What is cystic fibrosis screen positive inconclusive diagnosis? And what is it not?

Since screening for cystic fibrosis (CF) was incorporated into the newborn screening program, the number of recognised variants in the CF transmembrane conductance regulator (CFTR) gene has significantly increased. This has led to the discovery of combinations of gene variants with an uncertain prognosis. One outcome is the designation of 'cystic fibrosis screen positive inconclusive diagnosis' (CFSPID). While the majority of these children are expected to be unaffected by their CFTR variants, a small proportion have been seen to develop symptoms or increasing sweat chloride levels over time, which may reflect dysfunction of the CFTR protein.As the number of children with CFSPID increases, paediatricians and those working in primary care are more likely to encounter them in their practice. It is important that professionals have an understanding of CFSPID: what it is and, importantly, what it is not (ie, they do not have CF). In this article, we hope to explore this using some example cases, illustrating the ways in which these children may present symptomatically and how to manage them.

King's Variceal Prediction Score: A Novel Noninvasive Marker of Portal Hypertension in Pediatric Chronic Liver Disease.

BACKGROUND AND AIMS: Variceal haemorrhage can be a life-threatening complication of chronic liver disease in children. There is limited evidence about the optimal prophylactic management and selection criteria of children who will benefit from upper gastrointestinal endoscopy. METHODS: Children presenting in our centre with suspected portal hypertension or gastrointestinal bleeding and undergoing their first oesophagogastroduodenoscopy between 2005 and 2012 were included. Clinical, biochemical, and radiological data were collected. A separate validation cohort from May 2013 to October 2014 was obtained. RESULTS: Data on 124 treatment-naïve patients were collected; 50% had biliary atresia. Thirty-five (28%) children presented with gastrointestinal bleeding and overall 79 (64%) had clinically significant (grade II-III) varices. Clinical prediction rule, aspartate aminotransferase-platelet ratio index, and varices prediction rule had at optimal cut-off sensitivity and specificity of 76% and 59%, 60% and 55%, and 80% and 59%, respectively. Logistic regression yielded a new prediction rule of (3 × albumin ([g/dL]) -  (2 - equivalent adult spleen size [cm]). This King's variceal prediction score had a favourable areas under the curve of 0.772 (0.677-0.867) compared to clinical prediction rule 0.732 (0.632-0.832). At the optimal cut-off of 76 this yielded a sensitivity and specificity of 72% and 73% and a positive and negative predictive value of 82% and 60%, respectively. In the validation cohort areas under the curve was 0.818 (0.654-0.995) with sensitivity and specificity of 78% and 73%, respectively. CONCLUSIONS: Our new prediction score may be a useful tool in the selection of children with clinically significant varices eligible for a screening endoscopy.

Levelling the playing field through the London Network of the UK clinical trials accelerator platform.

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

An invisible threat? Aspergillus positive cultures and co-infecting bacteria in airway samples.

BACKGROUND: Aspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing. METHODS: Frequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010-2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates. RESULTS: Pa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02-1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium. CONCLUSIONS: Pa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed.

Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study.

BACKGROUND: Pseudomonas aeruginosa (Pa) and Aspergillus species (Asp) are the most common bacterial and fungal organisms respectively in CF airways. Our aim was to examine impacts of Asp infection and Pa/Asp co-infection. METHODS: Patients on the UK CF Registry in 2016 were grouped into: absent (Pa-), intermittent (Pai) or chronic Pa (Pac), each with Asp positive (Asp+) or negative (Asp-). Primary outcome was best percentage predicted FEV1 (ppFEV1) that year. Secondary outcomes were intravenous (IV) antibiotic courses, growth (height, weight, BMI) and additional disease complications. Associations between outcomes and infection-status were assessed using regression models adjusting for significant confounders (age, sex, Phe508del homozygosity and CF-related diabetes (CFRD)). RESULTS: 9,270 patients were included (median age 19 [IQR 9-30] years, 54% male, 50% Phe508del/F508del). 4,142 patients (45%) isolated Pa, 1,460 (16%) Asp. Pa-/Asp+ subjects had an adjusted ppFEV1 that was 5.9% lower than Pa-/Asp- (p < 0.0001). In patients with Pai or Pac, there was no additional impact of Asp on ppFEV1. However, there was a higher probability that Pac/Asp+ patients had required IV antibiotics than Pac/Asp- group (OR 1.23 [1.03-1.48]). Low BMI, ABPA, CF-liver disease and CFRD were all more frequent with Asp alone than Pa-/Asp-, though not more common in Pac/Asp+ than Pac/Asp-. CONCLUSIONS: Co-infection with Pa and Asp was not associated with reduced lung function compared with Pa alone, but was associated with additional use of IV antibiotics. Asp infection itself is associated with several important indicators of disease severity. Longitudinal analyses should explore the impact of co-infection on disease progression.

A Short extension to multiple breath washout provides additional signal of distal airway disease in people with CF: A pilot study.

BACKGROUND: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI2.5). METHODS: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCIShX). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores. RESULTS: HC/ CF group differences were larger with LCIShX than LCI2.5 (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI2.5. Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCIShX, 2.5% LCI2.5). PEx signal was significantly greater for LCIShX both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCIShX correlated with mucus plugging. CONCLUSIONS: UVLU captured within the LCIShX varies between individuals; the lack of relationship with LCI2.5 demonstrates that new, additional information is being captured. LCIShX repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status.

Delayed hepato-spleno-renal bypass for renal salvage following malposition of an infrarenal aortic stent-graft.

PURPOSE: To report a salvage maneuver for accidental coverage of both renal arteries during endovascular aneurysm repair (EVAR) of an infrarenal aortic aneurysm (AAA) and survey our surgical colleagues in the UK for their use of this bypass procedure. METHODS: A 74-year-old woman who had an EVAR complicated by renal failure secondary to malposition of the stent-graft underwent successful delayed renal revascularization with hepatorenal and splenorenal bypasses. This case prompted a literature review and preparation of an online 6-part questionnaire regarding the incidence and management of renal impairment following EVAR. The survey invitation was sent to all listed members of the Vascular Society of Great Britain and Ireland. RESULTS: Responses from 68 (10.5%) of the 650 vascular surgeons invited to participate in the survey were analyzed. The combined experience of those who completed the survey was >1500 EVAR procedures per annum. Forty percent (27/68) of the respondents had experienced a case of bilateral renal artery occlusion during EVAR. Two thirds (67%, 18/27) of these surgeons stated a preference for revascularizing the kidneys endovascularly, 7 surgeons would convert to open repair, 1 surgeon favored iliorenal bypass, and another suggested splenorenal bypass. Following intervention, 15 (56%) of 27 surgeons achieved revascularization that resulted in a return to baseline serum creatinine, 7 (26%) achieved partial recovery of the patient's serum creatinine, 3 (11%) had a patient on permanent dialysis, and 2 (7%) had patients who died (after open repair and endovascular procedure, respectively). CONCLUSION: Bilateral renal artery occlusion caused by malposition of a stent-graft is probably underreported. If revascularization of the kidneys by endovascular techniques fails, there is no consensus as to the optimal approach. Delayed revascularization should be considered if the kidneys show concentration of imaging contrast. Hepato-spleno-renal bypass, which has not heretofore been indicated for renal salvage post EVAR, can provide a good functional result in this situation.