A novel cystic fibrosis-pregnancy service: Two-year review after introduction of elexacaftor/tezacaftor/ivacaftor

Background: As a quality service improvement response since elexacaftor/ tezacaftor/ivacaftor (ELX/TEZ/IVA) became available and the yearly average number of cystic fibrosis (CF) pregnancies (n = 7 pre-2020, n = 33 in 2021) increased significantly at an adult CF center (~600 people with CF), a monthly multidisciplinary CF-maternal health virtual clinic was established with antenatal virtual CF exercise classes dedicated to providing adaptive, specialist support to this cohort, aswell as outreach guidance and education to local obstetric teams. Method(s): This was a single-center retrospective reviewof Royal Brompton Hospital CF-Maternal Health multidisciplinary team clinic records and a patient survey from March 2020 to March 2022. Result(s): Of 47 pregnancies in 41 women (median age 30;) eligible for ELX/ TEZ/IVA at start of pregnancy, 40% (n = 19) were unplanned, and 19% (n = 9) used assisted conception. Three women with a history of infertility conceived naturally, having required assisted conception for previous pregnancies, and five women had multiple pregnancies during the study period. ELX/TEZ/IVA was continued in 60% (n = 28), delayed in 28% (n = 13), and stopped in 13% (n = 6) of pregnancies through maternal choice and careful clinical counselling. Pre-pregnancy pulmonary status was poorer in women who continued than in those who delayed or stopped (Table 1). Of those who stopped, 85% (n = 5) restarted because of pulmonary deterioration by the third trimester. Prenatal CF complications included at least one episode of minor hemoptysis in 21% (n = 9/41) of women, at least one infective exacerbation in 55% of pregnancies (n = 26/47), and noninvasive ventilation in one woman. Other pregnancy-associated complications included one case of ovarian hyperstimulation syndrome, one case of sub-segmental pulmonary embolism, and two cases of pregnancy-induced hypertension. Excluding 10 first trimester terminations, 10 current pregnancies, and one patient relocation, obstetric outcomes available for 26 pregnancies confirmed a live birth rate of 85% (n = 22/26) and a 15% first-trimester miscarriage rate (n = 4). Obstetric complications included preterm delivery rate of 23% (n = 6/26), including two cases of COVID infection resulting in two neonatal intensive care unit admissions, one case of endometritis after cesarean section, and a fourthdegree perineal tear. There were no ectopic pregnancies, maternal or neonatal deaths, or reports of infant cataracts or congenital malformations. Median gestational age was 37/40 weeks (range 29-40). Mode of delivery was via cesarean section in 45% (n = 10/22, of which twowere emergency) and vaginal in 55% (n = 12/22), of which 83% (n = 10/12) were via induction of labor for diabetes (CF or gestational) indication. Deliveries were supported and occurred equally at local obstetric units and in tertiarycare obstetric hospital settings (50%, n = 11/22). Patient-experience survey responses cited high levels of confidence in health optimization and prioritization during pregnancy and praised excellent inter-health care provider communication and peer-to-peer emotional support provided among expectant mothers in the virtual prenatal exercise groups. Table 1. Baseline demographic and clinical characteristics of elexacaftor/tezacaftor/ivacaftoreligible expectant mothers according to therapeutic decision (Table Presented) Conclusion(s): In the absence of clinical trial safety data, the novel approach of a dedicated CF-maternal health multidisciplinary team clinic with local obstetric outreach support has ensured regular specialist clinical and emotional peer-to-peer support for this cohort of women eligible for ELX/ TEZ/IVA to ensure optimal outcomes and experiences of their pregnancies, where appropriate, close to home.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

The feasibility and advantages of an at-home intravesical therapy service for benign conditions

Introduction & Objectives: Intravesical instillations of GAG-layer replacement are utilised in a number of benign bladder conditions and are traditionally delivered in an outpatient setting. Our unit was considering the feasibility of an at-home service when the COVID-19 pandemic resulted in the sudden cancellation of non-essential services. This provided impetus to rapidly change service delivery so this effective therapy could continue to be available. Here we outline the implementation of an at-home intravesical therapy service & report on early patient satisfaction outcomes. Materials & Methods: The product was chosen based on local use and practical advantages. Collaboration with the company ensured optimal planning and initiation. Review of regulations & cost-effective analysis led to dispensation via a community pharmacy after appropriate tuition. Patients were identified via the unit's intravesical treatment database. Inclusion criteria were the willingness to learn intermittent catheterisation, to have the medication administered at home, and to conduct telephone review. Tuition was delivered by qualified urology nurses in a single 30-60 minute session, utilising video and diagrams. Patients that were shielding were instructed by community bladder nurses. PROMS data were collected via a unit-designed questionnaire. Clinical outcome data were collected from follow-up notes. Results: Between March 2020 and January 2021, 65 patients (mean age 50 years) commenced at-home therapy. 22 (88%) were female. The first patient was instructed 11 days after compulsory cessation of outpatient instillations. Efficacy was 65%-83% across different indications (bladder pain, recurrent UTIs, chemical cystitis, radiation cystitis & ketamine bladder). 25 patients returned the PROMS questionnaire. 20 had previously had outpatient nurse-delivered instillations, 5 were treatment naive. 20 performed self-catheterisation, 1 used the adapter, 4 received assistance from a relative/carer. Whilst some patients reported difficulty with catheter insertion, medicine instillation and/or UTI following administration, 72% completed the course at home. 11/20 experiencing both service models preferred at-home administration;9/20 preferred the hospital option. Positive feedback for at-home treatment included convenience, time saved, and privacy. Concerns were centred on technical aspects. Overall satisfaction was reported as very good, good or satisfactory by 18 (72%), and was linked to ability to continue treatment. Savings in our unit per treatment course or treatment year ranged between £180 & £470, dependent on the number of overall treatments. Conclusions: This study shows radical service change can be implemented quickly, safely and effectively. Careful patient selection and tuition enables cost-savings, freeing of outpatient space and improved patient satisfaction. We encourage other institutions to consider commencement of an at-home instillation service.

