Medication adherence to CFTR modulators in patients with cystic fibrosis: a systematic review.

BACKGROUND: In the last decade, a fundamental shift in the treatment of cystic fibrosis (CF) took place due to the introduction of CF transmembrane conductance regulator (CFTR) modulators. Adequate medication adherence is a prerequisite for their effectiveness, but little is known about adherence to CFTR modulators. We aimed to assess the extent of medication adherence to CFTR modulators in patients with CF and assess which characteristics are associated with adherence. METHODS: A systematic review following PRISMA guidelines was performed. Studies needed to report adherence to CFTR modulators. Main outcomes were: 1) level of medication adherence and 2) associations of demographic and/or clinical characteristics with adherence. RESULTS: In total, 4082 articles were screened and 21 full-text papers were assessed for eligibility. Ultimately, seven studies were included. Most studies were retrospective and focused on adherence to ivacaftor or lumacaftor-ivacaftor with only one focusing on elexacaftor-tezacaftor-ivacaftor. The majority used pharmacy refill data with adherence determined with the proportion of days covered (PDC) or the medication possession ratio (MPR). One study additionally used electronic monitoring and patient self-reported adherence. Adherence was 0.62-0.99 based on pharmacy data (PDC or MPR), 61% via electronic monitoring and 100% via self-report. Age <18 years appeared to be associated with good adherence, as was a higher lung function. CONCLUSIONS: Despite the wide variety of adherence methods used, adherence to CFTR modulators is suboptimal, based on objective measures such as pharmacy refill data or electronic monitoring. CFTR modulator adherence measurement and definitions requires more standardisation with a preference for objective and granular methods.

Comparison of particles in exhaled air and multiple breath washout for assessment of small airway function in children with cystic fibrosis.

BACKGROUND: The introduction of modulator therapy for cystic fibrosis (CF) has led to an increased interest in the detection of small airway disease (SAD) as sensitive marker of treatment response. The particles in exhaled air (PExA) method, which records exhaled particle mass (PEx ng/L) and number (PExNR), detects SAD in adult patients. Our primary aim was to investigate if PExA outcomes in children with CF are different when compared to controls and associated with more severe disease. Secondary aims were to assess feasibility and repeatability of PExA in children with CF and to correlate PExA to multiple breath nitrogen washout (MBNW) as an established marker of SAD. METHODS: Thirteen healthy children (HC), 17 children with CF with normal lung function (CF-N) (FEV1 z-score ≥ -1.64) and six with airway obstruction (CF-AO) (FEV1 z-score < -1.64) between 8 and 18 years performed MBNW followed by PExA and spirometry. Children with CF repeated the measurements after 3 months. RESULTS: PEx ng/L and PExNR/L per liter of exhaled breath were similar between the three groups. The lung clearance index (LCI) was significantly higher in both CF-N and CF-AO compared to HC. All participants, except one, were able to perform PExA. Coefficient of variation for PEx ng/l was (median) 0.38, range 0-1.25 and PExNR/l 0.38, 0-1.09. Correlation between LCI and PEx ng/l was low, rs 0.32 (p = .07). CONCLUSION: PExA is feasible in children. In contrast to LCI, PExA did not differentiate healthy children from children with CF suggesting it to be a less sensitive tool to detect SAD.

Evaluation of a multiple breath nitrogen washout system in children.

INTRODUCTION: The multiple breath nitrogen washout (MBW) test offers a sensitive measure of airway function. In this study we aim to (a) assess the validity of the EasyOne Pro LAB (MBWndd ) in an in vitro lung model, (b) assess the feasibility, repeatability, and reproducibility of MBWndd and (c) compare outcomes with the Exhalyzer D (MBWEM ) and body plethysmography. METHODS: In vitro, functional residual capacity (FRC) measurements were assessed using a lung model under quasi-physiological conditions and compared to measured FRC. In vivo plethysmography and MBW were performed in a prospective study of children at two visits (n = 45 healthy; n = 41 cystic fibrosis [CF]). Bland-Altman plots were used to compare agreement between FRC and lung clearance index (LCI) measurements. RESULTS: In vitro FRCndd measurements were repeatable but lung volumes were underestimated (mean relative difference -5.4% (limits of agreement [LA] -9.6%; -1.1%), 95% confidence interval (CI) -6.27; -4.45). In vivo, compared to plethysmography, FRCndd was consistently lower (-19.3% [-40.5; 1.9], 95% CI [-23.9; -14.7]), and showed a volume dependency. LCIndd values were also higher in children with smaller lung volumes. The within-test coefficient of variation of the FRCndd and LCIndd were 4.9% in health, and 5.6% and 6.9% in CF respectively. LCIndd was reproducible between-visits (mean relative difference [LA] -3.7% [-14.8, -7.5; 95% CI -6.6; -0.73] in health [n = 17] and 0.34% [-13.2, 22.8; 95% CI -5.0; 5.69] in CF [n = 23]). When calculated using the same algorithm, LCIndd was similar to LCIEM in health. CONCLUSIONS: MBWndd measurements are feasible, repeatable, and reproducible, however, MBW-derived outcomes are not interchangeable with MBWEM .

