F. De Baets

Early referral to cystic fibrosis specialist centre impacts on respiratory outcome.

BACKGROUND Published studies concerning the impact of specialist care on lung disease in cystic fibrosis remain limited and most are either biased due to comparison with historical controls and/or underpowered. METHODS In this retrospective multicentric study, data from all CF children fulfilling the following criteria were collected: 1) Age 6-<18 at the end of 2003; 2) diagnosis before 8 y; 3) follow-up in an accredited CF Belgian centre; 4) at least 1 spirometry and respiratory culture available for 2003. Group A included children referred > or =2 years after the diagnosis. Patients from Group A were then matched with a single early referred patient on the basis of 2 criteria: same centre, as closest age as possible (Group B). RESULTS Data from 217 children were collected (Group A: 67/217). Late referred patients had a lower FEV(1) (77.2%+/-22.4 vs 86.7% pred.+/-19.4, p=0.01) and a higher prevalence of Pseudomonas aeruginosa (38.6 vs 17.5%, p<0.05). CONCLUSION In this population of CF children, a delay of 6.1 y (vs 0.1 y) between diagnosis and referral to a specialist clinic resulted in poorer respiratory outcome at age 13.

Pseudomonas aeruginosa in the home environment of newly infected cystic fibrosis patients

The source of acquisition of Pseudomonas aeruginosa in cystic fibrosis (CF) patients remains unknown. Patient-to-patient transmission has been well documented but the role of the environment as a source of initial infection is as yet unclear. In the present study, the origin of the first P. aeruginosa isolate in CF patients was investigated by comparing the P. aeruginosa genotype(s) from newly infected patients with genotypes of P. aeruginosa isolates from the home environment and from other patients from the same CF centre. A total of 50 newly infected patients were studied. P. aeruginosa could be cultured from 5.9% of the environmental samples, corresponding to 18 patients. For nine of these, the genotype of the environmental P. aeruginosa isolate was identical to the patients isolate. In total, 72% of the environmental P. aeruginosa isolates were encountered in the bathroom. Patient-to-patient transmission within the CF centre could not be ruled out for three patients. In summary, a low prevalence of Pseudomonas aeruginosa was found in the home environment of the newly infected cystic fibrosis patients. The bathroom should be targeted in any preventive cleaning procedures. An environmental source of the new infection could not be ruled out in nine patients.

Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients.

Genes of innate immunity may be involved in early onset of chronic Pa (Pseudomonas aeruginosa) colonization (cPaC) in cystic fibrosis (CF) patients. We studied 19 single nucleotide polymorphisms (SNPs) in 5 genes coding for proteins of the lectin complement pathway: MBL2 (Mannose binding lectin 2), MASP 1, 2, 3 (MBL-associated serine Protease) and FCN 1, 2 (Ficolin) gene in 96 CF patients. Association survival analysis using different genetic models was performed looking for an association between SNPs and age at onset of cPaC. CF patients who are MBL deficient are earlier chronic Pa colonized compared to MBL sufficient patients. Also patients with MBL2 genotype YO/YO, YO/XA, XA/XA, YA/YO and YA/XA are earlier chronic Pa colonized. CF patients heterozygous or homozygous for mutant alleles of two linked SNPs in the FCN1 gene (rs2989727 and rs1071583) are earlier colonized with Pa. Similarly, earlier onset of Pa colonization is seen in CF patients heterozygous for linked SNPs of FCN2 gene (rs7865453 and rs7851696) and MASP3 gene (rs7851696). Variants in MBL2, FCN1, FCN2 and MASP3 genes are significantly associated with earlier onset of chronic P. aeruginosa colonization.

