The German National Registry of Primary Immunodeficiencies (2012-2017).

Front Immunol. 2019;10:1272

Authors: El-Helou SM, Biegner AK, Bode S, Ehl SR, Heeg M, Maccari ME, Ritterbusch H, Speckmann C, Rusch S, Scheible R, Warnatz K, Atschekzei F, Beider R, Ernst D, Gerschmann S, Jablonka A, Mielke G, Schmidt RE, Schürmann G, Sogkas G, Baumann UH, Klemann C, Viemann D, von Bernuth H, Krüger R, Hanitsch LG, Scheibenbogen CM, Wittke K, Albert MH, Eichinger A, Hauck F, Klein C, Rack-Hoch A, Sollinger FM, Avila A, Borte M, Borte S, Fasshauer M, Hauenherm A, Kellner N, Müller AH, Ülzen A, Bader P, Bakhtiar S, Lee JY, Heß U, Schubert R, Wölke S, Zielen S, Ghosh S, Laws HJ, Neubert J, Oommen PT, Hönig M, Schulz A, Steinmann S, Schwarz K, Dückers G, Lamers B, Langemeyer V, Niehues T, Shai S, Graf D, Müglich C, Schmalzing MT, Schwaneck EC, Tony HP, Dirks J, Haase G, Liese JG, Morbach H, Foell D, Hellige A, Wittkowski H, Masjosthusmann K, Mohr M, Geberzahn L, Hedrich CM, Müller C, Rösen-Wolff A, Roesler J, Zimmermann A, Behrends U, Rieber N, Schauer U, Handgretinger R, Holzer U, Henes J, Kanz L, Boesecke C, Rockstroh JK, Schwarze-Zander C, Wasmuth JC, Dilloo D, Hülsmann B, Schönberger S, Schreiber S, Zeuner R, Ankermann T, von Bismarck P, Huppertz HI, Kaiser-Labusch P, Greil J, Jakoby D, Kulozik AE, Metzler M, Naumann-Bartsch N, Sobik B, Graf N, Heine S, Kobbe R, Lehmberg K, Müller I, Herrmann F, Horneff G, Klein A, Peitz J, Schmidt N, Bielack S, Groß-Wieltsch U, Classen CF, Klasen J, Deutz P, Kamitz D, Lassay L, Tenbrock K, Wagner N, Bernbeck B, Brummel B, Lara-Villacanas E, Münstermann E, Schneider DT, Tietsch N, Westkemper M, Weiß M, Kramm C, Kühnle I, Kullmann S, Girschick H, Specker C, Vinnemeier-Laubenthal E, Haenicke H, Schulz C, Schweigerer L, Müller TG, Stiefel M, Belohradsky BH, Soetedjo V, Kindle G, Grimbacher B

Abstract
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

PMID: 31379802 [PubMed - in process]

Clinical evaluation of the dental hard tissues in an adult population with cystic fibrosis.

Pol Arch Intern Med. 2019 Jul 31;:

Authors: Pawlaczyk-Kamieńska T, Borysewicz-Lewicka M, Śniatała R, Batura-Gabryel H

PMID: 31379359 [PubMed - as supplied by publisher]

Scedosporium apiospermum.

Trends Microbiol. 2019 Aug 02;:

Authors: Bouchara JP, Papon N

PMID: 31378439 [PubMed - as supplied by publisher]

Bilateral pneumonectomy to treat uncontrolled sepsis in a patient awaiting lung transplantation.

J Thorac Cardiovasc Surg. 2017 04;153(4):e67-e69

Authors: Cypel M, Waddell T, Singer LG, Del Sorbo L, Fan E, Binnie M, Ferguson ND, Keshavjee S

PMID: 28017368 [PubMed - indexed for MEDLINE]

Diagnostic Approach to Monogenic Inflammatory Bowel Disease in Clinical Practice: A Ten-Year Multicentric Experience.

