Invasive Pulmonary Fungal Infections in Cystic Fibrosis.

Invasive pulmonary mycosis is after allergic bronchopulmonary aspergillosis (ABPA) a frequent and severe complication of CF lung disease. Among CF caregivers, there is an insecurity when and how to treat infections of the lung parenchyma caused by different fungi in patients with CF. This case series provides a multicenter experience on diagnostic, manifestation, and treatment of non-ABPA cases of pulmonary. Non-ABPA cases of pulmonary mycoses in patients with CF have been collected from the CF Centers in Berlin, Essen, Worms, Frankfurt (Germany), Leeds (UK), and Barcelona (Spain). Non-ABPA was defined as total serum IgE level <500 kU/L. Scedosporium and Lomentospora species seem to be more virulent in patients with CF and have been successfully treated with triple antifungal drug regimens in several cases. Rare fungi including yeasts can have pathogenic potential in CF. In this series, antibiotic treatment failure was the main indicator for the initiation of antifungal treatment. For an early and effective treatment of pulmonary mycoses in CF, the identification of biomarkers and of risk factors beyond antibiotic treatment failure is crucial and urgently needed. Furthermore, treatment efficacy studies are necessary for the different causative agents of these infections.

Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: data from the German Pediatric Impedance Group.

OBJECTIVE: To validate the use of combined multichannel intraluminal impedance (MII)-pH (MII-pH) monitoring for detecting gastroesophageal reflux (GER) in children in daily clinical practice. STUDY DESIGN: The patients were divided into 3 symptom groups based on the main indication for the procedure. MII-pH monitoring was performed in 700 children presenting with symptoms suggestive of GER, including 329 children with pulmonary symptoms, 325 with gastrointestinal symptoms, and 46 with neurologic symptoms. The MII-pH results were compared with pH monitoring alone, and retrograde bolus movements, symptom index, and symptom association probability were compared. RESULTS: Overall, 270 measurements were abnormal: 101 (37%) showed abnormal MII-pH study, 49 (18%) showed only pathological pH measurements and 120 measurements (45%) had an abnormal MII recording only. Extraintestinal symptoms of GER were seen more often in younger children and were more often related to a normal pH study but an abnormal MII study. Infants had a significantly higher number of retrograde bolus movements than older children. Symptom index and symptom association probability showed moderate agreement (Cohen kappa, 0.54). CONCLUSIONS: From this large systematically standardized data collection of MII-pH measurements in children, we conclude that 45% of the patients with abnormal GER would not have been recognized by 24-hour pH measurement alone. Our findings confirm that MII-pH is superior to pH monitoring alone in detecting GER.

Inter- and intraobserver agreement in 24-hour combined multiple intraluminal impedance and pH measurement in children.

OBJECTIVES: Assessment of intra- and interobserver agreement in multiple intraluminal impedance (MII) measurement between investigators from different institutions. METHODS: Twenty-four 18- to 24-hour MII tracings were randomly chosen from 4 different institutions (6 per center). Software-aided automatic analysis was performed. Each result was validated by 2 independent investigators from the 4 different centers (4 investigator combinations). For intraobserver agreement, 6 measurements were analyzed twice by the same investigator. Agreement between investigators was calculated using the Cohen kappa coefficient. RESULTS: Interobserver agreement: 13 measurements showed a perfect agreement (kappa > 0.8); 9 had a substantial (kappa 0.61-0.8), 1 a moderate (kappa coefficient 0.41 to 0.6), and 1 a fair agreement (kappa coefficient 0.11-0.4). Median kappa value was 0.83. Intraobserver agreement: 5 tracings showed perfect and 1 showed a substantial agreement. The median kappa value was 0.88. CONCLUSIONS: Most measurements showed substantial to perfect intra- and interobserver agreement. Still, we found a few outliers presumably caused by poorer signal quality in some tracings rather than being observer dependent. An improvement of analysis results may be achieved by using a standard analysis protocol, a standardized method for judging tracing quality, better training options for method users, and more interaction between investigators from different institutions.

Screening for coeliac disease in 1624 mainly asymptomatic children with type 1 diabetes: is genotyping for coeliac-specific human leucocyte antigen the right approach?

