"Antibiotic hypersensitivity reactions in Cystic Fibrosis: A thorough inspection on a stumbling block in patient care".

One hurdle in the management of CF, a disease characterized by progressive endobronchial infection, is the presence of hypersensitivity reactions to antimicrobials due to prolonged and repetitive treatment courses. The aim of this review is to compile existing data and provide insight to medical professionals on a long-debated topic for optimum patient care. Clinical studies were inducted from the last 15 years and filtered based on their relativity to drug hypersensitivity reactions (DHRs), antibiotics and CF. After completing the selection process, 10 clinical studies were thoroughly examined. The most frequent antibiotic group related to DHRs were beta-lactams. Frequency of the most common overall type of reaction (immediate or nonimmediate) differed among clinical studies. Although severe reactions seem rare comparatively, they do occur during and even after completion of treatment regimens. The prevalence of true drug allergies should be confirmed using a variety of tests available, however, should not be confused with overall DHR rates. Genetic mutations, gender and lifetime antibiotic dose were not related with an increased risk for DHR development. On the contrary, the most important factor according to most studies was the cumulative antimicrobial dose in a given period of time, especially when delivered parenterally. DHRs are an indisputable problem in the management of CF patients. Understanding possible risk factors and increased awareness is vital in both hospital and outpatient settings as early detection can decrease the severity of the reactions.

The Psychological Impact on Parents of Children who Receive an Inconclusive Diagnosis for Cystic Fibrosis following Newborn Screening: A Systematic Mini-Review.

Newborn screening (NBS) has been available for the diagnosis of cystic fibrosis (CF) over the last decades. Through the implementation of NBS, a new designation emerged, that of CF related metabolic syndrome (CRMS) or cystic fibrosis screen positive inconclusive diagnosis (CFSPID). As there is uncertainty regarding the clinical progression of these infants to CF, some studies have investigated the psychological impact of CRMS/CFSPID on their parents. This systematic narrative review aimed to describe the findings of the relevant studies. The number of studies is limited and the study samples are relatively small. It seems that there is a negative impact of CRMS/CFSPID on parental mental health. While some studies indicated similar levels of parental anxiety among those with infants diagnosed with CF and those with CRMS/CFSPID, not all studies reached the same conclusion. Parental uncertainty represents another mental dimension of the impact associated with the designation of CRMS/CFSPID. These observations suggest that parents of infants with CRMS/CFSPID should be provided with effective communication, and it may also be beneficial to consider parental mental screening. More robust and long-term studies are required to detect differences in parental emotional status between those with infants diagnosed with CF and those with CRMS/CFSPID.

Children with cystic fibrosis are still receiving inconclusive diagnosis despite undergoing newborn screening.

AIM: We aimed to familiarise clinicians with the terms cystic fibrosis transmembrane conductance regulator related metabolic syndrome (CRMS) and cystic fibrosis screen positive inconclusive diagnosis (CFSPID). We also sought to highlight the monitoring and outcomes of children that match these designations. METHODS: A literature review was performed by searching PubMed from its inception until 30 November 2022. All relevant articles were included in this narrative review. RESULTS: Despite the implementation of newborn screening programmes for cystic fibrosis (CF), the diagnosis remains uncertain in some newborn infants with elevated immunoreactive trypsinogen. In 2016, a unified definition for CRMS/CFSPID was established to categorise these children. While many of them remain healthy, a portion of these children may develop CF. As a result, it is crucial to monitor them regularly. CONCLUSION: CRMS/CFSPID is a designation and not a diagnosis. Longer longitudinal studies are needed to shed light on the most appropriate follow-up of these children. Paediatricians need to be knowledgeable about this condition in order to administer proper care, and children should be in contact with their local CF centre.

Dietary intake, weight status, pulmonary function, and metabolic profile in children with cystic fibrosis with or without pancreatic sufficiency.