Survey of Pseudomonas aeruginosa genotypes in colonised cystic fibrosis patients

The current authors aimed to examine whether cystic fibrosis (CF) patients in Belgium shared Pseudomonas aeruginosa genotypes and to compare the genotypes of isolates from the same patients during two consecutive years. A Belgian databank of the P. aeruginosa genotypes of all colonised CF patients was created. Sputum samples from a total of 276 P. aeruginosa colonised patients during 2003, and from a subgroup of 95 patients in 2004, were analysed. Patients were asked about any social contact between each other by questionnaire. All P. aeruginosa isolates exhibiting different colonial morphology on McConkey agar were first genotyped using arbitrarily primed PCR, whereafter single representatives of each randomly amplified polymorphic DNA-type were further genotyped by fluorescent amplified fragment length polymorphism analysis. In the 213 patients from whom P. aeruginosa could be cultured (resulting in 910 isolates), a total of 163 genotypes were found. The majority (75%) of patients harboured only one genotype. In most of the limited number of clusters, previous contacts between patients could be suspected. In 80% of the patients studied during both years, P. aeruginosa genotype remained unchanged. In conclusion, most colonised cystic fibrosis patients harbour only one Pseudomonas aeruginosa genotype, despite showing different colonial morphotypes. The number of clusters is limited, and most patients seem to retain the same genotypic strain during both years.

Inhaled steroids compared with disodium cromoglycate in preschool children with episodic viral wheeze

In school children with atopic asthma the beneficial effects of disodium cromoglycate (DSCG) and beclomethasone dipropionate (BDP) are well‐established. In preschool children, wheezing is quite common, and in the majority of cases the symptoms are episodic and reported to be associated with viral infections rather than atopy. We compared the efficacy of regular treatment with DSCG and BDP for prevention of wheezing in preschool children. We were interested to establish whether regular treatment with inhaled anti‐inflammatory drugs could lead to a decrease in bronchial responsiveness. In 15 patients (median age, 56 months; range, 43–66 months) bronchial responsiveness was assessed by measuring specific airway resistance (sRaw) during a histamine provocation test. The concentration of histamine eliciting a 100% increase in sRaw (PC100his) was determined. In a double‐blind crossover study, patients inhaled either DSCG 10 mg three times a day or BDP 100 μg three times a day for 2 months. After a wash‐out period, treatment was changed to BDP or DSCG, respectively. Daily peak flow measurements were carried out, and exacerbations were noted. PC100his was measured at the start and end of each treatment period.

Tuberculin skin test versus interferon-gamma release assays for the diagnosis of tuberculosis infection

AbstractObjective:Accurate detection of latent tuberculosis infection (LTBI) is becoming increasingly important due to the increasing use of immunosuppressive medications and the human immunodeficiency epidemic, which have increased the risk for reactivation to active tuberculosis (TB) infection. LTBI is detected by tuberculin skin test (TST) and interferon-gamma release assays (IGRAs). The latter include T-SPOT®.TB (Oxford Immunotec) and QuantiFERON®-TB Gold In-Tube (QFT-GIT; Cellestis). We examined the value of TST versus IGRAs in the diagnosis of TB infection by meta-analysis based on data derived from a systematic literature review.Methods:PubMed was searched for articles in English published between January 2010 and July 2012 in which TST and IGRA were performed simultaneously in individuals with and without active TB infection. A random effect model meta-analysis was performed to determine pooled sensitivity and specificity values for TST, T-SPOT.TB, and QFT-GIT. Owing to the absence of a gold stand...Abstract Objective: Accurate detection of latent tuberculosis infection (LTBI) is becoming increasingly important due to the increasing use of immunosuppressive medications and the human immunodeficiency epidemic, which have increased the risk for reactivation to active tuberculosis (TB) infection. LTBI is detected by tuberculin skin test (TST) and interferon-gamma release assays (IGRAs). The latter include T-SPOT®.TB (Oxford Immunotec) and QuantiFERON®-TB Gold In-Tube (QFT-GIT; Cellestis). We examined the value of TST versus IGRAs in the diagnosis of TB infection by meta-analysis based on data derived from a systematic literature review. Methods: PubMed was searched for articles in English published between January 2010 and July 2012 in which TST and IGRA were performed simultaneously in individuals with and without active TB infection. A random effect model meta-analysis was performed to determine pooled sensitivity and specificity values for TST, T-SPOT.TB, and QFT-GIT. Owing to the absence of a gold standard for the diagnosis of LTBI, active TB infection was used as a surrogate for LTBI. Results: Nineteen studies were included. T-SPOT.TB was significantly more sensitive [90% (95% confidence interval: 85–95) versus 64% (46–81)] than TST. The specificity of T-SPOT.TB was higher than the specificity of TST, but there was overlap between confidence intervals [77% (68–85) versus 57% (41–72)]. QFT-GIT seemed to be more sensitive than TST [75% (61–86) versus 64% (48–78)] but similarly specific [71% (62–86) versus 70% (57–81)]. Conclusions: IGRAs, especially T-SPOT.TB, are more effective at detecting TB infection than TST. Despite their higher cost, they have added value and can be requested in addition to TST.

