Elexacaftor-Tezacaftor-Ivacaftor as a Final Frontier in the Treatment of Cystic Fibrosis: Definition of the Clinical and Microbiological Implications in a Case-Control Study.

The use of modulator drugs that target the Cystic Fibrosis transmembrane conductance regulator (CFTR) is the final frontier in the treatment of Cystic Fibrosis (CF), a genetic multiorgan disease. F508del is the most common mutation causing defective formation and function of CFTR. Elexacaftor-tezacaftor-ivacaftor is the first triple combination of CFTR modulators. Herein, we report on a one-year case-control study that involved 26 patients with at least one F508del mutation. Patients were assigned to two similar groups, and patients with the worse clinical condition received treatment with the triple combination therapy. The study aimed to define the clinical and especially microbiological implications of treatment administration. The treatment provided significant clinical benefits in terms of respiratory, pancreatic, and sweat function. After one year of therapy, airway infection rates decreased and pulmonary exacerbations were dramatically reduced. Finally, treated patients reported a surprising improvement in their quality of life. The use of triple combination therapy has become essential in most CF people carrying the F508del mutation. Although the clinical and instrumental benefits of treatment are thoroughly known, further investigations are needed to properly define its microbiological respiratory implications and establish the real advantage of life-long treatment with elexacaftor-tezacaftor-ivacaftor.

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.

Congenital emphysematous lung disease associated with a novel Filamin A mutation. Case report and literature review.

BACKGROUND: Progressive lung involvement in Filamin A (FLNA)-related cerebral periventricular nodular heterotopia (PVNH) has been reported in a limited number of cases. CASE PRESENTATION: We report a new pathogenic FLNA gene variant (c.7391_7403del; p.Val2464Alafs*5) in a male infant who developed progressive lung disease with emphysematous lesions and interstitial involvement. Following lobar resection, chronic respiratory failure ensued necessitating continuous mechanical ventilation and tracheostomy. Cerebral periventricular nodular heterotopia was also present. CONCLUSIONS: We report a novel variant of the FLNA gene, associated with a severe lung disorder and PNVH. The lung disorder led to respiratory failure during infancy and these pulmonary complications may be the first sign of this disorder. Early recognition with thoracic imaging is important to guide genetic testing, neuroimaging and to define optimal timing of potential therapies, such as lung transplant in progressive lung disease.

Clinical expression of cystic fibrosis in a large cohort of Italian siblings.

BACKGROUND: A clinical heterogeneity was reported in patients with Cystic Fibrosis (CF) with the same CFTR genotype and between siblings with CF. METHODS: We investigated all clinical aspects in a cohort of 101 pairs of siblings with CF (including 6 triplets) followed since diagnosis. RESULTS: Severe lung disease had a 22.2% concordance in sib-pairs, occurred early and the FEV1% at 12 years was predictive of the severity of lung disease in the adulthood. Similarly, CF liver disease occurred early (median: 15 years) and showed a concordance of 27.8% in sib-pairs suggesting a scarce contribution of genetic factors; in fact, only 2/15 patients with liver disease in discordant sib-pairs had a deficiency of alpha-1-antitrypsin (a known modifier gene of CF liver phenotype). CF related diabetes was found in 22 pairs (in 6 in both the siblings). It occurred later (median: 32.5 years) and is strongly associated with liver disease. Colonization by P. aeruginosa and nasal polyposis that required surgery had a concordance > 50% in sib-pairs and were poorly correlated to other clinical parameters. The pancreatic status was highly concordant in pairs of siblings (i.e., 95.1%) but a different pancreatic status was observed in patients with the same CFTR mutations. This suggests a close relationship of the pancreatic status with the "whole" CFTR genotype, including mutations in regulatory regions that may modulate the levels of CFTR expression. Finally, a severe course of CF was evident in a number of patients with pancreatic sufficiency. CONCLUSIONS: Physicians involved in care of patients with CF and in genetic counseling must be aware of the clinical heterogeneity of CF even in sib-pairs that, at the state of the art, is difficult to explain.

A case report on filamin A gene mutation and progressive pulmonary disease in an infant: A lung tissued derived mesenchymal stem cell study.