OBJECTIVE: Nutritional status and growth is well associated with disease outcomes and lung function in patients with cystic fibrosis (CF). Current dietary guidelines for the management of CF suggest a high-calorie, high-fat diet. Pancreatic insufficiency (PI) is present in most patients and contributes to malabsorption and malnutrition, but a considerable number of patients have pancreatic sufficiency (PS). The aim of this study was to compare weight status, clinical characteristics, and dietary intake of children with CF, with PS or PI. METHODS: Patients with a diagnosis of CF (sweat test ≥60 mmol/L) and/or two known mutations for CF, ages 1 to 19 y were included in the study. Weight status, pulmonary characteristics, and blood lipid concentrations were evaluated. Dietary intake was evaluated through four 24-h recalls and energy, macronutrient intake, and intake in terms of food groups were assessed. RESULTS: Included in the present analyses were 134 patients with CF (30 with PS and 104 with PI). The percentage of overweight/obesity (47%) was higher in children with PS than in those with PI (22%). Overall, children with PS had higher body mass index, blood lipid levels, and pulmonary function levels than those with PI (all P < 0.05). Total energy intake was lower in children with PS than in those with PI (P < 0.001), even after adjustment for age and sex (Padj < 0.001). CONCLUSIONS: Weight status, dietary intake, pulmonary function, and lipid profile differed significantly in children with CF by pancreatic status. Nevertheless, the percentage of overweight and obesity was higher in children with PS than in those with PI. To avoid obesity, dietary recommendations for a high-calorie, high-fat diet should be reconsidered in patients with CF regarding their pancreatic status.

Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review.

Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) is a new CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) modulator treatment, used over the last few years, which has shown an improvement in different clinical outcomes in patients with cystic fibrosis (CF). The objective of this study was a systematic research of the literature on the efficacy and safety of this CFTR modulator on patients with CF. A search of Pubmed was conducted for randomized clinical trials and observational studies published from 2012 to September 2022. The included full manuscripts comprised nine clinical trials and 16 observational studies, whose participants were aged ≥12 years or were children 6-11 years old with at least one Phe508del mutation and/or advanced lung disease (ALD). These studies reported that ELX/TEZ/IVA has a significant positive effect on the lung function of patients with CF, by ameliorating parameters such as FEV1, LCI, pulmonary exacerbations or sweat chloride concentration, increasing BMI and improving quality of their life. Its role in cystic fibrosis-related diabetes (CFRD) is not yet clear. It was found that this new CFTR modulator has an overall favorable safety profile, with mild to moderate adverse events. Further studies are needed for a deeper understanding of the impact of CFTR modulators on other CF manifestations, or the possibility of treating with ELX/TEZ/IVA CF patients with rare CFTR mutations.

Changes in Shear Wave Elastography after Lumacaftor/Ivacaftor Treatment in Children with Cystic Fibrosis.

BACKGROUND: Lumacaftor/Ivacaftor (LUM/IVA) is an approved combination therapy for cystic fibrosis (CF) patients homozygous for F508del. OBJECTIVE: This study aimed to detect changes in liver stiffness measurement (LSM) in patients under this treatment. METHODS: The study population consisted of CF patients homozygous for F508del, 6 to 11 years old, who had been treated for six months with LUM/IVA. Shear wave elastography (SWE) was performed in all of them, before and 6 months after the commencement of treatment. RESULTS: Thirty-one patients were included in the study. LSM values after treatment were significantly higher than the values before treatment (medians and interquartile ranges of LSM values before and after treatment: 5.6, 5.3-6.3 kPa and, 6.4, 6.0-7.6 kPa, respectively, p<0.001). CONCLUSION: SWE can detect early changes in LSM in some CF patients treated with LUM/IVA.

A Point Prevalence Survey of Healthcare-Associated Infections and Antimicrobial Use in Public Acute Care Hospitals in Crete, Greece.