Inflamm Bowel Dis. 2019 Aug 03;:

Authors: Lega S, Pin A, Arrigo S, Cifaldi C, Girardelli M, Bianco AM, Malamisura M, Angelino G, Faraci S, Rea F, Romeo EF, Aloi M, Romano C, Barabino A, Martelossi S, Tommasini A, Di Matteo G, Cancrini C, De Angelis P, Finocchi A, Bramuzzo M

Abstract
BACKGROUND AND AIMS: Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients' management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis.
METHODS: Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008-2017 who underwent a genetic workup were collected.
RESULTS: Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT.
CONCLUSION: A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients' management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.

PMID: 31375816 [PubMed - as supplied by publisher]

Short-term CFTR inhibition reduces islet area in C57BL/6 mice.

Sci Rep. 2019 Aug 02;9(1):11244

Authors: Khan D, Kelsey R, Maheshwari RR, Stone VM, Hasib A, Manderson Koivula FN, Watson A, Harkin S, Irwin N, Shaw JA, McClenaghan NH, Venglovecz V, Ébert A, Flodström-Tullberg M, White MG, Kelly C

Abstract
Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.

PMID: 31375720 [PubMed - in process]

[Italian Cystic Fibrosis Registry (ICFR). Report 2015-2016].

Epidemiol Prev. 2019 Jul-Aug;43(4S1):1-36

Authors: Giordani B, Amato A, Majo F, Ferrari G, Quattrucci S, Minicucci L, Padoan R, Floridia G, Salvatore D, Carnovale V, Puppo Fornaro G, Taruscio D, Salvatore M, Gruppo di lavoro RIFC

