Association between CFTR modulators and changes in iron deficiency markers in cystic fibrosis.

BACKGROUND: Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID. METHODS: In a multicenter retrospective cohort study across 4 United States CF centers 2012-2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 µg/dL (<10.7 µmol/L). RESULTS: A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3-10.6 %; p < 0.0001) and +34.4 µg/dL serum iron (95 % CI, +26.7-42.1 µg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8-8.0 %; p = 0.0001) and +22.1 µg/dL serum iron (95 % CI, +13.5-30.8 µg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9-14.8 %; p < 0.0001) and +46.0 µg/dL serum iron (95 % CI, +33.3-58.8 µg/dL; p < 0.0001) in males. Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT). CONCLUSIONS: ID remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin).

Use of CFTR modulators in special populations, part 1: Pregnancy and lactation.

Safety and efficacy data regarding cystic fibrosis transmembrane conductance regulator (CFTR) modulator use in the setting of pregnancy or breastfeeding remains lacking due to exclusion from key trials and lack of multicenter prospective and retrospective studies in the post-CFTR modulator era. A scoping review of English articles from the period of January 1, 2012, to July 31, 2023, was conducted utilizing PubMed and EmBase databases with the following terms: "special population (pregnancy, lactation, breastfeeding)" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use." Search results were reviewed by title and abstract for duplications and relevance. Relative to pregnancy or breastfeeding, a total of 18 publications were included for review. Majority of case reports and surveys concluded maternal and infant health were preserved throughout gestation. Likewise, breastfeeding infant case reports show possible changes in liver function and lens opacities, though risk may be increased with both in-utero and breastfeeding exposure. Ivacaftor (IVA) and lumacaftor (LUM) concentrations in fetal cord blood and maternal blood were found to be equivalent. Yet, low concentrations of IVA and LUM were detectable in breastmilk and infant plasma. Current safety data surrounding CFTR modulator use in the setting of pregnancy and lactation is relatively reassuring; however, long-term safety remains unclear, necessitating ongoing observation, and reporting by care teams. As such, treatment decisions should be individualized and coproduced.

Use of CFTR modulators in special populations, part 2: Severe lung disease.

Safety and efficacy data surrounding cystic fibrosis transmembrane regulator (CFTR) modulator administration for people with CF (pwCF) and severe lung disease elect has remained unclear as a result of exclusion from key trials. A scoping review of English language articles from the period of 1 January 2012, to 31 July 2023 was conducted utilizing PubMed and EmBase databases with the following terms: "severe lung disease" OR "advanced lung disease" AND "ivacaftor OR lumacaftor OR tezacaftor OR elexacaftor"; "cystic fibrosis transmembrane conductance regulator" AND "off label drug use." Search results were reviewed by title and abstract for relevance. Twenty articles specific to CFTR modulator use in the setting of severe lung disease were included for review, with few specific to pediatric-aged pwCF. PwCF and severe lung disease experienced significant improvement in pulmonary function, body weight, number of IV antibiotic days, and quality of life. A few studies reported a transient decline in pulmonary function among pwCF shortly after LUM/IVA initiation. However, preemptive reductions in the dose of LUM/IVA may mitigate this reaction. ELE/TEZ/IVA utilization in pwCF and severe lung disease appears to be devoid of the transient decline in pulmonary function observed with LUM/IVA while providing the same clinical benefit. Current available data regarding use of CFTR modulators in pwCF and severe lung disease is reassuring; however, there remains a lack data regarding outcomes among the pediatric population including long-term outcomes. Therefore, treatment decisions should be individualized and coproduced.

Comparison of Transplant Pharmacist Treatment Decisions Between Telehealth and Clinic Visits.

Introduction: Implementation of telehealth in high-risk patient populations provides opportunities for continuous interactions and has previously been shown to positively impact practice. However, there is a paucity of studies focused on telehealth in the liver transplant population specific to pharmacist care. Project Aim: Describe the importance of transplant pharmacist treatment decisions between telehealth, in-clinic, and asynchronous (eg chart review and electronic message support) visit types. Design: This was a single-center comparative evaluation of adult liver transplant recipients transplanted between May 1, 2020 and October 31, 2020 with a transplant pharmacist visit between May 1, 2020 and November 30, 2020. The primary outcome was the average number of treatment decisions per encounter and the average number of important treatment decisions per encounter. The importance of these treatment decisions was determined by a panel of three clinicians. Results: Twenty-eight patients met the inclusion criteria with 85 in-clinic, 42 telehealth, and 55 asynchronous visits. For all treatment decisions, there was no statistical difference in average number of treatment decisions per encounter between telehealth visits and in-clinic visits with an odds ratio (OR) of 0.822 (95% CI, 0.674-1.000; P = 0.051). Similarly, for important treatment decisions, there was no statistical difference between telehealth visits and in-clinic visits (OR 0.847; 95% CI, 0.642-1.116; P = 0.238). Conclusion: Transplant pharmacists can deliver recommendations with similar importance via telehealth compared to in-clinic visits based on the number of total and important treatment decisions.

Use of CFTR modulators in special populations, part 3: Solid organ transplant.