RATIONALE: Mesenchymal stem cells (MSC) play a crucial role in both the maintenance of pulmonary integrity and the pathogenesis of lung disease. Lung involvement has been reported in patients with the filamin A (FLNA) gene mutation. Considering FLNA's role in the intrinsic mechanical properties of MSC, we characterized MSCs isolated from FLNA-defective lung tissue, in order to define their pathogenetic role in pulmonary damage. PATIENT CONCERNS: A male infant developed significant lung disease resulting in emphysematous lesions and perivascular and interstitial fibrosis. He also exhibited general muscular hypotonia, bilateral inguinal hernia, and deformities of the lower limbs (pes tortus congenitalis and hip dysplasia). Following lobar resection, chronic respiratory failure occurred. DIAGNOSIS: Genetic testing was performed during the course of his clinical care and revealed a new pathogenic variant of the FLNA gene c.7391_7403del; (p.Val2464AlafsTer5). Brain magnetic resonance imaging revealed periventricular nodular heterotopia. INTERVENTIONS AND OUTCOMES: Surgical thoracoscopic lung biopsy was performed in order to obtain additional data on the pathological pulmonary features. A small portion of the pulmonary tissue was used for MSC expansion. Morphology, immunophenotype, differentiation capacity, and proliferative growth were evaluated. Bone marrow-derived mesenchymal stem cells (BM-MSC) were employed as a control. MSCs presented the typical MSC morphology and phenotype while exhibiting higher proliferative capacity (P <.001) and lower migration potential (P=.02) compared to control BM-MSC. LESSONS: The genetic profile and altered features of the MSCs isolated from FLNA-related pediatric lung tissue could be directly related to defects in cell migration during embryonic lung development and pulmonary damage described in FLNA-defective patients.

Chronic spontaneous urticaria or autoinflammatory disease? The therapeutic effect of omalizumab in a pediatric patient.

Chronic spontaneous urticaria (CSU) is a clinical condition characterized by spontaneous or inducible recurrent wheals. This condition may significantly affect quality of life of patients and of their families. Etiology is not identified in 25-85% of cases that are indicated as 'idiopathic', because all diagnostic tests are negative. Autoimmune processes may be present in 30-50% of patients, although a definite etiological diagnosis is seldom possible. Some patients, in fact, have autoantibodies against the high-affinity IgE receptor FcεR1 or IgE. These patients show an increased incidence of anti-thyroid autoantibodies and represent 30-50% of the patients designated as having CSU. Familial cold autoinflammatory syndrome (FCAS) must be distinguished from acquired cold urticaria, which is characterized by a rash occurring within a few minutes after cold exposure, and is often described as 'allergy to cold'. Cold urticaria (CU) is rare in childhood and is not linked to inflammatory markers. The treatment is based on antihistamines. However, in non-responders, a second-line treatment with omalizumab can show efficacy. We describe the clinical case of a 9-year-old-female with recurrent monthly episodes of fever, arthralgia, abdominal pain, and urticaria-angioedema who did not respond to steroids associated with antihistamines, however, showed the complete resolution of the disease with omalizumab.

Clinical impact of Pseudomonas aeruginosa colonization in patients with Primary Ciliary Dyskinesia.

BACKGROUND: Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD. METHODS: Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized. These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters. RESULTS: Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV1) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results. CONCLUSIONS: Lung PA colonization in PCD is associated with more severe disease as shown by the FEV1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients.

Diagnosis of Primary Ciliary Dyskinesia by a Targeted Next-Generation Sequencing Panel: Molecular and Clinical Findings in Italian Patients.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder that alters mucociliary clearance, with consequent chronic disease of upper and lower airways. Diagnosis of PCD is challenging, and genetic testing is hampered by the high heterogeneity of the disease, because autosomal recessive causative mutations were found in 34 different genes. In this study, we clinically and molecularly characterized a cohort of 51 Italian patients with clinical signs of PCD. A custom next-generation sequencing panel that enables the affordable and simultaneous screening of 24 PCD genes was developed for genetic analysis. After variant filtering and prioritization, the molecular diagnosis of PCD was achieved in 43% of the patients. Overall, 5 homozygous and 27 compound heterozygous mutations, 21 of which were never reported before, were identified in 11 PCD genes. The DNAH5 and DNAH11 genes were the most common cause of PCD in Italy, but some population specificities were identified. In addition, the number of unsolved cases and the identification of only a single mutation in six patients suggest further genetic heterogeneity and invoke the need of novel strategies to detect unconventional pathogenic DNA variants. Finally, despite the availability of mutation databases and in silico prediction tools helping the interpretation of variants in next-generation sequencing screenings, a comprehensive segregation analysis is required to establish the in trans inheritance and support the pathogenic role of mutations.