Abstract
INTRODUCTION: On the 27th of October 2017 the National Center for Rare Diseases of the Italian National Health Institute (NHI), clinicians of the Italian National Referral and Support Centres for Cystic Fibrosis, Paediatric Hospital "Bambino Gesù", Italian Cystic Fibrosis Society, and the Italian League for Cystic Fibrosis renewed the agreement about FC data flow for a 3 years period. The possibility to access data by third parties is among the most important new introduced within the agreement.
OBJECTIVES: Aim of the present report is to improve the know-how on cystic fibrosis (CF) through a better characterization of Italian patients. Furthermore, the present Report aims at improving the care of CF patient. In particular, the Report should contribute to the following objectives: * to analize medium- and long-term clinical and epidemiological trends of the disesase; * to identify the main health care needs at regional and national level in order to contribute to the healthcare programmes and to the distribution of resources; * to compare Italian data with international ones.
DESIGN: Analyses and results described in the present Report are referred to patients in charge to the Italian National Referral and Support Centers for Cystic Fibrosis in the period 2015-2016. Data were sent by Centres by means of a specific software (Camilla, Ibis Informatica). Data underwent to a double quality control (QC): the first by NHI and the second at a European level (before the inclusion of the italian data within the European Cystic Fibrosis Registry). These QCs assure the completeness and the accuracy of data as well as their consistency with European core data. Finally, in 2017, an additional CQ was performed to further reduce the number of missing data and consequently improve the precision and the consistency in the nomenclature adopted for genetic mutations.
SETTING AND PARTICIPANTS: A total of 29 different CF Centres (referral, support, and Paediatric Hospital "Bambino Gesù") sent their data referred to 2015-2016 years to ICFR . Data regarding Sardinia (Southern Italy) are missing and those from Treviso (Veneto Region, Northern Italy) and Rovereto (Trentino-Alto Adige Region, Northern Italy) are sent through Verona CF Centre.
RESULTS: The present Report has been organized into 10 sections. 1. Demography: estimated CF patients is 5,204 in 2015 and 5,362 in 2016; median age is 20.6 and 21.0, respectively. Prevalence is 8.6/100,000 residents in Italy in 2015 and 8.8 in 2016. Male percentage is 51.6% on average for 2015 and 2016; CF distribution showed higher frequency in patients aged from 7 to 35 years. The mean of patients aged more than 18 years is 56.5% on average in 2015 and 2016. 2. Diagnoses: most of the CF patients were diagnosed before 2 years of age (median value: 68%); a significant percentage of patients (median value: 13%) was diagnosed in adult age. 3. New diagnoses: new diagnoses were 169 in 2015 and 153 in 2016. Estimated incidence in 2015 was 1/4,176 living births in 2015 and 1/5,510 in 2016. 4. Genetics: 99.5% of patients underwent genetic analyses and in 96% of patients a mutation in Cystic Fibrosis Transmembrane Regulator (CFTR) gene was identified. [delta]508F was the most frequent mutation (44,7% in 2016). Furthermore, 16.0% and 3.4% of patients was characterized by the presence of at least one "residual function" mutation and gating, respectively. Finally, 21% of patients was a stop codons (class 1 mutation) carrier. 5. Lung function: FEV1 (forced expiratory volume in the first second) scores progressively decreased before adult age, in accordance with the natural history of the disease. FEV1% values in patients between 6 and 17 years of age is ≥70%; patients with a FEV1% value of 40% are less than 2% in the period 2015-2016. 6. Nutrition: most critical periods are during the first 6 months of life and during adolescence. Prevalence of malnourished male aged 12-17 years is constant in 2015-2016 and is always more than the prevalence observed in female. An increasing percentage of female patient with a suboptimal BMI value (35.5%) is observed among patients aged more than 18 years 7.
COMPLICATIONS: it was estimated that, in 2016, hepatopathies without cirrhosis (17.7%) is the principal complications in patients aged less than 18 years; in patients aged more than 18 years the principal complication was due to hepatopathies without cirrhosis (29.5%) and diabetes (23.3%). 8. Transplantation: in 2015-2016, 74 patients were bipulmunary transplanted; age was comprised between 8 and 52 years, median age at transplantation was 29,6 years. Median waiting times for transplantation is estimated in 17 months (24 months in 2015 and 14 months in 2016). 9. Microbiology: analyses were referred to test performed in 2016. Percentage of adult patients with chronic Pseudomonas aeruginosa infection is 52.1% compared to 15.2% of paediatric patients; Staphylococcus aureus infection is present in 53.2% of adult patients and 52.8% of paediatric ones; Burkholderia Cepacia complex is present almost exclusively in adult patients (4.3%); Nontuberculous mycobacteria is present in 1.2% and 0.4% of adult and paediatric patients, respectively; Stenotrophomonas maltophilia infection is present in the 6.1% of adult patients and 4.9 of paediatric patients. 10. Mortality: 102 patients (49 males and 53 females; median age 36.9 years in 2015 and 36.5 in 2016) died in 2015-2016 (transplanted patients are not included).
CONCLUSIONS: The present Report shows that Italian CF population is growing (median age) and paediatric mortality is decreasing. A very low percentage of paediatric population is characterized by complication of pulmonary function; adult patients are characterized by an increase of age at death (more than 36 years of age in 2016).

PMID: 31370382 [PubMed - in process]

Cholesterol Interaction Directly Enhances Intrinsic Activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

Cells. 2019 Jul 31;8(8):

Authors: Chin S, Ramjeesingh M, Hung M, Ereño-Oreba J, Cui H, Laselva O, Julien JP, Bear CE

Abstract
The recent cryo-electron microscopy structures of zebrafish and the human cystic fibrosis transmembrane conductance regulator (CFTR) provided unprecedented insights into putative mechanisms underlying gating of its anion channel activity. Interestingly, despite predictions based on channel activity measurements in biological membranes, the structure of the detergent purified, phosphorylated, and ATP-bound human CFTR protein did not reveal a stably open conduction pathway. This study tested the hypothesis that the functional properties of the detergent solubilized CFTR protein used for structural determinations are different from those exhibited by CFTR purified under conditions that retain associated lipids native to the membrane. It was found that CFTR purified together with phospholipids and cholesterol using amphipol: A8-35, exhibited higher rates of catalytic activity, phosphorylation dependent channel activation and potentiation by the therapeutic compound, ivacaftor, than did CFTR purified in detergent. The catalytic activity of phosphorylated CFTR detergent micelles was rescued by the addition of phospholipids plus cholesterol, but not by phospholipids alone, arguing for a specific role for cholesterol in modulating this function. In summary, these studies highlight the importance of lipid interactions in the intrinsic activities and pharmacological potentiation of CFTR.

