Histological characterization of liver involvement in systemic mastocytosis.

BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Health care resource utilization preceding death or lung transplantation in people with cystic fibrosis: HCRU before transplant or death in cystic fibrosis.

BACKGROUND: We studied the health care resource utilization (HCRU) and associated costs in the year preceding LT in pwCF or death without LT, and we estimated the overall cost of LT. METHODS: We performed a linkage between 2006 and 2017 data from the French CF Registry (FCFR) and the French health claims database (Système National des Données de Santé; SNDS). The HCRU and associated costs were described the year before LT or before death without LT, and two years after LT. RESULTS: Among the 7,671 patients included in the FCFR, 6,187 patients (80.7 %) were successfully matched to patients in the SNDS (males (m): 51.9 %, mean±SD age at the end of follow-up: 24.6 ± 13.6). Overall, 166 patients died without LT (m: 47.6 %, age at death: 30.4 ± 14.5) and 767 patients with primary LT (m: 48.2 %, age at transplantation: 28.0 ± 9.1) were identified. HCRU was lower among patients who died without receiving LT, with marked differences in the cost of hospital stays. The mean total cost per patient was €66,759 ± 38,249 in the year before death, €149,374 ± 62,678 in the year preceding LT, €63,919 ± 35,399 in the first year following LT, and €42,813 ± 39,967 in the second year of follow-up. CONCLUSION: Our results indicate that HCRU was two times lower in the year before death in non-transplant pwCF than in the year before LT, which may reflect inappropriate care of CF in patients who died without receiving LT. It also shows the cost associated with LT.

Multisystemic Effects of Elexacaftor-Tezacaftor-Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease.

Rationale: Limited data exist on the safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. Objectives: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. Methods: A prospective observational study, including all adults aged 18 years and older with percentage predicted forced expiratory volume in 1 second (ppFEV1) ⩽ 40 who initiated ETI from December 2019 to June 2021 in France, was conducted. PwCF were followed until August 8, 2022. Results: ETI was initiated in 434 pwCF with a median ppFEV1 of 30 (interquartile range, 25-35), including 27 with severe cystic fibrosis liver disease and 183 with diabetes. PwCF were followed for a median of 587 (interquartile range, 396-728) days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was due mostly to lung transplantation (n = 5) or death (n = 4). Absolute increase in ppFEV1 by a mean of +14.2% (95% confidence interval, 13.1-15.4%) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the youngest age quartile was almost twice that of the oldest quartile (P < 0.001); body mass index < 18.5 kg/m2 was found in 38.6% at initiation versus 11.3% at 12 months (P = 0.0001). Increases in serum concentrations of vitamins A and E, but not 25-hydroxy vitamin D3, were observed. Significant reductions in the percentages of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, and inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of patients with diabetes. Conclusions: ETI is safe in pwCF and advanced lung disease, with multisystem pulmonary and extrapulmonary benefits.

Ophthalmic vascular manifestations in eosinophil-associated diseases: a comprehensive analysis of 57 patients from the CEREO and EESG networks and a literature review.

Introduction: Eosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia. Methods: We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x109/L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations. Results: Fifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher's retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x109/L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x109/L in all cases (n=4). Discussion: This study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented.

The expanded French compassionate programme for elexacaftor-tezacaftor-ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response. METHODS: The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France's 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses. FINDINGS: The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV1 (ppFEV1) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV1 was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor. INTERPRETATION: In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population. FUNDING: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.

Standards for the care of people with cystic fibrosis (CF); recognising and addressing CF health issues.

This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey.