The long-term effect of elexacaftor/tezacaftor/ivacaftor on cardiorespiratory fitness in adolescent patients with cystic fibrosis: a pilot observational study.

BACKGROUND: Physical activity is a crucial demand on cystic fibrosis treatment management. The highest value of oxygen uptake (VO2peak) is an appropriate tool to evaluate the physical activity in these patients. However, there are several other valuable CPET parameters describing exercise tolerance (Wpeak, VO2VT1, VO2VT2, VO2/HRpeak, etc.), and helping to better understand the effect of specific treatment (VE, VT, VD/VT etc.). Limited data showed ambiguous results of this improvement after CFTR modulator treatment. Elexacaftor/tezacaftor/ivacaftor medication improves pulmonary function and quality of life, whereas its effect on CPET has yet to be sufficiently demonstrated. METHODS: We performed a single group prospective observational study of 10 adolescent patients with cystic fibrosis who completed two CPET measurements between January 2019 and February 2023. During this period, elexacaftor/tezacaftor/ivacaftor treatment was initiated in all of them. The first CPET at the baseline was followed by controlled CPET at least one year after medication commencement. We focused on interpreting the data on their influence by the novel therapy. We hypothesized improvements in cardiorespiratory fitness following treatment. We applied the Wilcoxon signed-rank test. The data were adjusted for age at the time of CPET to eliminate bias of aging in adolescent patients. RESULTS: We observed significant improvement in peak workload, VO2 peak, VO2VT1, VO2VT2, VE/VCO2 slope, VE, VT, RQ, VO2/HR peak and RR peak. The mean change in VO2 peak was 5.7 mL/kg/min, or 15.9% of the reference value (SD ± 16.6; p= 0.014). VO2VT1 improved by 15% of the reference value (SD ± 0.1; p= 0.014), VO2VT2 improved by 0.5 (SD ± 0.4; p= 0.01). There were no differences in other parameters. CONCLUSION: Exercise tolerance improved after elexacaftor/tezacaftor/ivacaftor treatment initiation. We suggest that the CFTR modulator alone is not enough for recovering physical decondition, but should be supplemented with physical activity and respiratory physiotherapy. Further studies are needed to examine the effect of CFTR modulators and physical therapy on cardiopulmonary exercise tolerance.

Improved Nutritional Outcomes and Gastrointestinal Symptoms in Adult Cystic Fibrosis Patients Treated with Elexacaftor/Tezacaftor/Ivacaftor.

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator modulator therapy improves nutritional status and quality of life. Clinical trials have shown pancreatic insufficiency conversion, mostly in pediatric patients treated with ivacaftor. Studies with elexacaftor/tezacaftor/ivacaftor (ETI) in older patients have not suggested restoration of exocrine pancreas function, but quality data in adults are lacking. Our aim was to show the effect of ETI in adults with cystic fibrosis (CF) on nutritional status and digestive function. We hypothesized improvement of nutritional parameters and gastrointestinal symptoms, reduction of pancreatic enzyme replacement therapy, but uncertain improvement in exocrine pancreatic function. METHODS: We prospectively enrolled adults with CF treated with ETI from August 2021 to June 2022. We measured anthropometric parameters, laboratory nutritional markers, change of fecal elastase, pancreatic enzymes replacement therapy needs, and gastrointestinal symptoms. RESULTS: In the cohort of 29 patients (mean age 29.1 years), 82.8% suffered exocrine pancreatic insufficiency. After ETI, mean BMI increased by 1.20 kg/m2 (p < 0.001), mean body weight by 3.51 kg (p < 0.001), albumin by 2.81 g/L, and prealbumin by 0.06 (both p < 0.001). Only 1 patient, initially pancreatic insufficient (4.5%, p < 0.001), developed pancreatic sufficiency, indicated by increased fecal elastase from 45 µg/g to 442.1 µg/g. Mean change in lipase substitution decreased by 1,969 units/kg/day (p < 0.001) and stools frequency by 1.18 per day (p < 0.001). CONCLUSION: Our data suggest increased nutritional parameters, lower pancreatic substitution requirements, and improved defecation in adult CF patients on ETI. Improvement in exocrine pancreatic function might be mutation-specific and needs further study.

Increasing incidence rate of breast cancer in cystic fibrosis - relationship between pathogenesis, oncogenesis and prediction of the treatment effect in the context of worse clinical outcome and prognosis of cystic fibrosis due to estrogens.