PMID: 31370288 [PubMed - in process]

Biatrial Remodeling in Patients with Cystic Fibrosis Running Title: Atrial Function in Cystic Fibrosis.

J Clin Med. 2019 Jul 31;8(8):

Authors: Dordevic A, Genger M, Schwarz C, Cuspidi C, Tahirovic E, Pieske B, Düngen HD, Tadic M

Abstract
BACKGROUND: Previous studies have focused on left and right ventricular remodeling in cystic fibrosis (CF), whereas atrial function has not been assessed in detail so far. We sought to investigate left and right atrial (LA and RA) function in patients with CF.
METHODS: This retrospective investigation included 82 CF patients (64 survivors and 18 non-survivors) who were referred to CF department over the period of four years, as well as 32 control subjects matched by age and gender. All participants underwent an echocardiographic examination including a strain analysis, which was performed offline and blinded for groups.
RESULTS: LA and RA volume indexes were significantly higher in CF patients than in controls and were particularly high in CF non-survivors. LA conduit and reservoir functions were significantly worse in CF survivors and non-survivors, compared with control subjects. RA phasic function was not different between controls, CF survivors and non-survivors. The parameters of lung function (forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1)) and the LA and RA volume indexes were predictors of mortality in CF patients. However, in a multivariate analysis, only FVC was an independent predictor of mortality in CF patients.
CONCLUSIONS: Our results suggest that both atria are enlarged, but only LA function is impaired in CF patients. LA reservoir and conduit function is particularly deteriorated in CF patients. Though statistical significance was not reached due to our limited sample size, there was a trend of deterioration of LA and RA function from controls across CF survivors to CF non-survivors. LA and RA enlargement represented predictors of mortality in CF patients.

PMID: 31370249 [PubMed]

Melioidosis in travelers: An analysis of Dutch melioidosis registry data 1985-2018.

Travel Med Infect Dis. 2019 Jul 29;:

Authors: Birnie E, Savelkoel J, Reubsaet F, Roelofs JJTH, Soetekouw R, Kolkman S, Cremers AL, Grobusch MP, Notermans DW, Wiersinga WJ, Dutch Melioidosis Study Group

Abstract
BACKGROUND: Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an opportunistic infection across the tropics. Here, we provide a systematic overview of imported human cases in a non-endemic country over a 25-year period.
METHODS: All 55 Dutch microbiology laboratories were contacted in order to identify all B. pseudomallei positive cultures from 1990 to 2018. A response rate of 100% was achieved. Additionally, a systematic literature search was performed, medical-charts reviewed, and tissue/autopsy specimens were re-assessed.
RESULTS: Thirty-three travelers with melioidosis were identified: 70% male with a median-age of 54 years. Risk factors were present in most patients (n = 23, 70%), most notably diabetes (n = 8, 24%), cystic fibrosis (n = 3, 9%). Countries of acquisition included Thailand, Brazil, Indonesia, Panama and The Gambia. Disease manifestations included pneumonia, intra-abdominal abscesses, otitis externa, genitourinary, skin-, CNS- and thyroid gland infections. Twelve (36%) patients developed sepsis and/or septic shock. Repeat episodes of active infection were observed in five (15%) and mortality in four (12%) patients. Post-mortem analysis showed extensive metastatic (micro)abscesses amongst other sites in the adrenal gland and bone marrow.
CONCLUSIONS: The number of imported melioidosis is likely to increase, given rising numbers of (immunocompromised) travelers, and increased vigilance of the condition. This first systematic retrospective surveillance study in a non-endemic melioidosis country shows that imported cases can serve as sentinels to provide information about disease activity in areas visited and inform pre-travel advice and post-travel clinical management.

PMID: 31369898 [PubMed - as supplied by publisher]

Exploring cardio-pulmonary interactions during constant workload submaximal cycle exercise in COPD patients.