Clinical application of inert gas Multiple Breath Washout in children and adolescents with asthma.

INTRODUCTION: Children with asthma often have normal spirometry despite significant disease. The pathology of the small airways in asthma may be assessed using Multiple Breath Washout (MBW) and calculating the Lung Clearance Index (LCI). There are only few studies using MBW in children with asthma and existing data regarding bronchodilator effect are contradictory. The aim of the present pilot study was to compare LCI in asthma and controls and assess the effect of salbutamol in children with asthma on the LCI. METHODS: Unselected patients with a diagnosis of asthma visiting the outpatient department of our hospital between 04-2010 and 03-2011 were recruited and compared to a healthy control group. MBW was performed as inert gas MBW using sulfurhexafluorid (SF6) as the tracer gas. Clinical data were documented and spirometry and MBW (EasyOne Pro, MBW module, NDD Switzerland) were performed before and after the use of salbutamol (200-400 µg). Healthy controls performed baseline MBW only. RESULTS: 32 children diagnosed with asthma (4.7-17.4 years) and 42 controls (5.3-20.8) were included in the analysis. LCI differed between patients and controls, with a mean LCI (SD) of 6.48 (0.48) and 6.21 (0.38) (P = 0.008). Use of salbutamol had no significant effect on LCI for the group. CONCLUSION: These pilot data show that clinically stable asthma patients and controls both have a LCI in the normal range. However, in patients the LCI is significantly higher indicating that MBW may have a role in assessing small airways disease in asthma.

Importance of neutropenia for development of invasive infections at various phases of treatment for hemato-oncological diseases in children.

INTRODUCTION: Prolonged neutropenia in patients with acute myeloid leukemia (AML), relapsed acute lymphoblastic leukemia (r-ALL), myelodysplastic syndrome (MDS), and those receiving hematopoietic stem cell transplantation (HSCT), is a well-known risk factor for infectious complications. Few data are available about the incidence and etiology of infectious episodes during the total treatment period associated with a decreased immunity. METHODS: Between January 2000 and December 2005 children diagnosed with AML, r-ALL, and MDS, and post-HSCT patients were included in the study. A retrospective review based on microbiological data was performed to describe the incidence and etiology of the infectious complications during the total treatment period. RESULTS: One hundred and thirty disease-specific patient episodes were included. Forty-two percent of 184 microbiologically proven infectious episodes were diagnosed in patients receiving chemotherapy, and 58% occurred in HSCT patients. During neutropenia, 123 (67%) infectious episodes were diagnosed; of the isolated species 83% were bacterial, 6% fungal, and 11% viral. In the period without neutropenia, 61 (33%) infectious episodes were diagnosed, with 38% bacterial, 3% fungal, and 59% viral species isolated. Of the infectious episodes diagnosed in patients treated with an HSCT, 52% (n = 55) occurred in the post-engraftment period. In contrast, in patients treated with chemotherapy, 92% of the infectious episodes were diagnosed during neutropenia. CONCLUSION: The number of proven infectious episodes in post-HSCT patients was not influenced by the presence of neutropenia, while in patients receiving chemotherapy significantly lower numbers of proven infectious episodes were diagnosed outside the neutropenic period.

[A neonate with a skin rash post partum]. / Een neonaat met huiduitslag direct post partum.

A term-born boy presented with a rash immediately post partum, consisting of erosions, crusts and a few vesicles. Skin biopsy showed dermal infiltration of S100 and CD1a immunopositive histiocytes. The diagnosis was 'congenital Langerhans cell histiocytosis of the skin'.

Disseminated aspergillosis in an adolescent with acute lymphoblastic leukemia.

Disseminated aspergillosis in immunocompromised patients has a mortality rate of almost 100%. Despite the development of new antifungal agents, the outcome of disseminated aspergillosis has only improved slightly, particular in patients with central nervous system (CNS) involvement. The use of combination antifungal therapy might improve the dismal outcome of disseminated aspergillosis. We describe a critically ill adolescent with acute lymphoblastic leukemia who was successfully treated with voriconazole and caspofungin for disseminated aspergillosis with involvement of the lung, brain and thyroid gland.