Cystic fibrosis (CF) is the most common genetic disease in the Caucasion population. Thanks to the CFTR modulators therapy, life expectancy will significantly improve. New therapeutic challenges can be expected, including diseases associated with ageing and higher incidence of cancer, as evidenced by recent epidemiological studies. The increasing incidence of tumors includes also breast cancer. The risk of breast cancer is higher in CF patients compared to the general population. Sex hormones, especially estrogens, also affect on the pathophysiology and immunology of the CF. Previous research, has demonstrated unequivocal survival rates for female CF patients compared to their male counterparts. Is demonstrated, that chemotherapy used for breast cancer affects the CFTR channel and CFTR modulator therapy has frequent side effects on breast tissue. In this review, we focus on the effects of female sex hormones on CF disease, pathophysiological relationships between CF and breast cancer, and the impact of antitumor treatment on both, malignant disease and CF. The potential for further investigation is also discussed.

COVID-19-Associated Paediatric Inflammatory Multisystem Syndrome (PIMS-TS) in Intensive Care: A Retrospective Cohort Trial (PIMS-TS INT).

Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) is a new disease in children and adolescents that occurs after often asymptomatic or mild COVID-19. It can be manifested by different clinical symptomatology and varying severity of disease based on multisystemic inflammation. The aim of this retrospective cohort trial was to describe the initial clinical presentation, diagnostics, therapy and clinical outcome of paediatric patients with a diagnosis of PIMS-TS admitted to one of the 3 PICUs. All paediatric patients who were admitted to the hospital with a diagnosis of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) during the study period were enrolled in the study. A total of 180 patients were analysed. The most common symptoms upon admission were fever (81.6%, n = 147), rash (70.6%, n = 127), conjunctivitis (68.9%, n = 124) and abdominal pain (51.1%, n = 92). Acute respiratory failure occurred in 21.1% of patients (n = 38). Vasopressor support was used in 20.6% (n = 37) of cases. Overall, 96.7% of patients (n = 174) initially tested positive for SARS-CoV-2 IgG antibodies. Almost all patients received antibiotics during in-hospital stays. No patient died during the hospital stay or after 28 days of follow-up. Initial clinical presentation and organ system involvement of PIMS-TS including laboratory manifestations and treatment were identified in this trial. Early identification of PIMS-TS manifestation is essential for early treatment and proper management of patients.

Cerebrovascular Complications of COVID-19 Disease in Children: A Single-Center Case Series.

This work presents a case series of four children diagnosed with severe cerebrovascular disease in association with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, yet no patient from the group met typical diagnostic criteria for multisystem inflammatory syndrome in children. Our aim was to highlight the possible vascular involvement and coagulopathies associated with SARS-CoV-2 infection in the pediatric population. Further data are needed to better understand the pathophysiological basis of this condition in children and to ensure its optimal management.

Causes of Intensive Care Unit Admissions in Children with SARS-CoV-2: A Single-Centre Observational Study.

Background: The proportion of intensive care unit (ICU) admissions in children that have and have not been directly caused by SARS-CoV-2 remains unclear. The aim of the study is to analyse a cohort of children admitted to the ICU with SARS-CoV-2 and determine whether the infection was the primary cause of their hospitalisation, a significant contributor, a suspected accomplice, or an incidental finding. Methods: This was a retrospective observational study of all the children admitted to the ICU with SARS-CoV-2 from March 2020 to February 2022 from the South Moravia region. The aim of the study was to assess whether the hospitalisation was likely to be directly caused by the virus (i.e., patients with acute COVID-19; the COVID group), whether the virus was a significant contributor to the hospitalisation (i.e., patients with multisystem inflammatory syndrome in children due to COVID-19; the MIS-C group), whether it may have contributed to the worsening of their underlying disease (the WORSENING group), or whether it was an incidental finding very likely unrelated to hospitalisation where SARS-CoV-2 positivity merely placed patients in the COVID-19 unit (the ISOLATION group). The groups were compared using a series of secondary outcomes. Results: The study population represented 150 paediatric ICU cases (age 8.6; IQR 3.5−13.3 years), with 66.7% being male. The COVID group represented 32.7% of cases (49/150); MIS-C, 30% (45/150); WORSENING, 14.7% (22/150); and ISOLATION, 22.7% (34/150). The median length of hospitalisation was found for the MIS-C group (11 days; 9 days in the ICU), the COVID group (6 days; five days in the ICU), WORSENING group (4.5 days; 4.5 days in the ICU) and the ISOLATION group (5.5 days; 3.5 days in the ICU), where the difference was significant (p < 0.001). Asymptomatic and mild cases were most common in the WORSENING (36.4% and 63.6%) and ISOLATION (52.9% and 44.1%) groups. Severe and critical cases were only present in the COVID (6.1% and 12.2%) and MIS-C (4.4% and 11.1%) groups; the severity difference was significant (p < 0.001). The groups did not differ significantly in the proportion of complete recovery and short- and long-term sequelae (p = 0.09). Conclusions: Patients with acute COVID-19 accounted for one-third of all ICU admissions, patients with MIS-C accounted for approximately another third, patients with worsening underlying disease accounted for 15%, and patients with incidental findings of SARS-CoV-2 positivity accounted for one-fifth of ICU admissions. A more significant disease was seen with acute COVID-19 and MIS-C.