J Appl Physiol (1985). 2019 Aug 01;:

Authors: Laveneziana P, Di Paolo M

PMID: 31369332 [PubMed - as supplied by publisher]

Impact of total body weight on rate of acute kidney injury in patients treated with piperacillin-tazobactam and vancomycin.

Am J Health Syst Pharm. 2019 Aug 01;76(16):1211-1217

Authors: Rutter WC, Hall RG, Burgess DS

Abstract
PURPOSE: Results of a study to determine whether obesity is associated with acute kidney injury (AKI) among patients receiving combination therapy with piperacillin-tazobactam and vancomycin are reported.
METHODS: A retrospective, single-center cohort study of patients who received combination therapy for at least 48 hours was conducted using data from the University of Kentucky Center for Clinical and Translational Science's Enterprise Data Trust. Patients with chronic kidney disease, baseline creatinine clearance of less than 30 mL/min, cystic fibrosis, or missing height or weight information were excluded.
RESULTS: A total of 8,125 patients were included in the cohort. Among the variables evaluated, total body weight of 91 kg or more was the variable most predictive of AKI. Patients with a weight of 91 kg or higher were more likely than lower-weight patients to have diabetes (39% versus 21%, p < 0.00001), hypertension (64% versus 47%, p < 0.00001), and heart failure (15% versus 13%, p = 0.007). The median daily vancomcyin dose was lower in patients with a weight of less than 91 kg (2,000 mg versus 3,000 mg, p < 0.00001); however, weight-based doses were lower in patients weighing 91 kg or more (25.5 mg/kg/day versus 27.9 mg/kg/day, p < 0.00001). AKI was more common in patients weighing 91 kg or more (24% versus 18%, p < 0.00001; adjusted odds ratio, 1.46 [95% confidence interval, 1.28-1.66]).
CONCLUSION: Increased total body weight increased the rate of AKI among patients concurrently treated with piperacillin-tazobactam and vancomycin independent of clinically important confounders, with an important breakpoint occurring at 91 kg.

PMID: 31369116 [PubMed - in process]

Composition of airway bacterial community correlates with chest HRCT in adults with bronchiectasis.

Respirology. 2019 Jul 30;:

Authors: O'Neill K, Einarsson GG, Rowan S, McIlreavey L, Lee AJ, Lawson J, Lynch T, Horsley A, Bradley JM, Elborn JS, Tunney MM

Abstract
BACKGROUND AND OBJECTIVE: In bronchiectasis (BE) not caused by cystic fibrosis, chronic, polymicrobial airway infection contributes to the underlying pathogenesis of disease. There is little information on whether bacterial community composition relates to clinical status. We determined the relationship between bacterial community composition, chest high-resolution computed tomography (HRCT) scores and clinical markers in BE.
METHODS: A subgroup of BE patients from a previous cross-sectional study were analysed. Spontaneously expectorated sputum was analysed using culture-independent sequencing on the Roche 454-FLX platform covering the V1-V3 region of the 16S rRNA marker gene. Chest HRCT scans, multiple breath washout, spirometry and blood inflammatory markers were collected. Spearman's rank (r) correlation coefficient was used to assess relationships.
RESULTS: Data from 21 patients were analysed (mean (SD) age: 64.0 (7.7); female : male 14:7; mean (SD) forced expiratory volume in 1 s (FEV1 ): 76.5 (17.2)). All bacterial community composition metrics (bacterial richness, diversity, evenness and dominance) correlated with percentage BE score, with more severe HRCT abnormality relating to lower bacterial richness, evenness and diversity (range r = -0.47 to -0.66; P < 0.05). Inflammation (C-reactive protein and white cell count) was greater in patients with lower diversity and richness (range r = -0.44 to -0.47; P < 0.05). Bacterial community characteristics did not correlate with lung function.
CONCLUSION: This is the first study to indicate a relationship between bacterial community characteristics by 16S rRNA marker gene sequencing, structural damage as determined by chest HRCT and clinical measures in BE. The association between loss of diversity and chest HRCT severity suggests that bacterial dominance with pathogenic bacteria may contribute to disease pathology.

