Cystic fibrosis and CFTR-related disorder with electrolyte imbalance at diagnosis: clinical features and outcome in an Italian cohort.

There is limited information available on the clinical data, sweat test trends, and outcomes of individuals with cystic fibrosis (CF) who present with an isolated episode of hypoelectrolytemia with metabolic alkalosis (HMA). This study describes a cohort of Italian individuals with HMA as presenting symptom. The study is a retrospective multicenter analysis of individuals who presented with HMA as an initial symptom and was followed at 8 Italian CF Centers, from March 1988 to March 2022. Demographic, clinical, microbiological, biochemical, and genetic data were extracted from local health records. Ninety-three individuals were enrolled in the study. At first evaluation, 82 (88.2%) were diagnosed with CF, and 11 received a CFTR-Related Disorder (CFTR-RD) diagnostic label. Twenty-three (85.1%) out of the 27 subjects who underwent CF neonatal screening (NBS) resulted falsely negative. After a mean observational period of 11.5 years, most of subjects had a mild pulmonary phenotype, pancreatic sufficiency, and rarely CF-related complications. Four CFTR-RD changed to a CF diagnosis during the study period, resulting in 86 (92.4%) subjects classified as CF. CONCLUSIONS:  Most CF patients presenting with isolated HMA have a mild course of disease and rarely CF-related complications. WHAT IS KNOWN: • Isolated episode of hypoelectrolytemia with metabolic alkalosis is a well-known onset symptom of Cystic Fibrosis in infancy. • There is limited information available on the clinical data and outcomes of individuals with Cystic Fibrosis who present with electrolyte imbalance at diagnosis. WHAT IS NEW: • Most patients with Cystic Fibrosis presenting with isolated hypoelectrolytemia and metabolic alkalosis have a mild course of disease and rarely CF-related complications. • Electrolyte imbalance at diagnosis of Cystic Fibrosis is a common symptom in children not screened for CF at birth, or in those who received a false negative result from newborn screening.

The Role of Bronchoscopy in the Management of Children With Cystic Fibrosis.

BACKGROUND: Currently, no consensus guidelines recommend routine bronchoscopy procedure in cystic fibrosis (CF), as no evidence is available concerning its use as either a diagnostic or therapeutic tool. Its efficacy is controversial, and no randomized controlled prospective trials are available to check its effectiveness. The aims of the present study were to evaluate the effectiveness of bronchoscopy as a diagnostic/therapeutic tool in CF children and adolescents; and to verify the effect of serial bronchoscopy on lung disease progression in subjects with CF not responding to a single procedure. METHODS: Data of patients who received bronchoscopy at 2 Italian CF centers were collected. Bronchoalveolar lavage was performed during the procedure including airway clearance with mucolytics, inhaled antibiotics, and/or surfactant instillation. RESULTS: A total of 16 patients in center 1 and 17 in center 2 underwent, respectively, 28 and 23 bronchoscopic procedure in the study period. Five patients in each center underwent >1 procedure. All procedures were generally well tolerated. No patient required admission to the pediatric intensive therapy unit. In 19.6% of bronchoalveolar lavages, growth of Aspergillus fumigatus was evident, although not detected by sputum analyses. After the procedure, an increase in mean percent predicted forced expiratory volume in the 1 second >10% was observed, and a significant decrease in pulmonary exacerbations yearly was evident. CONCLUSION: Based on the results, we suggest bronchoscopy is not to be considered an obsolete tool, and it remains useful in CF management, although in selected cases. We encourage to support longitudinal observational studies to standardize the procedure, focusing on the choice of drugs to be instilled, modalities and timing of serial bronchoscopy and subsequent follow-up in selected severe clinical conditions.

Clinical outcomes of a large cohort of individuals with the F508del/5T;TG12 CFTR genotype.

