezing to identify those patients in whom infantile asthma is developing. These findings probably also indicate that serum ECP may be used to identify the children who need early antiinflammatory treatment.

Laser acupuncture and probiotics in school age children with asthma: a randomized, placebo‐controlled pilot study of therapy guided by principles of Traditional Chinese Medicine

Traditional Chinese Medicine (TCM) postulates an interaction between the lung as a Yin‐organ and the large intestine as a Yang‐organ. The aim of this pilot study was to investigate in asthmatic school age children whether treatment with laser acupuncture and probiotics according to TCM portends a clinical benefit to standard medical treatment performed according to pediatric guidelines. Seventeen children aged 6–12 yr with intermittent or mild persistent asthma were enrolled in this randomized, placebo‐controlled, double‐blind pilot study. Eight patients received laser acupuncture for 10 wk and probiotic treatment in the form of oral drops (living non‐pathogenic Enterococcus faecalis) for 7 wk. Nine patients in the control group were treated with a laser pen which did not emit laser light and were given placebo drops. Peak flow variability (PFV) and forced expiratory volume in 1 s (FEV1) were measured and Quality of Life was assessed by a standardized questionnaire. Laser acupuncture and probiotics significantly decreased mean (standard deviation) weekly PFV as a measurement of bronchial hyperreactivity by −17.4% (14.2) in the TCM group vs. 2.2% (22.5) in the control group (p = 0.034). No significant effect was detected for FEV1, Quality of Life criteria and additional medication. As an exploratory result, patients in the TCM group had fewer days of acute febrile infections when compared with the control group [1.14 (1.4) vs. 2.66 (2.5), p = 0.18]. In conclusion, this pilot study generates the hypothesis that the interactive treatment of lung and large intestine according to TCM by laser acupuncture and probiotics has a beneficial clinical effect on bronchial hyperreactivity in school age children with intermittent or mild persistent asthma and might be helpful in the prevention of acute respiratory exacerbations. These results should be confirmed by further studies.

Increased Mortality After Pulmonary Fungal Infection Within the First Year After Pediatric Lung Transplantation

BACKGROUND Risk factors, morbidity and mortality from pulmonary fungal infections (PFIs) within the first year after pediatric lung transplant have not previously been characterized. METHODS A retrospective, multicenter study from 1988 to 2005 was conducted with institutional approval from the 12 participating centers in North America and Europe. Data were recorded for the first post-transplant year. The log-rank test assessed for the association between PFI and survival. Associations between time to PFI and risk factors were assessed by Cox proportional hazards models. RESULTS Of the 555 subjects transplanted, 58 (10.5%) had 62 proven (Candida, Aspergillus or other) or probable (Aspergillus or other) PFIs within the first year post-transplant. The mean age for PFI subjects was 14.0 years vs 11.4 years for non-PFI subjects (p < 0.01). Candida and Aspergillus species were recovered equally for proven disease. Comparing subjects with PFI (n = 58) vs those without (n = 404), pre-transplant colonization was associated with PFI (hazard ratio [HR] 2.0; 95% CI 0.95 to 4.3, p = 0.067). Cytomegalovirus (CMV) mismatch, tacrolimus-based regimen and age >15 years were associated with PFI (p < 0.05). PFI was associated with any prior rejection higher than Grade A2 (HR 2.1; 95% CI 1.2 to 3.6). Cystic fibrosis, induction therapy, transplant era and type of transplant were not associated with PFI. PFI was independently associated with decreased 12-month survival (HR 3.9, 95% CI 2.2 to 6.8). CONCLUSIONS Risk factors for PFI include Grade A2 rejection, repeated acute rejection, CMV-positive donor, tacrolimus-based regimen and pre-transplant colonization.

Respiratory viral infections within one year after pediatric lung transplant.

Abstract: To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric lung transplant recipients within the first post‐transplant year, a retrospective multicenter study of pediatric lung transplant recipients from 1988 to 2005 was conducted at 14 centers in the United States and Europe. Data were recorded for 1 year post transplant. Associations between RVI and continuous and categorical risk factors were assessed using Wilcoxons rank‐sum and χ2 tests, respectively. Associations between time to RVI and risk factors or survival were assessed by multivariable Cox proportional hazards models. Of 576 subjects, 79 subjects (14%) had 101 RVI in the first year post transplant. Subjects with RVI were younger than those without RVI (median ages 9.7, 13; P<0.01). Viruses detected included adenovirus (n=25), influenza (n=9), respiratory syncytial virus (n=21), parainfluenza virus (n=19), enterovirus (n=4), and rhinovirus (n=22). In a multivariable model for time to first RVI, etiology other than cystic fibrosis (CF), younger age, and no induction therapy were independently associated with risk of RVI. Cytomegalovirus serostatus and acute rejection were not associated with RVI. RVI was independently associated with decreased 12‐month survival (hazard ratio 2.6, 95% confidence interval 1.6–4.4). RVI commonly occurs after pediatric lung transplantation with risk factors including younger age and non‐CF diagnosis. RVI is associated with decreased 1‐year survival.

The risk, prevention, and outcome of cytomegalovirus after pediatric lung transplantation.

Background. A retrospective review of pediatric lung transplant recipients at 14 centers in North America and Europe was conducted to characterize the epidemiology and the risk factors for cytomegalovirus (CMV) and to explore the impact of preventative antiviral therapy. Methods. Data were recorded for 1 year posttransplant. Associations between CMV and continuous and categorical risk factors were assessed using Wilcoxon rank sum and chi-square tests, respectively. Associations between time to CMV and risk factors or survival were assessed by multivariable Cox proportional hazards models. Results. Within 12 months posttransplant, 172 of 577 subjects (29.8%) developed 218 CMV episodes (90 asymptomatic infection, 25 syndrome, and 103 disease). Forty-one subjects developed more than one episode of CMV. Donor or recipient CMV seropositivity was associated with increased risk of CMV episodes. Except for decreased prophylaxis in CMV D−/R− subjects, duration of prophylaxis did not vary by D/R serostatus. For CMV D+ subjects, not being on prophylaxis at the time of CMV episode increased the risk of CMV (D+/R+ hazard ratio 3.5, 95% confidence interval 1.4–8.4; D+/R− 1.9, 1.02–3.7). CMV was associated with increased mortality within the first posttransplant year among those with donor or recipient CMV seropositivity (hazard ratio 2.0: 95% confidence interval 1.1–3.6; P=0.024). Conclusions. CMV remains a serious complication after pediatric lung transplant, and the impact of prophylaxis is complex.

Human neutrophil lipocalin, a highly specific marker for acute exacerbation in cystic fibrosis

Cystic fibrosis (CF) is characterized by the production of abnormally thick secretions in the airways, chronic bacterial endobronchial infections and a chronic, predominantly neutrophilic inflammatory response. Therefore, myeloperoxidase (MPO) and lactoferrin are frequently used as inflammatory markers. Recently, a new protein in the neutrophil granules, human neutrophil lipocalin (HNL) has been discovered. The aim of the present study was to investigate HNL in sera of patients with CF and its relation to MPO and lactoferrin as well as to acute pulmonary exacerbation. Serum concentrations of HNL, MPO and lactoferrin were determined in 42 patients with CF and in 25 healthy subjects. Patients with CF were divided into groups with and without acute pulmonary exacerbation (APE) and also with and without colonization with Pseudomonas aeruginosa (Pa). Median serum levels of HNL (200.5 microg x L(-1)), MPO (595 microg x L(-1)) and lactoferrin (1,356.5 microg x L(-1)) were significantly increased in patients with CF compared to control subjects (57.7, 178 and 478 microg x L(-1), respectively; p<0.0001). CF patients with APE had significantly increased serum concentrations of HNL (321 versus 97.7 microg x L(-1); p<0.0001), MPO (1,125 versus 300 microg x L(-1); p<0.005) and lactoferrin (4,936 versus 980 microg x L(-1); p<0.001) compared with patients in stable clinical condition. Similarly, patients colonized with Pa had significantly higher concentrations of HNL, MPO and lactoferrin than Pa negative patients. These results indicate that in patients with cystic fibrosis, serum concentrations of human neutrophil lipocalin are markedly increased with a strong relationship to myeloperoxidase and lactoferrin. Thus, determination of serum human neutrophil lipocalin concentrations may be another useful diagnostic tool to monitor neutrophil inflammation in cystic fibrosis. The more marked difference in human neutrophil lipocalin compared with myeloperoxidase concentrations with no overlap between patients with acute pulmonary exacerbation and those in stable condition even suggests that human neutrophil lipocalin may be a more sensitive and specific discriminator.

Variability in immunization guidelines in children before and after lung transplantation

Abstract:  Lung transplant candidates and recipients are at high risk of infections from vaccine‐preventable diseases. However, well‐established guidelines neither exist for pre‐ and post‐transplant vaccination nor do monitoring guidelines for pediatric lung transplant recipients. To ascertain the current vaccination and monitoring practices of pediatric lung transplant centers, a self‐administered questionnaire was distributed to the 18 pediatric lung transplant centers within the International Pediatric Lung Transplant Collaborative in April 2006. Sixteen of 18 centers (89%) surveyed responded. Pretransplant, national vaccination guidelines are followed. Eleven centers reported following standardized vaccination guidelines post‐transplant. Vaccines were more commonly provided by the primary‐care physician pretransplant (69%) rather than post‐transplant (38%). Post‐transplant, 50% of the centers recommend live vaccines for household contacts but not for the transplant recipient. Pretransplant monitoring of response to prior vaccination was performed inconsistently except for varicella (88%). Only 44% of the transplant centers measure for response to vaccination post‐transplant, mostly hepatitis B. Current vaccination practices of pediatric lung transplant centers are heterogeneous. The lung transplant community would be well served by studies designed to evaluate the efficacy of vaccinations in this population.