PMID: 31364220 [PubMed - as supplied by publisher]

Distal intestinal obstruction syndrome: an important differential diagnosis for abdominal pain in patients with cystic fibrosis.

ANZ J Surg. 2019 Jul 30;:

Authors: Hort A, Hameed A, Middleton PG, Pleass HC

Abstract
As life expectancy for those with cystic fibrosis (CF) now exceeds 40 years of age, adult hospitals away from specialized CF services are being exposed more frequently to people with acute complications of CF. Well-known manifestations of CF include pulmonary disease and pancreatic insufficiency with malabsorption. However, a less well-known entity is distal intestinal obstruction syndrome (DIOS), which is an important cause of obstructive symptoms in people with CF that must be differentiated from other causes of bowel obstruction. However, one confounding factor is that adults with CF may have elements of both DIOS and mechanical bowel obstruction due to adhesions from previous operations. A recent tragic outcome in a young adult with CF highlights the need for all doctors, both junior and senior, especially those who are not directly involved in day-to-day CF care, to understand the features of DIOS and the appropriate management, which differs from that of a mechanical bowel obstruction. This review aims to highlight the clinical and pathophysiological features of DIOS, differentiate it from other causes of bowel obstruction and contrast management strategies. Improved knowledge of DIOS will help to facilitate appropriate recognition and permit optimal, multidisciplinary management of this CF complication.

PMID: 31364217 [PubMed - as supplied by publisher]

Clinical Use of Colistin in Biofilm-Associated Infections.

Adv Exp Med Biol. 2019;1145:181-195

Authors: Lora-Tamayo J, Murillo O, Ariza J

Abstract
Biofilm is an adaptive bacterial strategy whereby microorganisms become encased in a complex glycoproteic matrix. The low concentration of oxygen and nutrients in this environment leads to heterogeneous phenotypic changes in the bacteria, with antimicrobial tolerance being of paramount importance. As with other antibiotics, the activity of colistin is impaired by biofilm-embedded bacteria. Therefore, the recommendation for administering high doses in combination with a second drug, indicated for planktonic infections, remains valid in this setting. Notably, colistin has activity against metabolically inactive biofilm-embedded cells located in the inner layers of the biofilm structure. This is opposite and complementary to the activity of other antimicrobials that are able to kill metabolically active cells in the outer layers of the biofilm. Several experimental models have shown a higher activity of colistin when used in combination with other agents, and have reported that this can avoid the emergence of colistin-resistant subpopulations. Most experience of colistin in biofilm-associated infections comes from patients with cystic fibrosis, where the use of nebulized colistin allows high concentrations to reach the site of the infection. However, limited clinical experience is available in other scenarios, such as osteoarticular infections or device-related central nervous system infections caused by multi-drug resistant microorganisms. In the latter scenario, the use of intraventricular or intrathecal colistin also permits high local concentrations and good clinical results. Overall, the efficacy of intravenous colistin seems to be poor, but its association with a second antimicrobial significantly increases the response rate. Given its activity against inner bioflm-embedded cells, its possible role in combination with other antibiotics, beyond last-line therapy situations, should be further explored.

PMID: 31364079 [PubMed - in process]

Genetically diverse Pseudomonas aeruginosa populations display similar transcriptomic profiles in a cystic fibrosis explanted lung.

Nat Commun. 2019 Jul 30;10(1):3397

Authors: Kordes A, Preusse M, Willger SD, Braubach P, Jonigk D, Haverich A, Warnecke G, Häussler S

Abstract
Previous studies have demonstrated substantial genetic diversification of Pseudomonas aeruginosa across sub-compartments in cystic fibrosis (CF) lungs. Here, we isolate P. aeruginosa from five different sampling areas in the upper and lower airways of an explanted CF lung, analyze ex vivo transcriptional profiles by RNA-seq, and use colony re-sequencing and deep population sequencing to determine the genetic diversity within and across the various sub-compartments. We find that, despite genetic variation, the ex vivo transcriptional profiles of P. aeruginosa populations inhabiting different regions of the CF lung are similar. Although we cannot estimate the extent to which the transcriptional response recorded here actually reflects the in vivo transcriptomes, our results indicate that there may be a common in vivo transcriptional profile in the CF lung environment.