BACKGROUND: In recent years, patients with cystic fibrosis (CF) conductance regulator (CFTR) variant poly(T) sequences have been increasingly reported with a wide spectrum of clinical severity. We describe the long-term clinical outcomes and progression to a CF diagnosis over time in a large Italian cohort of patients carrying the CFTR F508del/5T;TG12 genotype. METHODS: A retrospective analysis of subjects from 10 CF centres in Italy with the F508del/5T;TG12 genotype was performed. Demographic, clinical, microbiological, and biochemical data, as well as information about the follow-ups and complications of the enroled patients, were collected. RESULTS: A total of 129 subjects (54 females; median age: 15.0 years, range: 0-58 years; 59 older than 18 years) were included. In terms of initial diagnoses, 30 were CF (23.3%), 41 were CFTR-related disorder (CFTR-RD) (31.7%), and 58 were CF transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID) (45.0%). After a median follow-up of 6.7 years (range 0.2-25 years), 15 patients progressed to CF, bringing the total number of CF diagnoses to 45/129 (34.9%). Most of these patients had mild lung diseases with pancreatic sufficiency and a low prevalence of CF-related complications. CONCLUSIONS: At the end of the study, 34.9% of subjects with the CFTR F508del/5T;TG12 genotype were diagnosed with CF. We suggest including patients with the F508del/5T;TG12 genotype in long-term follow-ups.

Clinical course and risk factors for severe COVID-19 among Italian patients with cystic fibrosis: a study within the Italian Cystic Fibrosis Society.

PURPOSE: To describe the clinical course of COVID-19 in patients with cystic fibrosis (CF) and to identify risk factors for severe COVID-19. METHODS: We conducted a prospective study within the Italian CF Society. CF centers collected baseline and follow-up data of patients with virologically confirmed SARS-CoV-2 infection between March 2020 and June 2021. Odds ratios (ORs) for severe SARS-CoV-2 (as defined by hospital admission) were estimated by logistic regression models. RESULTS: The study included 236 patients with positive molecular test for SARS-CoV-2. Six patients died, 43 patients were admitted to hospital, 4 admitted to intensive care unit. Pancreatic insufficiency was associated with increased risk of severe COVID-19 (OR 4.04, 95% CI 1.52; 10.8). After adjusting for age and pancreatic insufficiency, forced expiratory volume in one second (FEVp) < 40% (OR 4.54, 95% CI 1.56; 13.2), oxygen therapy (OR 12.3, 95% CI 2.91-51.7), underweight (OR 2.92, 95% CI 1.12; 7.57), organ transplantation (OR 7.31, 95% CI 2.59; 20.7), diabetes (OR 2.67, 95% CI 1.23; 5.80) and liver disease (OR 3.67, 95% CI 1.77; 7.59) were associated with increased risk of severe COVID-19, while use of dornase alfa was associated with a reduced risk (OR 0.34, 95% CI 0.13-0.88). No significant changes were observed in FEVp from baseline to a median follow-up of 2 months (median difference: 0, interquartile range: - 4; 5, P = 0.62). CONCLUSION: Clinical features indicative of severe form of CF are associated with increased risk of COVID-19 hospitalization. SARS-CoV-2 infected patients do not experience a deterioration of respiratory function.

Case Report: Analysis of Inflammatory Cytokines IL-6, CCL2/MCP1, CCL5/RANTES, CXCL9/MIG, and CXCL10/IP10 in a Cystic Fibrosis Patient Cohort During the First Wave of the COVID-19 Pandemic.

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, data registered in the European countries revealed increasing cases of infection in cystic fibrosis (CF) patients. In the course of this pandemic, we enrolled 17 CF patients for a study evaluating inflammatory markers. One of them developed COVID-19, giving us the possibility to analyze inflammatory markers in the acute phase as compared to levels detected before and after the infectious episode and to levels measured in the other CF patients enrolled to the study who did not experience COVID-19 and 23 patients referred to our center for SARS-CoV-2 infection.

Paranasal mucoceles in children with cystic fibrosis: Management of a not so rare clinical condition.