BACKGROUND: Both healthcare-associated infections (HAIs) and antimicrobial resistance are associated with an increased length of stay and hospital costs, while they have also been linked to high morbidity and mortality rates. In 2016 and 2017, the latest point prevalence survey (PPS) of HAIs and antimicrobial use in European acute care hospitals highlighted an HAI prevalence of 6.5%, while Greece had a higher HAI prevalence of 10%. The aim of this PPS was to record the prevalence of HAIs and antimicrobial use in all eight public acute care hospitals in Crete, Greece during the COVID-19 pandemic in order to highlight the types of infections and antimicrobial practices that need to be prioritized for infection control initiatives. METHODS: The PPS was conducted between 30 March and 15 April 2022, according to the ECDC standardized relevant protocol (version 5.3). Statistics were extracted using the ECDC Helics.Win.Net application (software version 4.1.0). RESULTS: A total of 1188 patients were included. The overall point prevalence of patients with at least one HAI was 10.6%. The most frequent types of infections were pneumonia (34.3%), bloodstream infections (10.5%), systemic infections and urinary tract infections (10.5% and 9.1%, respectively). In 14 (12.4%) cases, the pathogen responsible for HAI was SARS-CoV-2 following onsite spread, accounting for almost 10% of all HAIs. Microorganisms were identified in 60.1% of HAIs. Antimicrobials were administered in 711 (59.8%) patients, with 1.59 antimicrobials used per patient. CONCLUSION: The prevalence of HAI and antimicrobial use among hospitalized patients in Crete, Greece was similar to the national HAI prevalence in 2016 despite the enormous pressure on public hospitals due to the COVID-19 pandemic. Nevertheless, both HAI prevalence and antimicrobial use remain high, underlining the need to implement adequate infection control and antimicrobial stewardship interventions.

The links between allergen exposure and sensitization in children and adolescents: an overview for the clinician.

INTRODUCTION: The links between allergen exposure and sensitization are complex and depend not only on the type of allergen but on various genetic and environmental factors. AREAS COVERED: This review discusses the link between allergen exposure and atopic sensitization for different types of allergens and the factors that mediate or affect this link. For the purposes of this review search of PubMed was undertaken to identify English language articles using the terms 'sensitization' and 'allergen exposure' and 'children/or adolescents.' EXPERT OPINION: Regarding food sensitization, the available data for peanuts and eggs suggest that there is a window period between 4 and 6 months of age when the introduction of these foods may limit sensitization and clinically overt allergy to the respective foods. As far as it concerns aeroallergens, it seems that there is a complex and variable relationship between mite exposure and specific sensitization especially if the exposure occurs early in life. Early exposure to dog allergens does not seem to be associated with specific sensitization; regarding cats, the results are still inconsistent. Several factors may mediate the relationship between early exposure to allergens and the development of sensitization or clinical allergy.

Forced Oscillation Technique for Monitoring the Respiratory Status of Children with Cystic Fibrosis: A Systematic Review.

Spirometry is considered the gold standard method for monitoring lung function of patients with cystic fibrosis (CF) but it requires patients' cooperation and therefore it is not useful for the majority of preschool-aged children. Oscillometry is an alternative modality for lung function monitoring that requires minimal cooperation and can be applied in children as young as 3 years of age. Furthermore, it generates lesser aerosol compared to spirometry, an issue that is of considerable importance in the COVID-19 era. The aim of this review was to present the existing clinical data regarding the application of oscillometry in children and adolescents with CF. The method seems to have acceptable feasibility and repeatability. However, there is conflicting data regarding the correlation of oscillometry values with the clinical symptoms of CF patients either in clinically stable or in exacerbation periods. Furthermore, it is not clear to what extent oscillometry measurements correlate with the spirometry indices. Based on current evidence, spirometry cannot be substituted by oscillometry in the monitoring of the respiratory status of children and adolescents with CF.

Impact of COVID-19 Lockdown on Pulmonary and Nutritional Status in Children and Young Adults With Cystic Fibrosis, in Greece.

During the first wave of the coronavirus pandemic in 2020, Greece adopted strict lockdown measures. We aimed to investigate the effects of lockdown and the resultant changes in the standard of care, on the lung function and somatic growth of cystic fibrosis (CF) patients. We analyzed data on body mass index and lung function of 103 CF patients 5.0- to 23.0-years-old before and after the lockdown period. Body mass index did not change significantly, but there was a significant improvement in lung function after the end of the lockdown period.