PMID: 31363089 [PubMed - in process]

Pseudomonas aeruginosa Increases the Sensitivity of Biofilm-Grown Staphylococcus aureus to Membrane-Targeting Antiseptics and Antibiotics.

MBio. 2019 Jul 30;10(4):

Authors: Orazi G, Ruoff KL, O'Toole GA

Abstract
Pseudomonas aeruginosa and Staphylococcus aureus often cause chronic, recalcitrant infections in large part due to their ability to form biofilms. The biofilm mode of growth enables these organisms to withstand antibacterial insults that would effectively eliminate their planktonic counterparts. We found that P. aeruginosa supernatant increased the sensitivity of S. aureus biofilms to multiple antimicrobial compounds, including fluoroquinolones and membrane-targeting antibacterial agents, including the antiseptic chloroxylenol. Treatment of S. aureus with the antiseptic chloroxylenol alone did not decrease biofilm cell viability; however, the combination of chloroxylenol and P. aeruginosa supernatant led to a 4-log reduction in S. aureus biofilm viability compared to exposure to chloroxylenol alone. We found that the P. aeruginosa-produced small molecule 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO) is responsible for the observed heightened sensitivity of S. aureus to chloroxylenol. Similarly, HQNO increased the susceptibility of S. aureus biofilms to other compounds, including both traditional and nontraditional antibiotics, which permeabilize bacterial membranes. Genetic and phenotypic studies support a model whereby HQNO causes an increase in S. aureus membrane fluidity, thereby improving the efficacy of membrane-targeting antiseptics and antibiotics. Importantly, our data show that P. aeruginosa exoproducts can enhance the ability of various antimicrobial agents to kill biofilm populations of S. aureus that are typically difficult to eradicate. Finally, our discovery that altering membrane fluidity shifts antimicrobial sensitivity profiles of bacterial biofilms may guide new approaches to target persistent infections, such as those commonly found in respiratory tract infections and in chronic wounds.IMPORTANCE The thick mucus in the airways of cystic fibrosis (CF) patients predisposes them to frequent, polymicrobial respiratory infections. Pseudomonas aeruginosa and Staphylococcus aureus are frequently coisolated from the airways of individuals with CF, as well as from diabetic foot ulcers and other wounds. Both organisms form biofilms, which are notoriously difficult to eradicate and promote chronic infection. In this study, we have shown that P. aeruginosa-secreted factors can increase the efficacy of compounds that alone have little or no bactericidal activity against S. aureus biofilms. In particular, we discovered that P. aeruginosa exoproducts can potentiate the antistaphylococcal activity of phenol-based antiseptics and other membrane-active drugs. Our findings illustrate that polymicrobial interactions can dramatically increase antibacterial efficacy in vitro and suggest that altering membrane physiology promotes the ability of certain drugs to kill bacterial biofilms-knowledge that may provide a path for the discovery of new biofilm-targeting antimicrobial strategies.

PMID: 31363032 [PubMed - in process]

Use of continuous infusion ceftolozane-tazobactam with therapeutic drug monitoring in a patient with cystic fibrosis.

Am J Health Syst Pharm. 2019 Apr 08;76(8):501-504

Authors: Elizabeth Davis S, Ham J, Hucks J, Gould A, Foster R, Ann Justo J, Nicolau DP, Bookstaver PB

Abstract
PURPOSE: The safe and effective use of ceftolozane-tazobactam delivered via continuous infusion in a cystic fibrosis (CF) patient with reduced body weight and presumed augmented renal clearance is reported.
SUMMARY: A 30-year-old woman with CF was admitted for acute pulmonary exacerbations with positive respiratory cultures for Pseudomonas aeruginosa and extended-spectrum β-lactamase-producing Escherichia coli. Susceptibility testing confirmed multidrug resistance, and the patient was transitioned to ceftolozane-tazobactam for definitive therapy. A novel strategy of administering ceftolozane-tazobactam 6 g by continuous i.v. infusion over 24 hours was initiated during hospitalization and continued at discharge for a total of 10 days. Therapeutic drug monitoring over the first 36 hours of the continuous infusion confirmed adequate exposure. The patient had clinical resolution with return to baseline of pulmonary function tests and no noted adverse drug events.
CONCLUSION: A continuous infusion regimen of ceftolozane-tazobactam was successfully used in a CF patient with augmented renal clearance.