BACKGROUND: Solid organ transplant (SOT) recipients with cystic fibrosis (CF) may benefit from the pulmonary and extrapulmonary benefits associated with CF transmembrane conductance regulator modulators. Nevertheless, evolution of modulator safety and efficacy data prompts consideration. METHODS: The search terms "transplant" AND "ivacaftor"(IVA) OR "lumacaftor"(LUM) OR "tezacaftor" (TEZ) OR "elexacaftor" (ELX) were utilized to conduct a scoping review of English articles from the period of January 1, 2012 to December 31, 2022. Search results from PubMed and Embase databases were reviewed by title and abstract for relevance. Included studies reported efficacy and safety outcomes of modulators in SOT recipients. RESULTS: One hundred thirty-six patients from one cohort study (90 lung transplant recipients) and eight case reports and series (29 lung transplant recipients, 16 liver transplant recipients and one lung/liver transplant patient) were included. Post-modulator initiation, 33 patients did not necessitate tacrolimus dose adjustments, 10 required dose uptitration, and 43 required dose reductions. Moreover, LUM/IVA use with azole antifungals may lead to subtherapeutic levels but opposing effects sustained tacrolimus levels. Liver transplant recipients were more likely to experience elevations in transaminases requiring pharmacologic or medical interventions. Majority of patients experienced improvements in pulmonary function, fasting blood glucose, hemoglobin, body mass index, and rhinosinusitis symptoms. However, intolerance or lack of benefit prompted discontinuation of ELX/TEZ/IVA in over 40% of lung-transplant recipients in one study. CONCLUSION: Modulator therapy has been reported to produce pulmonary and extra-pulmonary benefits in the CF population with SOT. Considerations for modulator therapy initiation ought to include modulator pharmacokinetics, concomitant medications, and transplant type due to the complex nature of SOT recipients.

Acute kidney injury in cystic fibrosis patients treated with intravenous colistimethate sodium or tobramycin.

OBJECTIVES: Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin. METHODS: This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI. RESULTS: Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI. CONCLUSIONS: Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.

Evaluation of targeted versus universal prophylaxis for the prevention of invasive fungal infections following lung transplantation.

BACKGROUND: Antifungal prophylaxis to prevent invasive fungal infections (IFI) is widely used following lung transplantation, but the optimal strategy remains unclear. We compared universal with targeted antifungal prophylaxis for effectiveness in preventing IFI. METHODS: Adult patients who underwent lung transplantation at the University of Michigan from /1 July 2014-31 December 2017 were studied for 18 months post-transplant. Universal prophylaxis consisted of itraconazole with or without inhaled liposomal amphotericin B. Using specific criteria, targeted prophylaxis was given with voriconazole for patients at risk for invasive pulmonary aspergillosis (IPA) and with fluconazole or micafungin for patients at risk for invasive candidiasis. Risk factors, occurrence of proven/probable IFI, and mortality were analyzed for the two prophylaxis cohorts. RESULTS: Of 105 lung transplant recipients, 84 (80%) received a double lung transplant, and 38 (36%) of patients underwent transplant for pulmonary fibrosis. Fifty-nine (56%) patients received universal antifungal prophylaxis, and 46 (44%), targeted antifungal prophylaxis. Among 20 proven/probable IFI, there were 14 IPA, 4 invasive candidiasis, 1 cryptococcosis, and 1 deep sternal mold infection. Six (10%) IFI occurred in the universal prophylaxis cohort and 14 (30%) in the targeted prophylaxis cohort. Five of 6 (83%) IFI in the universal prophylaxis cohort, compared with 9/14 (64%) in the targeted prophylaxis cohort, were IPA Candida infections occurred only in the targeted prophylaxis cohort. The development of IFI was more likely in the targeted prophylaxis cohort than the universal prophylaxis cohort, HR = 4.32 (1.51-12.38), P = .0064. CONCLUSIONS: Universal antifungal prophylaxis appears to be more effective than targeted antifungal prophylaxis for prevention of IFI after lung transplant.

Oropharyngeal candidiasis outcomes in renal transplant recipients receiving nystatin versus no antifungal prophylaxis.

OBJECTIVE: To compare the incidence of oropharyngeal candidiasis (OC), or thrush, in renal transplant recipients receiving nystatin versus no antifungal prophylaxis. METHODS: This was a single-center, retrospective, non-inferiority study of adult renal transplant recipients (RTRs) who received nystatin for 30 days for OC prophylaxis (nystatin group) or no antifungal prophylaxis therapy (No PPX group). The primary outcome was the incidence of OC within 3 months post-transplant. Secondary outcomes included time to OC occurrence and severity of OC. The pre-specified non-inferiority margin was 10%. RESULTS: The incidence of OC within 3 months post-transplant among 257 RTRs was 7.8% (10/128) in the No PPX group and 4.7% (6/129) RTRs in the nystatin group, a risk difference of 3.2% (95% CI, -2.7% to 9.1%, non-inferiority P = .04). The median time to OC was 7.5 days (IQR 6.3-34.3 days) in the nystatin group and 9.5 days (IQR 5.3-30.5 days) in the No PPX group (P = .64). Esophageal candidiasis was observed in 10% (1/10) of RTRs with OC in the No PPX group compared to 16.7% (1/6) RTRs in the nystatin group (P = 1.00). All RTRs with OC achieved symptom resolution with fluconazole and/or nystatin. Two patients in the No PPX group required readmission for decreased oral intake, and OC was diagnosed and treated during their hospital day. CONCLUSIONS: In this retrospective study of adult RTRs, the absence of antifungal prophylaxis demonstrated non-inferiority to 30-day nystatin prophylaxis at reducing the incidence of OC within 3 months of transplant. OC prophylaxis may not be warranted after renal transplant.