OBJECTIVES: To investigate the frequency of coeliac disease (CD)-specific human leucocyte antigen (HLA) genotypes in paediatric patients with type 1 diabetes (T1D), who are known to have a higher prevalence of CD than the general population, and to evaluate whether HLA genotyping is a suitable first-line screening method for CD. STUDY DESIGN: The study was a multicentre observational analysis of patients with T1D aged <20 years of whom a subgroup had undergone HLA genotyping. Patient data were retrieved from the Diabetes Prospective Follow-up database, a large diabetes follow-up registry. The present analysis included data from 439 centres throughout Germany, Austria, Switzerland and Luxembourg. RESULTS: In March 2017, the database contained 75 202 patients with T1D (53% male, mean age (SD) 14.6 (4.1) years, mean age at diagnosis 8.8 (4.3) years and mean diabetes duration 5.8 (4.3) years). 1624 patients had undergone coeliac-specific HLA genotyping, of whom 1344 (82.8%) were positive for HLA-DQ2, HLA-DQ8 or both, while 17.2% had no coeliac-specific HLA-markers. 26.6% of at-risk patients had a clinical suspected diagnosis of CD, and 3.6% had biopsy-proven CD. CONCLUSIONS: Genotyping for HLA-DQ2, HLA-DQ8 or both is positive in the vast majority (>80%) of patients with T1D. Therefore, screening for coeliac-specific HLA genotypes as a first-line test is not a suitable method to exclude CD in T1D. Regular screening for coeliac-specific antibodies in T1D is still recommended.

Combined antifungal therapy is superior to monotherapy in pulmonary scedosporiosis in cystic fibrosis.

Cystic fibrosis (CF) is characterised by chronic airway infection with bacteria and fungi. Infections caused by Scedosporium/Lomentospora species can occur and are difficult to treat. Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. Our aim was to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment. In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9 months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV1, radiology, and symptoms. This data suggests that combined treatment is superior to monotherapy in patients with CF.

Prospective surveillance of antiviral resistance in hospitalized infants less than 12 months of age with A(H3N2) influenza infection and treated with oseltamivir.

BACKGROUND: Infants exhibit elevated influenza virus loads and prolonged viral shedding, which may increase the risk for resistance development, especially in cases of suboptimal exposure to antiviral therapy. METHODS: We performed a prospective surveillance of hospitalized infants undergoing oseltamivir therapy during the 2008-2009 and 2011-2012 influenza seasons at two paediatric hospitals in Germany. A total of 37 infants less than 1 year of age with laboratory confirmed influenza A(H3N2) infection received oseltamivir as per physician's order for 5 days (2008-2009 season: 2 mg/kg twice daily; 2011-2012 season: 2.0 mg/kg; 2.5 mg/kg and 3.0 mg/kg twice daily for infants <1 month; 2-3 months and 4-12 months, respectively). Virus load, the susceptibility to neuraminidase inhibitors (NAIs), and the presence of molecular markers of resistance to NAIs was assessed for influenza viruses recovered from respiratory samples collected at baseline and during follow-up visits. RESULTS: Overall, 73% of the infants continued to shed viral RNA detectable by reverse transcription (RT)-PCR after dose number 10 of oseltamivir; 12 infants shed viruses, 2 of them (both 9 months of age) shed resistant viruses. Resistance was characterized by ≥1,000-fold increase of 50% inhibitory concentration (IC50) for oseltamivir, up to 50-fold for zanamivir and elevated Km values when compared to susceptible A(H3N2) strains. Sanger sequencing revealed the selection of the NA-R292K substitution in both instances (after dose number 10 on day 6). CONCLUSIONS: Our data suggest that it may be relevant to monitor antiviral resistance systematically in all infants, considering that the European Medicines Agency has recently extended the licensure for oseltamivir to include full-term infants.

Pediatric herpes simplex virus encephalitis: a retrospective multicenter experience.

Knowledge on pediatric herpes simplex virus encephalitis is limited. Here we summarize 6 neonates and 32 children diagnosed by polymerase chain reaction (n = 37) or serological studies (n = 1), respectively. Diagnosis was difficult, as only 15 patients presented neurologic symptoms. Moreover, cerebrospinal fluid glucose, protein, and leukocytes were normal in 6 patients. Subsequently, all but 2 showed neurologic symptoms. Diffusion-weighted neuroimaging was the most sensitive early imaging method. Despite acyclovir treatment, 8 patients experienced early relapses, showing movement abnormalities, impaired vigilance, and seizures. Diffuse white matter changes, found in 3 of 5 relapse patients on neuroimaging, and a negative cerebrospinal fluid herpes simplex virus polymerase chain reaction suggested inflammatory processes. All relapse patients were again treated with acyclovir, and 3 responded to additional corticosteroid treatment. Whereas outcome after relapses was poor, overall outcome was good. No child died; 14 were asymptomatic at discharge, and neuroimaging remained normal in 7 of 30 patients studied.