Cytomegalovirus immunoglobulin decreases the risk of cytomegalovirus infection but not disease after pediatric lung transplantation.

BACKGROUND Cytomegalovirus (CMV) has been associated with morbidity, including chronic allograft rejection, in transplant recipients. Data from adult centers suggests that CMV hyperimmune globulin (CMVIG) and ganciclovir together are superior in preventing CMV viremia than ganciclovir alone. METHODS A retrospective review of pediatric lung transplant recipients at 14 sites in North America and Europe was conducted to evaluate the effect of adding cytomegalovirus immunoglobulin (CMVIG) prophylaxis to at least 3 weeks of intravenous ganciclovir therapy in pediatric lung transplant recipients. Data were recorded for the first year after transplantation. Associations between time to CMV and risk factors, including CMVIG use, were assessed by multivariable Cox proportional hazards models. RESULTS Of 599 patients whose records were reviewed, 329 received at least 3 weeks of ganciclovir, with 62 (19%) receiving CMVIG. CMVIG was administered more frequently with CMV donor-positive/recipient-negative serostatus (p < 0.05). In multivariable models, patients who did not receive CMVIG as part of their prophylaxis were 3 times more likely to develop CMV infection (hazard ratio, 3.4; 95% confidence interval, 1.2-9.5) independent of CMV serostatus. However, CMVIG administration was not associated with decreased risk of episodes of CMV disease. Receipt of CMVIG was not associated with decreased risks of post-transplant morbidities (acute rejection, respiratory viral infection or early bronchiolitis obliterans) or morbidity within the first year after pediatric lung transplantation. CONCLUSION The use of CMVIG in addition to antiviral prophylaxis in pediatric lung transplantation requires further evaluation.

Clinical pharmacology study of Bramitob, a tobramycin solution for nebulization, in comparison with Tobi.

AbstractBackground and objectives To compare in vitro characteristics and pharmacokinetics of Bramitob®, a preservative-free tobramycin solution for nebulization, and Tobi® in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa infection. MethodsIn vitro characteristics of Bramitob® and Tobi® were evaluated using Pari TurboBoy™/LC Plus® and the Systam 290 LS™ nebulizers. In the randomized, double-blind, two-way crossover pharmacokinetic study, 11 patients with CF received a single nebulized dose (300mg) of Bramitob® or Tobi®, separated by a 7-day washout period. Plasma and sputum tobramycin concentrations were measured immediately before and over 24 hours after administration. Results Bramitob® and Tobi® performed alike during nebulization. The fine particle fraction was 33–37% and the mass median aerodynamic diameter was <5µm. Nine patients completed the pharmacokinetic study. Tobramycin plasma profiles after administration of Bramitob® or Tobi® were similar, with a peak at 90 and 72 minutes after inhalation of Bramitob® and Tobi®, respectively. The elimination half-life was ∼5 hours for both products. The relative bioavailability of Bramitob® to Tobi® was 1.01, indicating comparable systemic exposure. Peak sputum concentration of tobramycin was 816 ± 681 µg/g for Tobi® and 1289 ± 851 µg/g for Bramitob® and was >400 µg/g (threshold sufficient for an antibacterial effect against P. aeruginosa) in 5 out of 9 patients receiving Tobi® and 8 out of 9 patients receiving Bramitob®. All adverse events were considered mild and judged not related to the study drugs. ConclusionsIn vitro performance of Bramitob® was similar when nebulized with Pari TurboBoy™/LC Plus® and Systam 290 LS™ nebulizers and comparable to that of Tobi®. The systemic bioavailability of tobramycin was similar after administration of either Bramitob® or Tobi®; however, in sputum samples the tobramycin peak concentration was slightly greater after administration of Bramitob® than after Tobi®.

Lung transplantation in children and young adults: a 20-year single-centre experience

Lung transplantation in adults is an accepted therapeutic option, whereas there is ongoing debate on its positive impact on survival in children. We report our experience of the first 20 yrs of paediatric lung transplantation at a single centre in Austria. Patient survival, organ survival and freedom from bronchiolitis obliterans were estimated by Kaplan–Meier curves. Pre- and post-transplant parameters were assessed and their influence on patient and organ survival evaluated by univariate tests and stepwise multivariate analyses. A total of 55 transplantations were performed in 43 patients. 1- and 5-yr patient survival rates were 72.1% and 60.6%, respectively, and 52.6% of patients were found to be free from bronchiolitis obliterans syndrome at 5 yrs post-transplant. Analysing different eras of transplantation suggests an improvement over the years with a 5-yr survival rate of 70.6% in the second decade. A positive effect of pre-transplant diabetes mellitus and immunosuppression was found with the newer drug tacrolimus, and a negative effect of pre-transplant in-hospital admission was reported. A high rate of successful re-transplantation prolonged total patient survival.