Oral Immunotherapy for Egg Allergy: A Double-Blind Placebo-Controlled Study, with Postdesensitization Follow-Up.

BACKGROUND: Oral immunotherapy (OIT) may be an effective treatment for food allergy in children. It is not clear if the OIT-induced effect is achieved by desensitization (transient state dependent on regular antigen exposure), or by tolerance (persistent condition where the ability to consume the food is retained even after a period of withdrawal). OBJECTIVE: The aim of this study was to investigate the efficacy of OIT-egg desensitization in a double-blind placebo-controlled study, and to evaluate if, after desensitization, tolerance can be maintained. METHODS: Children with egg allergy were randomized to OIT or placebo for 4 months. At the end of the controlled phase, a double-blind food challenge was repeated to confirm the achieved desensitization. Those subjects found to be desensitized were placed on an egg-containing diet for 6 months, followed by an egg avoidance phase for 3 months, when the food challenge was repeated to determine the maintained tolerance. RESULTS: A total of 31 children were randomized to OIT with dehydrated egg white (n = 17) or placebo (n = 14). Of the 17 active patients (1 dropout), 16 achieved desensitization and started the 6-month egg-containing diet. After 3-month of egg avoidance, 31% remained tolerant. In the control group, only 1 passed the final food challenge. Egg-specific IgG4 increased only in the active group. Five active OIT patients had side effects. CONCLUSION: Egg OIT results in desensitization in almost all subjects, although tolerance was maintained in only 1/3 of them after a 3-month period of withdrawal. Side effects were encountered, but the procedure appeared safe. In hen egg allergy, OIT is effective for desensitization.

Stunting is an independent predictor of mortality in patients with cystic fibrosis.

BACKGROUND & AIMS: Some studies have shown a direct relationship between nutritional status and survival in Cystic Fibrosis (CF) patients. Body wasting, defined as a percentage of the ideal body weight for age, has been shown to be an independent predictor of mortality in CF. With respect to height only two studies were performed and these studies suggested that stunting is an important determinant of survival but both did not adjust statistical analysis for confounding variables. We aimed at determining the association between stunting and risk of mortality in CF patients. METHODS: 393 CF patients older than 6 years of age, 95 deceased, as cases, and 298 live, as controls, were enrolled in a nested case-control study. Stunting was defined by a height percentile < 5th. We performed a multivariate statistical analysis including height percentile and the following possible confounding variables: age, gender, Body Mass Index (BMI), Forced Expiratory Volume in 1 s (FEV1), genotype, pancreatic status, CF-related diabetes, colonization with Pseudomonas aeruginosa and/or Burkholderia cepacia. RESULTS: In the adjusted analyses stunting (OR 2.22 [IC 95%1.10-4.46]), wasting (OR 5.27 [IC 95% 2.66-10.41]), and FEV1 < 40% of predicted (OR 10.60 [IC 95% 5.43-20.67]) resulted the covariates that significantly predict the risk of mortality. CONCLUSIONS: Our study shows, for the first time, that stunting is a significant and independent risk factor for mortality in CF patients, and warrants an intervention of nutritional rehabilitation. Considering that nutritional interventions in stunted patients should be prolonged, are invasive and expensive, and might affect self-esteem and body image, their efficacy should be fully assessed by Randomised Controlled Trials.

Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate.

BACKGROUND: Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis. METHODS: We did a multicentre trial in two phases. We enrolled patients aged 5-30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3-6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01812551. FINDINGS: We screened 540 patients and enrolled 171 (mean age 13·8 years, SD 5·9, range 5-30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16·3% in the alendronate group (n=65) versus 3·1% in the placebo group (n=63; p=0·0010). 19 of 57 young people (33·3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, five patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not differ significantly for other adverse events. INTERPRETATION: Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density. FUNDING: Telethon Foundation (Italy).

Nebulized hypertonic saline containing hyaluronic acid improves tolerability in patients with cystic fibrosis and lung disease compared with nebulized hypertonic saline alone: a prospective, randomized, double-blind, controlled study.