Virus load kinetics and resistance development during oseltamivir treatment in infants and children infected with Influenza A(H1N1) 2009 and Influenza B viruses.

BACKGROUND: Infants and small children are the most effective transmitters of influenza, while bearing a high risk of hospitalization and adverse disease outcomes. This study aims to investigate virus load kinetics and resistance development during oseltamivir therapy in infants and children infected with influenza A(H1N1) 2009 and influenza B viruses. METHODS: Virus load in nasopharyngeal samples and phenotypic/genotypic neuraminidase inhibitor resistance were determined at baseline, at day 5 and in additional follow-up samples, if available. Patient-specific viral clearance indices CLν(i) were determined along with estimates of the time required to achieve nondetectable virus load. RESULTS: No evidence of baseline oseltamivir resistance was detected in 36 patients infected with influenza A(H1N1) 2009 (n = 27) or influenza B (Victoria, Yamagata; n = 9) before oseltamivir therapy. On average, viral loads were lower for influenza type B (median = 5.9·10/mL) than for drug-resistant (median = 2.6·10/mL) and sensitive A(H1N1) 2009 (median = 4.8·10/mL), P = 0.04 and P = 0.09, respectively. Time required to achieve nondetectable virus load was significantly longer in drug-resistant A(H1N1) 2009 (median 15.4 days) compared with drug-sensitive A(H1N1) 2009 (P = 0.003; median 7.7 days) and drug-sensitive influenza B (P = 0.001; median 5 days). No evidence of viral rebound was observed once viral clearance was achieved. CONCLUSIONS: Our data indicate that influenza subtyping in combination with baseline viral load measurements might help to optimize the duration of antiviral therapy in the individual child. Lower than expected virologic response rates in patients without malabsorption or compliance issues may suggest resistance development.

Gastroesophageal Reflux and Body Movement in Infants: Investigations with Combined Impedance-pH and Synchronized Video Recording.

The aim of this paper was to investigate the temporal association of gastroesophageal reflux (GER) and body movement in infants. GER were registered by combined impedance-pH, documentation of body movement was done by video. Videorecording time (Vt) was divided into "resting time" and "movement time" and analyzed for occurrence of GER. Association was defined as movement 1 minute before/after the beginning of a GER. Statistical evaluation was by Fisher's exact test. In 15 infants, 341 GER were documented during Vt (86 hours). 336 GER (99%) were associated with movement, only 5 episodes (1%) occured during resting time. Movement was significantly associated with the occurrence of GER (P < .0001). There is a strong temporal association between GER and body movement in infants. However, a clear distinction between cause and effect could not be made with the chosen study design. Combined impedance-pH has proven to be the ideal technique for this approach.

Oseltamivir for treatment of influenza in infants less than one year: a retrospective analysis.

BACKGROUND: Influenza causes proportionately more hospitalizations and deaths in infants in their first year of life than in older children. Oseltamivir is an effective treatment for childhood influenza, but few data are available in infants <1 year. METHODS: Medical records of infants <1 year admitted to hospital during the influenza seasons 2003-2007 were retrospectively analyzed to evaluate clinical presentation, and safety and outcome with oseltamivir therapy. Eligible infants were those with fever (>38 degrees C), influenza-like symptoms of sudden onset, positive rapid influenza test and parental consent, who received oseltamivir within 48 hours of the start of symptoms. Infants vaccinated against influenza or receiving immunosuppressants were excluded. RESULTS: In 157 evaluable infants (mean age 6.3 [SD 3.2] months; 86 boys), the most common presenting symptoms other than fever were rhinitis, pharyngitis, cough, feeding difficulties, and otitis media. During treatment, additional symptoms were observed in 78 (50%) infants; most of these were gastrointestinal (vomiting and diarrhea) and of mild intensity. Fever resolved in 128 (82%) infants within 36 hours of starting oseltamivir (136 [87%] within 48 hours). Complications were recorded in 84 patients (54%), the most serious of which were meningitis in 1 infant (1%), pneumonia in 9 (6%), and otitis media in 2 (1%). Twenty infants received antibiotics for secondary infections (10 [6%] before admission). CONCLUSIONS: The clinical presentation of influenza and outcome of oseltamivir treatment in infants <1 year was similar to that previously reported in older children, but mild gastrointestinal symptoms were common.