PURPOSE: Paranasal mucocele (PM) is reported as a complication in children with cystic fibrosis (CF) in up to 4% of patients. The objective of this study was to identify PMs in the personal large series of children with CF and to assess their diagnosis and treatment. MATERIAL AND METHODS: Medical records of children with CF and PM who were admitted and treated by means of endoscopic nasal surgery between 2004 and 2020 were retrospectively reviewed. RESULTS: Thirty-four patients were included in the study (mean age 7.7 years). CT scan of sinuses showed a total of 53 PMs. Nasal endoscopic findings suggestive for PM were present in almost 80% of patients. PMs were located in the maxillary, ethmoid, and sphenoid sinuses in 29/34 (85.3%, bilateral in 17 cases), 4/34 (11.8%) and 1/34 (2.9%) patients, respectively. Marsupialization of PMs was performed in all patients using an endoscopic transnasal approach. No complications were observed. Resolution of symptoms and normalization of the endoscopic nasal picture was evident in all patients. After a mean follow-up of 85 months, no recurrences were observed. CONCLUSIONS: To the best of our knowledge, this is the largest series of CF patients with PMs. Even if not frequently reported in the literature, PMs should not be considered an uncommon finding in patients affected by CF. Routine nasal endoscopy is mandatory to favor early diagnosis. Endoscopic transnasal marsupialization represents the gold standard of care for patients with CF and PM(s).

Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome.

Background: SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD). Objective: With this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations. Methods: We investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission. Results: Patients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19. Conclusions: Our results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.

Immune response in children with COVID-19 is characterized by lower levels of T-cell activation than infected adults.

Study of immunological features of immune response in 14 children (aged from 12 days up to 15 years) and of 10 adults who developed COVID-19 show increased number of activated CD4 and CD8 cells expressing DR and higher plasmatic levels of IL-12 and IL-1ß in adults with COVID-19, but not in children. In addition, plasmatic levels of CCL5/RANTES are higher in children and adults with COVID-19, while CXCL9/MIG was only increased in adults. Higher number of activated T cells and expression of IL-12 and CXCL9 suggest prominent Th1 polarization of immune response against SARS-CoV2 in infected adults as compared with children.

Should isolated Pseudo-Bartter syndrome be considered a CFTR-related disorder of infancy?

BACKGROUND: Infants that are negative to cystic fibrosis (CF) newborn screening (NBS) programs, or in countries without NBS, may present with metabolic alkalosis and severe salt depletion, a well-known clinical manifestation of CF termed Pseudo-Bartter syndrome (PBS). Here, we report the cases of three CF-negative children, who carry rare mutations in the CF transmembrane conductance regulator (CFTR) gene, and, for whom, PBS was the only manifestation of CFTR protein dysfunction. There is no diagnostic label for these cases. METHODS: Medical records of patients followed at our Cystic Fibrosis Centre were revised and data were collected for all patients who presented with an isolated PBS. The syndrome was defined as an episode of dehydration with low levels of serum sodium (<134mmol/L), potassium ( <3.4mmol/L), and chloride ( <100mmol/L), with metabolic alkalosis (bicarbonatemia >27mmol/L) in the absence of renal tubulopathy. RESULTS: Three out of 73 (4%) CF infants presented with a severe metabolic alkalosis with salt depletion; two of these required admission to the intensive care unit. Two infants had a negative NBS, and one was identified as a CF carrier. Sweat test was repeatedly in the negative/borderline ranges for all patients. Less than two CF causing mutations were identified (F508del/R1070W, F508del; L467F/P5L, R1066H/P5L). During a mean follow-up of 9 years, the children had no other CF manifestations. CONCLUSION: We suggest that PBS as the sole manifestation of CFTR dysfunction might be considered a CFTR-related disorder of infancy.

Elastic aortic properties in cystic fibrosis adults without cardiovascular risk factors: A case-control study.