BACKGROUND: Hypertonic saline inhalation has been shown to be effective in patients with cystic fibrosis and lung disease. However, adverse events including marked airway narrowing are reported and a bronchodilator must be given before the administration of the product. METHODS: We carried out a prospective, randomized, double-blind, parallel-group, controlled study of a hypertonic saline solution containing hyaluronic acid (Hyaneb) versus standard hypertonic saline therapy to assess whether the presence of hyaluronic acid would improve the tolerability of hypertonic saline. RESULTS AND CONCLUSIONS: The results showed that nebulized Hyaneb was more effective in reducing the need for ß(2) bronchodilators and caused a significant reduction in the incidence of adverse effects compared with nebulized hypertonic saline solution alone. Its safety profile indicates that Hyaneb can be used for the treatment of lung disease in cystic fibrosis.

Inhaled surfactant in the treatment of accidental talc powder inhalation: a new case report.

The use of talcum powder is incorrectly part of the traditional care of infants. Its acute aspiration is a very dangerous condition in childhood. Although the use of baby powder has been discouraged from many authors and the reports of its accidental inhalation have been ever more rare, sometimes new cases with several fatalities have been reported. We report on a patient in which accidental inhalation of baby powder induced severe respiratory difficulties. We also point out the benefits of surfactant administration. Surfactant contributed to the rapid improvement of the medical and radiological condition, preventing severe early and late complications and avoiding invasive approaches.

Epidemiological assessment of Respiratory Syncytial Virus infection in hospitalized infants, during the season 2005-2006 in Palermo, Italy.

OBJECTIVES: Respiratory Syncytial Virus (RSV) is the leading cause of hospitalization for lower respiratory tract infections (LRTI) in young children worldwide.We evaluate the epidemiological and clinical patterns of RSV infection in infants hospitalized for LRTI in in Palermo, South Italy, Sicily. METHODS: We collected the demographic details of infants hospitalized to G. Di Cristina Children's Hospital in Palermo for LRTI between November 2005 and May 2006. We also included all cases occurred in newborns hospitalized in the Neonatal Intensive Care Unit (NICU) Of Palermo. RESULTS: During the studied period, 335/705 hospitalized infants for LRTI were enrolled in the study. The trend of hospitalization started in late winter and lasting until May 2006 with an epidemic peak in spring. 178/335 infants tested for viral infection showed RSV disease. Three cases occurred in preterm newborns hospitalized from birth in NICU. The likelihood to be RSV+, rather than RSV negative (RSV-) was higher for infants < 6 months and lower for infants with history of breast feeding (P < 0.05). RSV infection was associated with a higher likelihood to be admitted to intensive care unit and to a longer hospitalization and oxygen therapy. CONCLUSION: The study shows that, in Sicily, RSV is an important cause of LRTI in infants. The seasonal distribution shows that both LRTI and RSV infections peak in late spring, in contrast to Northern Italy. Our data could help to define the regional appropriate start of prophylactic interventions.

Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 mutations.

Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by perturbed or absent beating of motile cilia, which is referred to as Kartagener syndrome (KS) when associated with situs inversus. We present a German family in which five individuals have PCD and one has KS. PCD was confirmed by analysis of native and cultured respiratory ciliated epithelia with high-speed video microscopy. Respiratory ciliated cells from the affected individuals showed an abnormal nonflexible beating pattern with a reduced cilium bending capacity and a hyperkinetic beat. Interestingly, the axonemal ultrastructure of these respiratory cilia was normal and outer dynein arms were intact, as shown by electron microscopy and immunohistochemistry. Microsatellite analysis indicated genetic linkage to the dynein heavy chain DNAH11 on chromosome 7p21. All affected individuals carried the compound heterozygous DNAH11 mutations c.12384C>G and c.13552_13608del. Both mutations are located in the C-terminal domain and predict a truncated DNAH11 protein (p.Y4128X, p.A4518_A4523delinsQ). The mutations described here were not present in a cohort of 96 PCD patients. In conclusion, our findings support the view that DNAH11 mutations indeed cause PCD and KS, and that the reported DNAH11 nonsense mutations are associated with a normal axonemal ultrastructure and are compatible with normal male fertility.