Effect of rapid influenza testing on the clinical management of paediatric influenza.

BACKGROUND: Rapid tests are now widely available to assist the diagnosis of influenza; implementation may optimise the use of antiviral and antibiotic agents in the clinical management of influenza. OBJECTIVE: To explore the clinical management of children with influenza-like illness (ILI) when rapid influenza tests were and were not performed. METHODS: Between 15 January 2007 and 30 April 2007, a standardised questionnaire was used to record the clinical features of children aged 1-12 years who presented to office-based paediatricians in Germany with febrile ILI during periods of local influenza activity. For each paediatric contact, a clinical diagnosis of either 'influenza positive', 'influenza negative' or 'suspected ILI' was made. Where performed, the outcome of a Clearview Exact Influenza A + B rapid test was recorded. Prescriptions for antiviral agents and antibiotic medications were also recorded. RESULTS: A total of 16 907 questionnaires were evaluated. After fever (an entry criteria for all children), cough (84.6%), fatigue/decreased activity (83.0%), rhinorrhoea (73.7%) and headache (67.1%) were the most common symptoms. Influenza was clinically diagnosed in 56.8% (9596/16 907) of cases. The antiviral oseltamivir was prescribed for 24.6% (178/725) of children who were influenza positive by symptom assessment alone and 60.1% (4618/7685) of children who were influenza positive by rapid test. Antibiotics were less commonly prescribed for children who were influenza positive by rapid test [3.5% (271/7685) versus 17.2% (125/725) for symptom assessment alone]. CONCLUSIONS: In children with ILI, a positive rapid test result for influenza promotes the rational use of antiviral agents and reduces the inappropriate use of antibiotic medications.

Effects of thickened feeding on gastroesophageal reflux in infants: a placebo-controlled crossover study using intraluminal impedance.

OBJECTIVE: Thickening of formula feedings is part of the therapeutic approach for gastroesophageal reflux (GER) in infants. However, its mechanism of action, especially regarding the occurrence of nonacid (pH >4) GER, has not yet been clearly described. The aim of this randomized, placebo-controlled crossover study was to examine the influence of formula thickened with carob (St. John's bread) bean gum on acid and nonacid GER. METHODS: Infants with recurrent regurgitation and without other symptoms were fed alternately (A-B-A-B-A-B) with thickened (A) and nonthickened (B) but otherwise identical formula. Documentation of GER episodes during the study was performed by simultaneous intraesophageal impedance measurement (intraluminal electrical impedance; IMP) and pH monitoring. The IMP technique is able to detect bolus movements inside a luminal organ. The use of multiple measuring segments on a single catheter allowed the analysis of direction, height, and duration of the bolus transport. Continuous videorecording and visual surveillance of regurgitation frequency and amount resulted in a severity score. RESULTS: Fourteen infants (42 +/- 32 days old) were examined during 6 feeding intervals each for a total measuring time of 342 hours. A total of 1183 GER episodes and 83 episodes of regurgitation were registered. Regurgitation frequency (15 vs 68 episodes) and amount (severity score 0.6 vs 1.8) were significantly lower after feedings with thickened formula. The difference regarding the occurrence of GER documented by IMP was also pronounced (536 vs 647 episodes). Although not statistically significant, maximal height reached by the refluxate in the esophagus was decreased after thickened feedings. Mean GER duration and the frequency of acid (pH <4) GER were not altered. CONCLUSIONS: Thickened feeding has a significant effect on the reduction of regurgitation frequency and amount in otherwise healthy infants. This effect is caused by a reduction in the number of nonacid (pH >4) GER episodes, but also because of a decrease of mean reflux height reached in the esophagus. However, the occurrence of acid GER is not reduced. The combination of IMP and pH monitoring allows the complete registration and description of these GER episodes. Thickening of formula feedings with carob bean gum is an efficient therapy for uncomplicated GER in infants.

