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.

The mitigating effect of exogenous carbon monoxide on chronic allograft rejection and fibrosis post-lung transplantation.

BACKGROUND: Small airway inflammation and fibrosis or bronchiolitis obliterans (BO) is the predominant presentation of chronic lung allograft dysfunction (CLAD) post-lung transplantation. Carbon monoxide (CO) is a critical endogenous signaling transducer with known anti-inflammatory and anti-fibrotic effects but its therapeutic potential in CLAD remains to be fully elucidated. METHODS: Here we investigate the effect of inhaled CO in modulating chronic lung allograft rejection pathology in a murine orthotopic lung transplant model of BO (B6D2F1/J→DBA/2J). Additionally, the effects of CO on the activated phenotype of mesenchymal cells isolated from human lung transplant recipients with CLAD were studied. RESULTS: Murine lung allografts treated with CO (250 ppm × 30 minutes twice daily from days 7 to 40 post-transplantation) demonstrated decreased immune cell infiltration, fibrosis, and airway obliteration by flow cytometry, trichrome staining, and morphometric analysis, respectively. Decreased total collagen, with levels comparable to isografts, was noted in CO-treated allografts by quantitative hydroxyproline assay. In vitro, CO (250 ppm × 16h) was effective in reversing the fibrotic phenotype of human CLAD mesenchymal cells with decreased collagen I and ß-catenin expression as well as an inhibitory effect on ERK1/2 MAPK, and mTORC1/2 signaling. Sildenafil, a phosphodiesterase 5 inhibitor, partially mimicked the effects of CO on CLAD mesenchymal cells and was partially effective in decreasing collagen deposition in murine allografts, suggesting the contribution of cGMP-dependent and -independent mechanisms in mediating the effect of CO. CONCLUSION: These results suggest a potential role for CO in alleviating allograft fibrosis and mitigating chronic rejection pathology post-lung transplant.

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.

Palliative care aspects of wound healing in complex patients: a case report.

DECLARATION OF INTEREST: The authors have no conflicts of interest to declare.

Comparison of standard versus low-dose valganciclovir regimens for cytomegalovirus prophylaxis in high-risk liver transplant recipients.

PURPOSE: The purpose of this study was to compare the safety and efficacy of two valganciclovir (VGCV) institutional dosing protocols for cytomegalovirus (CMV) prophylaxis in liver transplant (LT) recipients with CMV serotype donor +/recipient- (D+/R-). METHODS: This was a single-center review of CMV D+/R- adult LT recipients who received VGCV 450 mg/day for 90 days (low-dose) or VGCV 900 mg/day for 180 days (standard-dose). The primary outcome was incidence of CMV disease at 1 year. Secondary outcomes included rates of CMV syndrome, end-organ disease, breakthrough infection, and resistance. Neutropenia, early discontinuation of VGCV, growth colony stimulating factors use (G-CSF), biopsy-proven rejection (BPAR), graft loss, and death at 1 year were analyzed. RESULTS: Ninety-six CMV D+/R- LT recipients were included. Although no difference in CMV disease was observed (low-dose 26% vs. standard-dose 23%, p = 0.71), 75% of CMV infections in the low-dose group presented with end-organ disease. Ganciclovir (GCV) resistance was observed only in the low-dose group (n = 2). Significantly more patients in the standard-dose group developed neutropenia (low-dose 10% vs 60% standard-dose, p < 0.001). In the standard-dose group, 29% required early discontinuation of VGCV (vs. 5% in the low-dose group, p < 0.001), and 20% were treated with G-CSF. Both cohorts had similar rates of BPAR, graft loss, and death at 1 year. CONCLUSIONS: VGCV 900 mg/day for 180 days had higher rates of hematologic adverse effects resulting in frequent treatment interruptions. However, the occurrence of two cases of GCV-resistant CMV disease raises concerns about routinely using low-dose VGCV prophylaxis.

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.

Comparison of Vancomycin Pharmacokinetics in Cystic Fibrosis Patients Pre and Post-lung Transplant.