Rollout of Kaftrio® to adult cystic fibrosis patients at the Royal Brompton Hospital during a global pandemic

Objectives: To review the rollout process for Kaftrio® at this large adult CF Centre following approval by the European Medicines Agency (EMA) in June 2020, EMA marketing authorisation and commissioning by NHS England on 21st August 2020, taking into consideration the limitations imposed on clinical services due to COVID-19. Methods: Recent rollout of Symkevi® meant that this adult CF service had already developed processes for the identification of suitable patients and medication distribution. Due to COVID-19 restrictions, innovative methods for clinical review, patient discussion, testing for liver function and occasionally genotype were developed. Furthermore, contract extensions and new paperwork for Homecare companies had to be produced as medication was delivered to patients’ homes. This established process involving multidisciplinary digital consultations, Bluetooth spirometry and self-administered postal blood tests was therefore replicated. Additionally, to ensure access for as many patients as possible we re-checked some genetic mutation results, especially where diagnosis pre-dated current testing technology. Results: This table shows the rate at which our patients were able to access Kaftrio®. Two thirds of patients had access to Kaftrio® a month after it was commissioned and 265 of the 348 eligible patients were taking Kaftrio® within 2 months. [Table presented] Conclusion: Using our experience from the launch of Symkevi®, we were able to adapt to this much larger rollout to despite the limitations imposed by the pandemic. To ensure that patients would benefit from early access we started putting processes in place before Kaftrio® was licensed by the EMA. As soon as commissioning was announced by NHS England, we were ready to start prescribing. This allowed our patients to access Kaftrio® very quickly with 144 out of 348 eligible patients taking their initial dose just over 2 weeks later and 286 patients on treatment after just over 2 months.

Unique cardiometabolic immune signatures in severe-COVID-19 patients and survivors

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly pathogenic corona virus which causes COVID-19 and resulted in millions of deaths and led to a global public health emergency. SARS-CoV-2 infected patients exhibit a wide variety of clinical manifestations ranging from asymptomatic to severe complications and death. SARS-CoV-2 infection can lead to excessive immune activation, inflammation and multi-organ damage. Clinical data showed that COVID-19 may promote the development of cardiovascular disorders (CVDs). Immune activation, thrombosis, cytokine storm, and altered adhesion molecule expression on leukocyte populations, have been proposed as possible mechanisms that trigger COVID-19 associated CVDs. A lack of systematic studies on how SARS-CoV-2 infection triggered immune responses that may lead to CVDs, hinder early risk identification and therapeutic interventions. Methods: In this study, by using deep immune cell profiling (high dimensional flowcytometry) in fresh whole blood and extensive plasma cytokine and chemokine profiling, we explore potential mechanisms that could lead to CVDs in severe COVID-19 patients that did not have previous known CVDs (ICU) (n=20) as well as patients recovered from COVID-19 (RD) (n=30) compared to healthy donors (n=17). To identify the major statistically significant immune signatures that predict CVD risk in ICU patients and RD, we performed parametric (ANOVA) and non-parametric (Kruskal-Wallis) statistical tests with Dunn's and Tukey's post hoc tests. Integrative correlation and network analysis were performed by computing Spearman's coefficients. Correlations with r > 0.3 , r <-0.3 and P < 0.01 were considered significant. Results: We found that significantly elevated eosinophils, neutrophils and increased circulating levels of tissue factor, fatty acid binding protein 4 and, LPS binding protein in ICU patients suggested increased immune activation and thrombotic risk. Interestingly, we found significant elevation of several immune parameters (TIMP-1, TIMP-2, M-CSF, Monocytes) that were associated with cardiometabolic risk, even 3-4 months after the recovery of initial COVID-19 infection in RD. Furthermore, we found unique relationship with cytokine and cellular responses in ICU and RD groups compare with HD. Conclusion: Our data strongly suggest a possible mechanistic link between SARS-CoV-2 induced dysregulated immune responses and increased cardiometabolic risk in severe COVID-19 patients.