PMID: 31361864 [PubMed - in process]

Motor Performance in South African Children with Cystic Fibrosis.

Phys Occup Ther Pediatr. 2019 Jul 30;:1-9

Authors: Corten L, Morrow BM

Abstract
Aims: This study aimed to investigate motor performance in children with cystic fibrosis (CF) and the relationship with respiratory and anthropometric outcome measures. Methods: A cross-sectional exploratory study investigated 12 children with CF, mean (SD) age 6.17 (0.67) years, using the Movement Assessment Battery for Children 2nd edition (MABC-2), spirometry, body weight, height, body mass index, and age-related anthropomorphic z-scores. Results: MABC-2 total scores indicated 9/12 (75%) children performed below average (<50th percentile), of which 4/12 children (33.3%) had motor delay and 2/12 (16.7%) were at risk for motor delay. The balance subscale showed the lowest scores, with 5/12 (41.7%) participants performing at or below the 5th percentile and a median (IQR) percentile score of 9.00 (5.00-62.50). A significant negative correlation was found between the manual dexterity subscale and both height and height for age z-scores (p = 0.017 and p = 0.019, respectively), as well as peak expiratory flow in liter (p = 0.027). The balance subscale scores were positively correlated with forced expiratory volume in %predicted (p = 0.048). No other significant correlations were found. Conclusion: Children with CF may be at risk for delayed motor development, particularly their balance skills. Poor lung function might affect motor development but further research is recommended.

PMID: 31359799 [PubMed - as supplied by publisher]

An investigation into biomarkers for the diagnosis of ABPA and aspergillus disease in cystic fibrosis.

Pediatr Pulmonol. 2019 Jul 29;:

Authors: Keown K, Abbott S, Kuzeljevic B, Rayment JH, Chilvers MA, Yang CL

Abstract
BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease due to Aspergillus fumigatus (Af) which occurs in 10% of patients with cystic fibrosis (CF). ABPA is associated with increased morbidity and accelerated lung function decline; however, existing diagnostic criteria are nonspecific and diagnosis remains challenging. As ABPA is driven by Th2 inflammation, the aim of this study was to evaluate exhaled nitric oxide (FE NO ), eosinophilic cationic protein (ECP), peripheral eosinophil count, and bronchodilator response (BDR) in patients with CF.
METHODS: A prospective observational cohort study of pediatric CF patients in a tertiary center. Patients had a clinical and serologic ABPA assessment, FENO , serum ECP, peripheral eosinophil count, and assessment of BDR. Patients were stratified into three groups; ABPA, Af sensitized (AFS), and non-ABPA non-Af-sensitized (non-AFS).
RESULTS: A total of 62 patients were included in the study: 13% ABPA, 19% AFS, and 68% non-AFS. Mean FENO was higher in the ABPA group at 37.8 ppb compared to AFS 15.1 ppb (P = .05) and non-AFS 13.7 ppb (P = .04). Mean peripheral eosinophil count in ABPA group was also higher at 1000 cells/uL, compared to AFS 221 cells/uL (P = .03) and non-AFS 220 cells/uL (P = .03). Mean BDR in ABPA group was 13% compared to 5.5% in non-AFS (P = .01). Serum ECP was higher in patients with ABPA positive compared to the other groups, although this was not statistically significant.
CONCLUSION: In children with cystic fibrosis, FENO and peripheral eosinophil counts are elevated in ABPA compared to those that are just sensitized to Aspergillus and may serve as useful diagnostic tests.

PMID: 31359612 [PubMed - as supplied by publisher]