Genetic variations in toll-like receptor pathway and lung function decline in Cystic fibrosis patients

The toll-like receptor (TLR) family maintains pulmonary homeostasis by pathogen recognition, clearance and regulation of inflammation. Genes affecting inflammation response play a key role in modifying Cystic fibrosis (CF) lung disease severity. We assessed the impact of single nucleotide polymorphisms (SNPs) of TLR genes (TLR1 to TLR10, CD14, lipopolyssacharide-binding protein (LBP)) on lung function in CF patients. Each SNP was tested for time-dependent effect on FEV1, using six genetic models. In addition, we investigated associations between SNP genotypes and extreme subject specific slopes of FEV1 decline. Variant alleles of polymorphisms of TLR2 rs1898830, rs5743708, and rs3804100 demonstrated a consistent association with lung disease severity (p = 0.008, p = 0.006 and p = 0.029 respectively). Patients homozygous for variant C allele of TLR5 polymorphism rs5744174 are more frequently associated with extreme fast FEV1 decline (OR: 20 (95% Confidence Interval:1.85-216.18)). Patients homozygous AA for TLR1 polymorphism rs5743551 are more frequently associated with faster decline of FEV1 compared to heterozygous genotype (OR:7.33 (95% CI:1.63-33.11). Our findings indicate that variations in TLR1, TLR2 and TLR5 genes may influence CF lung function decline. Further functional analysis is required to provide new insights into the pathogenesis of TLRs in CF lung disease severity.

Achromobacter xylosoxidans induced bronchiolitis obliterans in cystic fibrosis.

We report a 12‐year‐old boy with progressive bronchiolitis obliterans caused by Achromobacter xylosoxidans (Ax) colonization after liver transplantation, resulting in a steep decline in lung function. Pediatr Pulmonol. 2014; 49:414–416.

Bronchiolitis obliterans in children: a ghostly journey to the origin.