INTRODUCTION: The presence of CFTR in smooth muscle and endothelial cells, systemic inflammation, and oxidative stress could explain vascular alterations in cystic fibrosis. Aortic elastic properties are determinants of left ventricular function by means of ventriculo-arterial coupling and indicators of cardiovascular risk. OBJECTIVES: The purpose of the present study was to compare clinically stable patients affected by cystic fibrosis without overt pulmonary hypertension with controls to evaluate aortic tissue Doppler elastic properties, such as distensibility, stiffness, and strain. METHODS: A total of 22 adults affected by cystic fibrosis, and 24 healthy volunteers matched for age and sex were enrolled. None had known cardiovascular risk factors, secondary diabetes, neither aortic stenosis nor regurgitation. All people underwent blood pressure measurement and transthoracic echocardiography. RESULTS: Aortic diameter measured at Valsalva sinuses was significantly higher in patients with cystic fibrosis than healthy people, median 32.0 (interquartile range 29.8-35.0) vs 24.3 (22.2-30.0) mm; P < 0.001. Aortic distensibility was significantly lower among patients than controls, being 2.4 (1.3-3.3) vs 5.6 (3.4-8.3) per mm Hg (P < 0.001), while stiffness higher, 7.7 (6.0-14.8) vs 3.7 (2.9-6.7); P < 0.001. Finally, M-mode strain of ascending aorta was lower in patients, 4.1 (3.4-7.3)% than in controls, 13.4 (7.7-19.4)%; P < 0.001. CONCLUSION: For the first time in humans, we demonstrated subclinical alterations in aortic elastic properties in young adults affected by cystic fibrosis without pulmonary hypertension or secondary diabetes. This phenomenon could influence left ventricular function earlier by means of ventriculo-arterial coupling and may be a tool to identify patients who benefit from a closer follow-up.

Focus on echocardiographic right ventricular strain analysis in cystic fibrosis adults without cardiovascular risk factors: a case-control study.

Strain echocardiography is able to detect subclinical ventricular systolic and diastolic dysfunction. Prolonged survival to cystic fibrosis favors heart and vessel involvement. The purpose of the present study was to compare clinically stable adult patients affected by cystic fibrosis without overt pulmonary hypertension with controls to evaluate right ventricular (RV) systolic and diastolic function by means of strain and tissue Doppler imaging (TDI), respectively. 22 adults affected by cystic fibrosis and 24 healthy volunteers matched for age and sex were enrolled. None had known cardiovascular risk factors or overt pulmonary hypertension. All people underwent blood pressure measurement and transthoracic echocardiography. Cystic fibrosis patients showed higher sPAP [median 25 (IQR 21-30) vs 22 (22-22) mmHg; p = 0.02] and more frequent RV diastolic dysfunction (p < 0.001). Among cases, some RV systolic parameters were significantly altered than controls, such as TAPSE [20 (18-24) vs. 23 (21-28) mm; p = 0.001], FAC [34 (26-44) vs. 49 (48-50)%; p < 0.001], midwall tissue strain [- 25.0 (- 31.3 to - 22.8) vs. - 30.5 (- 31.8 to - 29.3)%; p = 0.03], apical tissue strain [- 22 (- 29.3 to - 19.0) vs. - 30.5 (- 32.8 to - 28.3)%; p = 0.001] and 2D strain [- 22.0 (- 25.1 to - 19.0) vs. - 29.5 (- 31.8 to - 27.3)%; p < 0.001]. Finally, 2D strain correlated with spirometric FEV1 (ρ = - 0.463, p = 0.03) and nearly with FEF25-75% (ρ = - 0.393, p = 0.07). Our study confirmed a RV subclinical systo-diastolic dysfunction in clinically stable patients affected by cystic fibrosis without overt pulmonary hypertension nor cardiovascular risk factors. This may be due to systemic inflammation and temporary recurrent pulmonary hypertension. We retain that RV 2D strain and TDI echocardiography could become an important tool in the follow-up of these patients.

Macro- and microvascular functions in cystic fibrosis adults without cardiovascular risk factors: A case-control study.