Tick-Borne Encephalitis in an 8.5-Month-Old Boy Suspected of Febrile Seizures.

Tick-borne encephalitis (TBE) is a serious viral neuroinfection affecting humans in large areas of Europe and Asia. TBE can occur at any age, but only a few reports of TBE in infants younger than 1 year have been published. Here, we report a case of severe TBE in an 8.5-month-old boy presenting with seizures at the beginning of the neurological phase.

Unvaccinated child tetanus from nasal toy battery.

We present the case report of an unvaccinated Czech child with tetanus. The child had not received any vaccines due to its parent's refusal. The disease originated from the wound in the nose caused by a small flat battery. The typical onset of tetanus followed after two weeks, rapidly progressing to respiratory failure with the need for mechanic ventilation despite intensive treatment. The child spent five weeks in the hospital. Mild long-term sequelae persisted 5 months.

Skin wipe test: A simple, inexpensive, and fast approach in the diagnosis of cystic fibrosis.

OBJECTIVE: To assess the performance of a newly developed skin wipe test (SWT) for the diagnosis of cystic fibrosis (CF). STUDY DESIGN: Spontaneously formed sweat from the forearm was wiped by a cotton swab moistened with 100 µL of deionized (DI) water and extracted into 400 µL of DI water (SWT). The conventional Macroduct sweat test (ST) was performed simultaneously. SWT samples of 114 CF patients, 76 healthy carriers, and 58 controls were analyzed by capillary electrophoresis with contactless conductivity detection and Cl- /K+ and (Cl- + Na+ )/K+ ion ratios were evaluated. Chloride concentrations from Macroduct ST were analyzed coulometrically. RESULTS: Analysis of 248 SWT samples and simultaneous Macroduct ST samples showed comparable method performance. Two ion ratios, Cl- /K+ and (Cl- + Na+ )/K+ , from the SWT samples and Cl- values from the ST samples were evaluated to diagnose CF. Sensitivity of the SWT method using the Cl- /K+ ratio (cutoff value 3.9) was 93.9%, compared to 99.1% when using the (Cl- + Na+ )/K+ ratio (cutoff value 5.0) and 98.3% in using Macroduct Cl- (cutoff value higher or equal to 60 mmol/L). The methods' specificities were 97.8%, 94.0%, and 100.0%, respectively. CONCLUSIONS: The developed SWT method with capillary electrophoretic analysis for CF diagnosis performs comparably to the conventional Macroduct ST. The SWT method is simple, fast, inexpensive, and completely noninvasive. Use of an ion ratio in obtained SWT samples is proposed as a new diagnostic parameter that shows significant promise in CF diagnostics.

Clinical and laboratory characteristics of enteroviral meningitis in children, including qRT-PCR and sequencing analysis.

AIMS: Enteroviruses (EVs) are the most common agents of aseptic meningitis. Some serotypes can cause serious neuroinfection leading to death. The aim of this study was to determine the representation of EVs in the etiology of aseptic meningitis in children and to analyze the demographic, clinical, laboratory, and epidemiological characteristics of patients with EV meningitis. PATIENTS AND METHODS: This was a prospective study including 147 patients in three groups: EV meningitis, tick-borne encephalitis, and aseptic meningitis with unidentified agent. RESULTS: Boys with EV meningitis predominated over girls. The average patient age was 11 years. Compared to the control group, these patients suffered more from stiff back (P=0.010), vomiting and nausea (P=0.009). They had shorter symptom duration (P<0.001), higher C-reactive protein in blood (P<0.001), higher predominance of polynuclears (P=0.026), and greater lactate (P=0.003) in cerebrospinal fluid (CSF). The serotype seen most frequently (68%) was ECHO virus (ECV) 30. CONCLUSIONS: Enteroviruses play the most important role in the differential diagnosis of aseptic meningitis. Short symptom duration, slightly higher inflammatory parameters in blood, predominance of polynuclears, and elevated CSF lactate have predictive value in diagnosing this disease. ECV 30 (frequently the agent of epidemics in the Czech Republic) was the aseptic meningitis agent most often seen.

New approach for cystic fibrosis diagnosis based on chloride/potassium ratio analyzed in non-invasively obtained skin-wipe sweat samples by capillary electrophoresis with contactless conductometric detection.