BACKGROUND: Vancomycin is commonly used to treat acute cystic fibrosis (CF) exacerbations associated with methicillin-resistant Staphylococcus aureus (MRSA). Multiple studies have demonstrated pharmacokinetic differences of antimicrobials in the CF population. Very little data exist regarding pharmacokinetics postlung transplant, but 2 studies have noted changes in tobramycin pharmacokinetics. No such studies exist evaluating vancomycin in CF patients postlung transplant. METHODS: A retrospective cohort review of CF patients who underwent lung transplantation and received vancomycin pre- and posttransplant was conducted. CF patients who underwent transplant between 2007 and 2016 at 4 medical centers throughout the United States were included. The primary endpoint was the change in elimination rate constant. The secondary endpoints were subgroup analyses of patients grouped by age, time posttransplant, and number of nephrotoxic medications. RESULTS: A total of 25 patients were included, of which just under half were pediatric. Patients were significantly older and heavier posttransplant and had higher serum creatinine and number of nephrotoxic medications. The change in elimination rate constant from pre- to posttransplant was -0.50 hr-1 which was statistically significant (P < .001). This significant decrease was consistent among all subgroups of patients evaluated with the exception of pediatric patients. CONCLUSION: Vancomycin pharmacokinetics are significantly altered in CF patients in the posttransplant setting as evidenced by a decrease in elimination rate constant. This decrease may be related to a decrease in renal clearance and higher numbers of nephrotoxic medications posttransplant. Regardless, pretransplant vancomycin regimens may not predict appropriate posttransplant regimens.

Impact of direct-acting antivirals for hepatitis C virus therapy on tacrolimus dosing in liver transplant recipients.

INTRODUCTION: Direct-acting antivirals (DAAs) have transformed hepatitis C virus (HCV) management post-liver transplant. As HCV clears during DAA treatment, hepatic metabolism improves, resulting in decreased tacrolimus concentrations that may require dose adjustment. The purpose of this study was to determine appropriate management of immunosuppression in liver transplant recipients during and following treatment of HCV. METHODS: This study was a single-center retrospective analysis of 71 liver transplant recipients who were treated for HCV with DAAs. The primary outcome was change in dose-normalized tacrolimus concentrations from the start of DAA treatment to 12 weeks following therapy. RESULTS: The mean change in log-transformed dose-normalized tacrolimus concentrations was a reduction of 0.43 ng/mL/mg (95% CI; 0.26-0.60, P < 0.0001). The greatest decrease occurred in the first 4 weeks of treatment, after which levels stabilized. The overall mean tacrolimus concentration was 4.8 ng/mL (±2.5). Two patients (3%) developed acute cellular rejection and two patients (3%) had graft loss and died. CONCLUSION: From the start of treatment to 12 weeks post-DAA therapy, liver transplant recipients experienced a significant decrease in dose-normalized tacrolimus concentrations. In conclusion, close monitoring of tacrolimus concentrations is warranted during and following treatment with DAAs, as dose increases may be indicated in order to maintain therapeutic concentrations to prevent graft rejection.

Safety and Efficacy of Biologic Agents for the Management of Inflammatory Bowel Disease After Liver Transplantation.

Primary sclerosing cholangitis (PSC) frequently progresses to end-stage liver disease and cirrhosis, requiring liver transplantation. Approximately 70% of patients with PSC have concomitant inflammatory bowel disease (IBD) during their clinical course. After liver transplantation for PSC, corticosteroids and other high-intensity immunosuppressants are initiated to keep IBD in remission. Patients with IBD that is refractory to these agents may need to be managed with biologic therapies. Biologic agents, however, may further increase the risks for malignancy and infection due to their immunosuppressive effects. Thus, to gain a better understanding of the risks and benefits of these agents in this high-risk patient population, we performed a literature search of the PubMed database (2002-2017) to identify studies assessing the efficacy and safety of various biologic agents for the management of IBD in liver transplant recipients. No randomized controlled studies or retrospective comparative studies were identified; however, 15 case reports and case series were identified that met our inclusion criteria. From these case reports, we identified 67 patients who developed de novo or recurrent IBD after liver transplantation and received anti-tumor necrosis factor-α or anti-integrin therapy. Of the 13 published cases reporting clinical response or remission of IBD activity in liver transplant recipients (59 patients), clinical response or remission of IBD was reported in 38 (64.4%) of those patients. Adverse complications reported included cholangitis, oral candidiasis, Clostridium difficile colitis, bacterial pneumonia, cryptosporidiosis, Epstein-Barr virus-positive posttransplantation lymphoproliferative disease, and hepatotoxicity. Given the limited literature (case reports and case series) highlighted in this review, biologic agents such as tumor necrosis factor-α inhibitors and integrin inhibitors commonly used for moderate to severe IBD may be appropriate after liver transplantation; however, consideration of risk versus benefit should always occur in a patient-specific manner.

Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1ß processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1ß maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1ß secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.