Increasing survival from cystic fibrosis show untypical systems involvement, such as cardiocirculatory. In particular, the presence of CFTR in smooth muscle and endothelial cells, systemic inflammation and oxidative stress could explain vascular alterations in these patients. We aimed at noninvasely evaluating macro- and microvascular dysfunction in cystic fibrosis adults without cardiovascular risk factors. Twenty-twoadults affected by cystic fibrosis and 24 healthy volunteers matched for age and sex were enrolled. None had known cardiovascular risk factors. All people underwent blood pressure measurement, microvascular function assessment by EndoPAT-2000 device (calculating RH-PAT index) and macrovascular evaluation by pulse wave velocity (PWV). RH-PAT index was significantly lower in patients than in controls (1.74±0.59 vs 2.33±0.34; p<0.001). Thirteen patients of 22 had a value inferior to the threshold of 1.67 (59.1%), while no controls had (p<0.001). Carotid-femoral PWV did not differ between the two groups (5.2±1.5 m/s vs 5.4±1.1; p=0.9), while brachial-ankle one did (11.0±2.2 m/s vs 10.1±0.8 m/s; p=0.04).Adults patients affected by cystic fibrosis show peripheral endothelial dysfunction, which is the first alteration in atherosclerotic phenomenon. Moreover, arterial stiffness measured by PWV unclearly seems to differ respect of healthy people, perhaps because PWV alterations are typical of above 50 years old people. It is unclear what prognostic role of future developing of atherosclerotic disease these findings could be, but it seems evident that cystic fibrosis directly affects cardiovascular system itself.

Acute Scedosporium apiospermum Endobronchial Infection in Cystic Fibrosis.

Fungi are known pathogens in cystic fibrosis patients. A boy with cystic fibrosis boy presented with acute respiratory distress. Bronchoscopy showed airways obstruction by mucus plugs and bronchial casts. Scedosporium apiospermum was identified as the only pathogen. Bronchoalveolar lavage successfully resolved the acute obstruction. Plastic bronchitis is a new clinical picture of acute Scedosporium endobronchial colonization in cystic fibrosis patients.

Effect of high-dose sublingual immunotherapy on respiratory infections in children allergic to house dust mite.

BACKGROUND: Allergic rhinitis is characterized by eosinophil inflammation. Allergic inflammation may induce susceptibility to respiratory infections (RI). House dust mite (HDM) sensitization is very frequent in childhood. Allergen immunotherapy may cure allergy as it restores a physiologic immune and clinical tolerance to allergen and exerts anti-inflammatory activity. OBJECTIVE: This study investigated whether six-month high-dose, such as 300 IR (index of reactivity), HDM-sublingual immunotherapy (SLIT) could affect RI in allergic children. METHODS: Globally, 40 HDM allergic children (18 males; mean age, 9.3 years) were subdivided in 2 groups: 20 treated by symptomatic drugs (group 1) and 20 by high-dose HDM-SLIT (group 2), since September 2012 to April 2013. The daily maintenance dose of HDM-SLIT was 4 pressures corresponding to 24, 4.8, and 60 µg, respectively of the major allergens Dermatophagoides pteronyssinus (Der p) 1, Der p 2, and Dermatophagoides farinae (Der f) 1. RI was diagnosed when at least 2 symptoms or signs, and fever were present for at least 48 hours. A family pediatrician provided diagnosis on a clinical ground. RESULTS: SLIT-treated children had significantly (p = 0.01) less RI episodes (3.5) than control group (5.45). About secondary outcomes, SLIT-treated children had less episodes of pharyngo-tonsillitis (p < 0.05) and bronchitis (p < 0.005), and snoring (p < 0.05) than control group. In addition, SLIT-treated children had less fever (p < 0.01) and took fewer medications, such as antibiotics (p < 0.05) and fever-reducers (p < 0.01), than control group. CONCLUSION: This preliminary study might suggest that also a short course (6 months) of high-dose SLIT, titrated in µg of major allergens, could reduce RI in allergic children.