A new approach for sweat analysis used in cystic fibrosis (CF) diagnosis is proposed. It consists of a noninvasive skin-wipe sampling followed by analysis of target ions using capillary electrophoresis with contactless conductometric detection (C4D). The skin-wipe sampling consists of wiping a defined skin area with precleaned cotton swab moistened with 100 µL deionized water. The skin-wipe sample is then extracted for 3 min into 400 µL deionized water, and the extract is analyzed directly. The developed sampling method is cheap, simple, fast, and painless, and can replace the conventional pilocarpine-induced sweat chloride test commonly applied in CF diagnosis. The aqueous extract of the skin-wipe sample content is analyzed simultaneously by capillary electrophoresis with contactless conductometric detection using a double opposite end injection. A 20 mmol/L L-histidine/2-(N-morpholino)ethanesulfonic acid and 2 mmol/L 18-crown-6 at pH 6 electrolyte can separate all the major ions in less than 7 min. Skin-wipe sample extracts from 30 study participants-ten adult patients with CF (25-50 years old), ten pediatric patients with CF (1-15 years old), and ten healthy control individuals (1-18 years old)-were obtained and analyzed. From the analyzed ions in all samples, a significant difference between chloride and potassium concentrations was found in the CF patients and healthy controls. We propose the use of the Cl-/K+ ratio rather than the absolute Cl- concentration and a cutoff value of 4 in skin-wipe sample extracts as an alternative to the conventional sweat chloride analysis. The proposed Cl-/K+ ion ratio proved to be a more reliable indicator, is independent of the patient's age, and allows better differentiation between non-CF individuals and CF patients having intermediate values on the Cl- sweat test. Figure New approach for cystic fibrosis diagnosis based on skin-wipe sampling of forearm and analysis of ionic content (Cl-/K+ ratio) in skin-wipe extracts by capillary electrophoresis with contactless conductometric detection.

Cost-of-illness analysis and regression modeling in cystic fibrosis: a retrospective prevalence-based study.

BACKGROUND: Economic data pertaining to cystic fibrosis (CF), is limited in Europe generally, and completely lacking in Central and Eastern Europe. We performed an analysis of all direct costs associated with CF relative to key disease features and laboratory examinations. METHODS: A retrospective prevalence-based cost-of-illness (COI) study was performed in a representative cohort of 242 CF patients in the Czech Republic, which represents about 65 % of all Czech CF patients. Medical records and invoices to health insurance companies for reference year 2010 were analyzed. RESULTS: The mean total health care costs were €14,486 per patient, with the majority of the costs going towards medicinal products and devices (€10,321). Medical procedures (€2676) and inpatient care (€1829) represented a much smaller percentage of costs. A generalized linear model showed that the strongest cost drivers, for all cost categories, were associated with patient age and lung disease severity (assessed using the FEV1 spirometric parameter), when compounded by chronic Pseudomonas aeruginosa airway infections. Specifically, maximum total costs are around the age 16 years; a FEV1 increase of 1 % point represented a cost decrease of: 0.9 % (medicinal products), 1.7 % (total costs), 2.8 % (procedures) and 7.0 % (inpatient care). CONCLUSIONS: COI analysis and regression modeling using the most recent data available can provide a better understanding of the overall economic CF burden. A comparison of our results with other methodologically similar studies demonstrates that although overall costs may differ, FEV1 can nonetheless be utilized as a generally transferrable indicator of the relative economic impact of CF.

[Salmonellosis - a real threat for infants].

Salmonella spp. are a common cause of bacterial gastroenteritis. In infants, Salmonella infection is uncommon, posing a higher risk for a severe course. The authors present a case of a 3-month-old infant with suspected Salmonella sepsis. Also discussed are the correct approach to therapy and potential errors in the treatment of the youngest age groups.

[Pertussis in a 4-month-old infant with unrecognized cystic fibrosis]. / Pertusse u kojence s nepoznanou cystickou fibrozou.

We present a case report of a small boy with cystic fibrosis complicated by pertussis and pneumothorax. The child had not been vaccinated against Bordetella pertussis due to the failure to thrive and was infected with the bacterium at the age of 4 months. The course of the disease was severe, with respiratory distress and spontaneous pneumothorax. The diagnosis of pertussis was serologically confirmed. A suspicion for cystic fibrosis increased after an unusually prolonged course of the disease and a history of the failure to thrive. A comprehensive diagnostic procedure revealed Pseudomonas aeruginosa respiratory infection, anemia, pancreatic insufficiency, a positive sweat test and the presence of two CFTR gene mutations. The patient, treated with comprehensive cystic fibrosis therapy, recovered from acute respiratory illness and started to thrive soon.