Association of vitamin A status with lung function in children and adolescents with cystic fibrosis.

IMPORTANCE: Vitamin A (or retinol) has considerable antioxidative and anti-inflammatory attributes and it may have protective effects on the respiratory health of patients with cystic fibrosis (CF). This issue, however, remains controversial. OBJECTIVE: The purpose of the present study was to investigate the relationship between serum retinol levels (SRL) and force expiratory volume in 1 second (FEV1) in patients with CF. METHODS: All patients with pancreatic insufficiency attending the CF Department of "Agia Sofia" Children's Hospital in Athens, Greece, aged 6 to 19 years during the 2012-2016 period, who could perform spirometry effectively, were included in the study. The impact of SRL on FEV1 was examined longitudinally and analyzed with generalized estimating equations. RESULTS: The study included 231 patients and 851 SRL measurements were performed. In 25 (3.2%) cases the SRL were below the 5th percentile of reference distribution; none was above the 95th percentile. The analysis showed that SRL was positively correlated with the FEV1 (P < 0.001). INTERPRETATION: In this sample of children and adolescents with CF, vitamin A deficiency was rare. Our results suggest a positive relationship between SRL and FEV1.

The Current Practice of Noninvasive Ventilation in Patients With Cystic Fibrosis.

In patients with cystic fibrosis (CF), despite the availability of many different pharmacologic agents, lung function deteriorates and lung disease progresses and leads to hypercapnic respiratory failure in some patients. In such cases, noninvasive ventilation (NIV) seems to be a promising technique that can be used on demand. This review summarizes the current applications of NIV in clinical settings as well as findings of the clinical trials that involved the delivery of NIV on variable occasions, such as an adjunct to physiotherapy, in nocturnal hypoventilation, and acute and chronic respiratory failure. NIV has been used in patients with CF and with advanced lung disease who are not considered candidates for lung transplantation. It can stabilize lung function, although its effect on hypercapnia is not always evident. Nocturnal NIV has been used in patients with CF and with hypoventilation during sleep but without clear benefits on daytime [Formula: see text] NIV as an adjunct to chest physiotherapy may be helpful when desaturation is observed during physiotherapy and when there are signs of respiratory muscle fatigue. NIV use in CF has been increasing, mainly in adult CF centers, and offers patients an opportunity to reach lung transplantation or to overcome acute hypercapnic respiratory failure.

Correlation of computed tomography findings and lung function in children and adolescents with cystic fibrosis.

BACKGROUND: The timely and appropriate monitoring of pulmonary status is of utmost importance for patients with cystic fibrosis (CF). Computed tomography (CT) has been used in clinical and research settings for tracking lung involvement in CF patients. However, as CT delivers a considerable amount of radiation, its sequential use in CF patients remains a concern. The application of CT, therefore, should take into account its potential risks. This review aims to understand whether and to what extent the CT findings correlate with the findings from other monitoring tools in CF lung disease. DATA SOURCES: PubMed was searched for articles about the correlation of chest CT findings with spirometric indices and with lung clearance index in children and adolescents with CF. The most relevant articles were reviewed and are presented herein. RESULTS: Most studies have shown that forced expiratory volume in the first second (FEV1) and other spirometric indices correlate moderately with CT structural lung damage. However, at the individual level, there were patients with FEV1 within the normal range and abnormal CT and vice versa. Furthermore, longitudinal studies have indicated that the deterioration of structural lung damage does not occur in parallel with the progression of lung function. Lung clearance index is a better predictor of CT findings. CONCLUSIONS: In general, the existing studies do not support the use of lung function tests as surrogates of chest CT.

Association of vitamin D status with lung function measurements in children and adolescents with cystic fibrosis.