Esophageal pH monitoring and impedance measurement: a comparison of two diagnostic tests for gastroesophageal reflux.

BACKGROUND: pH monitoring is the standard diagnostic tool for gastroesophageal reflux in infants. However, this method does not document the reflux of all kinds of fluid from the stomach into the esophagus, but only documents acid material. The parameters that define reflux episodes by pH monitoring have been derived empirically from observations of many infants considered healthy and ill. Acid reflux is a continuum, some reflux is normal and doubt exists as to how much reflux is abnormal. In this study, one of the standardized protocols for analyzing pH recordings was evaluated and compared with simultaneously obtained intraesophageal impedance measurement (IMP), a pH-independent method of detecting bolus movement within the esophagus. METHODS: The esophagi of 50 infants with reflux symptoms were measured, using both standard pH probe and multiple-site impedance measurement. A standard protocol for analyzing esophageal pH records was used. The sampling rate for pH values was 15/min. Acid reflux was defined as pH less than 4.0 (threshold pH) for at least 15 seconds (minimal duration) with at least 30 seconds (latency time) between separate episodes. The software used could adjust independently or in combinations the sampling rate and these reflux criteria. Thereby it was determined whether changes in the criteria for acid reflux improved the sensitivity and predictive value of pH monitoring when compared with reflux episodes defined by IMP. RESULTS: During 318 hours of recording in 50 infants, 1,887 episodes of reflux occurred according to IMP. Only 282 (14.9%) of the IMP-determined episodes were acid reflux episodes. No alkaline reflux episodes occurred. Among the 270 pH probe-determined episodes using the standard criteria of acid reflux, only 153 (sensitivity, 54.3%; positive predictive value, 56.7%) were accompanied by unmistakable retrograde bolus movement using IMP measurements. Retrograde bolus movement did not accompany the other 117 episodes. Using a sampling rate of 15/min, a pH threshold of 4.0, a minimal duration of reflux episodes of 8 seconds, and a latency time of 60 seconds, the positive predictive value of pH probe results increased to 60.7%. Variations in the sampling rate or criteria for defining acid reflux did not significantly improve the accuracy of the pH probe results versus IMP-defined episodes. CONCLUSIONS: Most reflux episodes that occur in infants are undetectable by standard pH probe monitoring. pH monitoring does not detect all reflux in the esophagus but is useful for detecting acidity in the esophagus and determining the duration of its presence. Combining pH monitoring with impedance measurement is a valuable diagnostic tool for gastroesophageal reflux in infants.

Randomized double-blind study of the nutritional efficacy and bifidogenicity of a new infant formula containing partially hydrolyzed protein, a high beta-palmitic acid level, and nondigestible oligosaccharides.

OBJECTIVES: The aim of this study was to evaluate the nutritional efficacy and bifidogenic characteristics of a new infant formula containing partially hydrolyzed whey protein, modified vegetable oil with a high beta-palmitic acid content, prebiotic oligosaccharides, and starch. METHODS: In a double-blind study, healthy formula-fed term infants aged younger than 2 weeks were randomized to receive either the new infant formula (NF) or a standard formula (SF) until the age of 12 weeks. Anthropometric measurements were taken at enrollment, 6 weeks, and 12 weeks. In a subsample of infants, blood samples were taken at 6 weeks and stool samples were taken at enrollment and 6 weeks. Blood samples were analyzed for biochemical measures of protein status and amino acids, and stools were analyzed for total bacteria and bifidobacteria. Mothers completed a feeding diary and questionnaire at 6 and 10 weeks. RESULTS: One hundred fifty-four infants were enrolled in the study; 102 completed the trial. The growth of infants in both formula groups was in line with published growth curves. During the first 6 weeks, NF girls gained more weight and head circumference than the SF girls. These velocity differences were not maintained throughout the 12-week study period. The NF stools had a higher proportion of bifidobacteria at 6 weeks compared with the SF stools, and they were softer. There were no clinically significant differences in the blood biochemical and amino acid values between groups. Both formulas were well tolerated by the infants. CONCLUSIONS: When compared with a standard infant formula, the new formula supported satisfactory growth, led to higher counts of bifidobacteria in the feces, produced blood bio-chemical values typical of formula-fed infants, and was well tolerated.