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.

Asthma, bronchial hyperresponsiveness, allergy and lung function development until early adulthood: A systematic literature review.

BACKGROUND: It is unclear in which periods of life lung function deficits develop, and whether these are affected by risk factors such as asthma, bronchial hyper-responsiveness (BHR) and allergic comorbidity. The goal of this systematic review was to identify temporal associations of asthma, BHR and allergic comorbidity with large and small lung function development from birth until peak function in early adulthood. METHODS: We searched MEDLINE, EMBASE, Web of Science and CINAHL for papers published before 01.01.2020 on risk factors and lung function measurements of large and small airways. Studies were required to report lung function at any time point or interval from birth until peak lung function (age 21-26) and include at least one candidate risk factor. RESULTS: Of the 45 papers identified, 44 investigated cohorts and one was a clinical trial with follow-up. Asthma, wheezing, BHR and allergic sensitization early in life and to multiple allergens were associated with a lower lung function growth of large and small airways during early childhood compared with the control populations. Lung function development after childhood in subjects with asthma or persistent wheeze, although continuing to grow at a lower level, largely tracked parallel to non-affected individuals until peak function was attained. CLINICAL IMPLICATIONS AND FUTURE RESEARCH: Deficits in lung function growth develop in early childhood, and children with asthma, BHR and early-life IgE (poly)sensitization are at risk. This period is possibly a critical window of opportunity to identify at-risk subjects and provide treatment aimed at preventing long-term sequelae of lung function.

Differences in lung clearance index and functional residual capacity between two commercial multiple-breath nitrogen washout devices in healthy children and adults.

Multiple-breath nitrogen washout (MBNW) and its clinical parameter lung clearance index (LCI) are gaining increasing attention for the assessment of small airway function. Measurement of LCI relies on accurate assessment of functional residual capacity (FRC). The EasyOne Pro LAB (ndd) and Exhalyzer D (EM) are two commercially available MBNW devices. The aim of the study was to compare these two devices in vitro and in vivo in healthy subjects with regard to FRC, LCI and secondary outcome parameters and to relate FRCMBNW to FRC measured by body plethysmography (pleth) and helium dilution technique. MBNW measurements were performed using a lung model (FRC between 500 and 4000 mL) in vitro and in 38 subjects aged 6-65 years followed by helium dilution and pleth in vivo using fixed and relaxed breathing techniques. In vitro accuracy within 5% of lung model FRC was 67.3% for ndd, FRC was >5% higher for EM in all tests. In vivo, FRCpleth ranged from 1.2 to 5.6 L. Mean differences (limits of agreement) between FRCpleth and FRCMBNW were -7.0%, (-23.2 to 9.2%) and 5.7% (-11.2 to 22.6%) using ndd and EM, respectively. FRCndd was consistently lower than FRCEM (-11.8% (-25.6 to 2%)). LCI was comparable between the two devices (-1.3% (-21.9 to 19.3%)). There was a difference of >10 % in LCI in 12 of 38 subjects. Using the most recent software updates, both devices show relevant deviations in FRC measurement both in vitro and in vivo and individual differences in LCI in a significant proportion of subjects. The devices are therefore not interchangeable.

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'.

[A child with an oesophageal foreign body for 1.5 years]. / Kind met 1,5 jaar een corpus alienum in de oesofagus.

A 2-year-old boy presented with a 1.5-year history of recurrent cough, wheeze and feeding problems. An x-ray of the thorax and an oesophagogram showed constriction of the trachea and proximal portion of the oesophagus. On endoscopy a foreign body was found, embedded in extensive granulation tissue. This could only be removed surgically via oesophagotomy, and turned out to be a plastic toy coin.

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.