Bronchiolitis obliterans (BO) is a rare fibrosing form of chronic obstructive lung disease after lung transplantation, smoke inhalation or after a severe viral insult to the lower respiratory tract, resulting in narrowing and sometimes complete obliteration of the small airways. BO in children mostly follows a severe viral lower respiratory tract infection. Several studies have suggested that the disease is more common in the southern hemisphere; people from Asian descent appear to be especially susceptible. Recently the HLA haplotype DR8-DQB1.0302, an allele highly represented in the Amerindian population, was associated with an increased incidence of BO, providing a possible explanation for the high frequency in South American countries. Adenovirus is the leading infectious cause of BO worldwide; however, isolated cases after RSV, measles, influenza, parainfluenza and Mycoplasma pneumoniae are reported. Severe respiratory compromise during the acute adenovirus pneumonia predisposes to an evolution to BO. A rare but severe and often progressive form of BO was observed as a complication of the Stevens--Johnson syndrome. A clinical diagnosis is made when after a severe viral bronchiolitis, or sometimes pneumonia with respiratory insufficiency, tachypnoea, wheezing and hypoxaemia persists for at least 60 days. Symptoms may wax and wane over weeks to months. Physical examination reveals crackles and wheeze by chest auscultation, a barrel chest, tachypnoea and sometimes hypoxaemia. The chest X-ray shows hyperinflation, bilateral interstitial prominence, atelectasis and consolidations. HRCT thorax is characterised by mosaic perfusion, vascular attenuation and central bronchiectasis. Lung function reveals dramatic hyperinflation: increased residual volume (RV), thoracic gas volume (TGV) and a pronounced obstructive flow volume curve: decreased FEV1, FEV1/FVC and midexpiratory flows (FEF25-75, FEF50). From a pathological point of view BO is characterised by partial or complete obstruction of the lumens of terminal and respiratory bronchioles by inflammatory and fibrous tissue. Two major histopathological types are reported, which can be part of a continuum. The first rare type is characterised by inflammatory and granulation tissues obstructing the small airways, extending into the alveoli causing atelectasis and alveolar consolidation. This type is known as BO with organising pneumonia or as it is more usually named now, cryptogenic organising pneumonia. The second, much more common type known as constrictive bronchiolitis is characterised by inflammation and fibrosis of the wall of bronchioles leading to a fixed obstruction and sometimes occlusion of the airway. The latter is found in 97% of childhood BO. BAL fluid (BALF) of BO patients contains increased levels of interleukins (IL-6, IL-8), Tumour necrosis factor, and neutrophils as hallmarks of ongoing inflammation. Increased levels of CD8+ T-cells suggest an impact of T-lymphocyte driven inflammation. The paper of Mallol et al. in the current issue of Allergologia et Immunopathologia shows that in 21 children with BO, oxidants such as 8-isoprostane derived from triglycerides and carbonyls from proteins are obviously increased in BAL fluid, whereas anti-oxidants such as catalase and gluthatione peroxidase are normal or increased respectively. Neutrophils, eosinophils and alveolar macrophages, recruited by a toxic respiratory impact (viral infection, smoke inhalation, etc) are notorious producers of Reactive Oxygen species (ROS), but also epithelial and endothelial cells can provide ROS. ROS enhances inflammation and tissue damage. ROS (superoxide and hydrogen peroxide) reacts with a number of substrates to generate harmful radicals. Increased ROS production is reported in patients with asthma and CF. The paper of Mallol et al. reports in BO, a pathologic setting of patients with ongoing respiratory inflammation driven by interleukins and TNFattracting inflammatory cells, increased ROS and c.q. oxidants. The values of the antioxidants are somewhat unequivocal; an increase in glutathione oxidase could counteract the increase in oxidants, whereas the lack of increase in catalase in an inflammatory region with increased oxidants can enhance inflammation. The study did not find any correlation between oxidant concentration and lung function deficit. Oxidants were, however, measured in BALF without any estimation of the absolute concentration, facilitating comparison between samples. The concentration measured,

239 Intake of pancreatic enzymes: Consistent with the guidelines?

Objectives Pancreatic enzyme (PE) replacement therapy is required in pancreatic insufficient CF patients to prevent malnutrition, nutrient deficiency and control abdominal maldigestion symptoms. This study evaluates and compares the actual PE intake with current expert recommendations (ER). Methods The dietary intake, measured by a 3-day dietary diary with PE intake (Creon® 10000, 25000 and 40000) for each meal was reviewed during a dietary consult. Intake is compared to the ER expressed as lipase units (IU)/g fat, /kg body-weight (BW)/day and /kgBW/meal. Results are presented as median (range). Results 54 patients [age 12.8 y (1, 50); 27 males] with BMI z-score –0.3 (–1.9, 1.5) and FEV1% 85.7 (31.8,114.1) (n = 43) were included. Results are presented in the table. TableComparison of PE intake with expert recommendationsGuidelineNumber of patientsTotalIntake greater than advised intakeIn accordance with advised intaken (%)Intake, median (range)n (%)Intake, median (range)Child: 400–800 IU/g fat2424 (100%)5,885 (1,106–13,875)–Adolescent-adult: 4,000 IU/g fat3026 (87%)7,316 (3,220–16,888)4 (13%)2,983 (2,857–3,135)10,000 IU/kgBW/d5440 (74%)18,753 (10,110–36,194)14 (26%)6,996 (2,455–9,711)2,000 IU/kgBW/meal5442 (78%)4,445 (2,210–8,691)12 (22%)1,398 (1,052–1,973) Conclusion The majority of our patients has a pancreatic enzyme intake above the current recommendations without known side effects. Research is needed to formulate recommendations based on achieving optimal digestion rather than using a protective dosing strategy.