BACKGROUND: Vitamin D status is considered a potential determinant of lung function in cystic fibrosis (CF). The aim of this retrospective longitudinal study was to investigate the decline of spirometric values in association with vitamin D status. METHODS: The data regarding 25-hydroxy vitamin D (25OHD) serum levels, spirometric measurements (FEV1, FVC, FEF25-75%), and factors known to be associated with the decline of lung function in CF were retrospectively collected over a 5-year period. The spirometric indices were recorded as the best and the average value of each year, as well as the value, recorded concurrently or closely with 25OHD level measurement. RESULTS: A significantly positive relationship was observed between 25OHD serum levels and the best annual value of FEV1 (P = .034), and the values of FEV1 (P = .010) and FVC (P = .018) measured concurrently or closely with serum 25OHD levels. The evolution of the best annual value of FEV1 was worse in patients with a mean 5-year value of 25OHD levels less than 20 ng/mL compared with patients with a mean 5-year value of ≥30 ng/mL (P < .001), or ≥20 to <30 (P < .001). There was no significant difference between patients with mean 5-year 25OHD levels ≥30 ng/mL and ≥20 to <30 ng/mL (P = .76). CONCLUSIONS: Vitamin D status is associated with lung function in patients with CF. Levels of 25OHD above 20 ng/mL were associated with higher best annual FEV1.

Longitudinal changes in lung function following initiation of lumacaftor/ivacaftor combination.

BACKGROUND: The combination of lumacaftor and ivacaftor (LUM/IVA) is a recently approved CFTR modulator treatment for homozygous F508del CF patients. Our study aimed at evaluating the change in the rate of lung function decline after one-year treatment with LUM/IVA. METHODS: The study evaluated patients homozygous for F508del, 12 to 23 years old. All had been treated for one year with LUM/IVA. The collected data included the percent predicted values of FEV1 (ppFEV1) and FVC (ppFVC), and the FEV1/FVC ratio (FEV1/FVC), that corresponded to 12, 24, and 36 months prior to, and 12 months after the initiation of LUM/IVA; also, the 3 highest values of the ppFEV1 (and the corresponding ppFVC, and FEV1/FVC) for the periods 0-12 months, 12-24 months, and 24-36 months prior to as well as the 12-month period after the initiation of LUM/IVA. The baseline lung function was estimated before the commencement of the drug. Data were analyzed longitudinally with generalized estimating equations models and continuous linear splines. A single knot was used that corresponded to the time point of LUM/IVA initiation. RESULTS: Fifty-two patients were analyzed. The multivariate longitudinal analysis of spirometric indices with linear splines demonstrated a significant change in the slopes of ppFEV1 and ppFVC decline, reflecting a significant improvement after the initiation of LUM/IVA treatment. CONCLUSIONS: In this real-world study, lung function improved over a relatively short time period of only one year, after the commencement of LUM/IVA.

Isolation of Candida auris from cystic fibrosis patient, Greece, April 2019.

We report the first isolation of Candida auris in Greece from a sputum culture of a cystic fibrosis patient in their 20s under posaconazole treatment. The pathogen was identified as C. duobushaemulonii by VITEK2YST, but as C. auris by MALDI-TOF MS. This case underscores the need for species-level identification of all non-albicans Candida (NAC) isolates from cystic fibrosis patients and patients with predisposing factors to fungal infection.

Vitamin K and cystic fibrosis: A gordian knot that deserves our attention.

Cystic fibrosis (CF) is an inherited genetic disorder with multiorgan involvement. Gastrointestinal tract dysfunction leads to fat and fat-soluble vitamins (A,D,E,K) malabsorption and deficiency of these vitamins. Subclinical vitamin K (VK) deficiency seems to be a common problem in CF patients. However, despite the rest of fat-soluble vitamins being routinely supplemented, this is not a universal clinical practice for VK. Inefficient levels of VK may have significant effects on blood coagulation and bone formation. There are also some data indicating that VK may play a key role on regulation of inflammation. Supplementing CF patients with VK seems rational, but the appropriate dosing regimens are still a matter of debate. This review will try to delineate the problem and communicate the latest opinions on this controversial issue.