Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor treatment in children aged 6-11 years with cystic fibrosis in a real-world setting.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF. METHODS: This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV1, LCI2.5, body mass index (BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models. RESULTS: The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy. CONCLUSIONS: Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood.

Covid-19 in cystic fibrosis patients compared to the general population: Severity and virus-host cell interactions.

BACKGROUND: People with cystic fibrosis (pwCF) are considered at risk of developing severe forms of respiratory viral infections. We studied the consequences of COVID-19 and virus-host cell interactions in CF vs. non-CF individuals. METHODS: We enrolled CF and non-CF individuals, with /without COVID-like symptoms, who underwent nasopharyngeal swab for detection of SARS-CoV-2. Gene expression was evaluated by RNA sequencing on the same nasopharyngeal swabs. Criteria for COVID-19 severity were hospitalization and requirement or increased need of oxygen therapy. RESULTS: The study included 171 patients (65 pwCF and 106 non-CF individuals). Among them, 10 pwCF (15.4 %) and 43 people without CF (40.6 %) tested positive at RT-PCR. Symptomatic infections were observed in 8 pwCF (with 2 requiring hospitalization) and in 11 individuals without CF (6 requiring hospitalization). Host transcriptomic analysis revealed that genes involved in protein translation, particularly ribosomal components, were downregulated in CF samples irrespective of SARS-CoV-2 status. In SARS-CoV-2 negative individuals, we found a significant difference in genes involved with motile cilia expression and function, which were upregulated in CF samples. Pathway enrichment analysis indicated that interferon signaling in response to SARS-CoV-2 infection was upregulated in both pwCF and non-CF subjects. CONCLUSIONS: COVID-19 does not seem to be more severe in CF, possibly due to factors intrinsic to this population: the lower expression of ribosomal genes may downregulate the protein translation machinery, thus creating an unfavorable environment for viral replication.

Severity of SARS-CoV-2 infection in a hospital population: a clinical comparison across age groups.

BACKGROUND: Children tend to have milder forms of COVID-19 than adults, however post-acute complications have been observed also in the paediatric population. In this study, we compared COVID-19-related outcomes and long-term complications between paediatric and adult patients infected by SARS-CoV-2. METHODS: The study is based on individuals enrolled from October 2020 to June 2021 in the DECO COVID-19 multicentre prospective study supported by the Italian Ministry of Health (COVID-2020-12371781). We included individuals with RT-PCR -confirmed SARS-CoV-2 infection, who were evaluated in the emergency department and/or admitted to COVID-dedicated wards. The severity of SARS-CoV-2 infection was compared across age groups (children/adolescents aged < 18 years, young/middle-aged adults aged 18-64 years and older individuals) through the relative risk (RR) of severe COVID-19. Severity was defined by: 1) hospitalization due to COVID-19 and/or 2) need or supplemental oxygen therapy. RR and corresponding 95% confidence intervals were estimated using log-binomial models. RESULTS: The study included 154 individuals, 84 (54.5%) children/adolescents, 50 (32.5%) young/middle-aged adults and 20 (13%) older adults. Compared to young/middle-aged adults the risk of hospitalization was lower among paediatric patients (RR: 0.49, 95% CI: 0.32-0.75) and higher among older adults (RR: 1.52, 95% CI: 1.12-2.06). The RR of supplemental oxygen was 0.12 (95% CI: 0.05-0.30) among children/adolescents and 1.46 (95% CI: 0.97-2.19) among older adults. Three children developed multisystem inflammatory syndrome (MIS-C), none was admitted to intensive care unit or reported post-acute Covid-19 complications. CONCLUSIONS: Our study confirms that COVID-19 is less severe in children. MIS-C is a rare yet severe complication of SARS-CoV-2 infection in children and its risk factors are presently unknown.

Cepacia syndrome in cystic fibrosis: A systematic review of the literature and possible new perspectives in treatment.

BACKGROUND: Cepacia syndrome (CS) is an acute, necrotizing pneumonia with a high mortality rate, occurring in patients with cystic fibrosis (CF) infected with Burkholderia cepacia complex (BCC). Due to its low incidence, data on this condition are limited. METHODS: We conducted a systematic review of the reported cases of CS by searching MEDLINE, Embase and the Cochrane Library to improve knowledge of this rare but potentially lethal condition. RESULTS: We included 15 eligible articles, describing 18 cases (9 females) of CS. Median age at onset was 22 years (range: 10-60 years); median time to CS after first infection by BCC was 5 years (range: 1-26 years). Burkholderia cenocepacia was the most frequently reported causative agent. All patients received intravenous antibiotic treatment (most frequently including cotrimoxazole), while inhaled antibiotics were used in five patients (27.8%). Immunosuppressant agents were the most commonly prescribed supportive treatment (n = 7, 38.9%). Half of the patients died (9/18, 50%). CONCLUSIONS: This study describes epidemiological, clinical characteristics, and prognosis of CS cases reported over the last 24 years. CS is a rare yet severe complication of BCC infection in patients with CF, which occurs several years after BCC colonization and has a negative outcome in 50% of the patients. Data are too scanty to identify the most effective therapeutic approach.

Impact of COVID-19 on Lung Disease in People with Cystic Fibrosis: A 6-Month Follow-Up Study on Respiratory Outcomes.

BACKGROUND: The impact of COVID-19 on respiratory outcomes in people with cystic fibrosis (pwCF) has not been clearly characterized. We evaluated changes in respiratory function indicators derived from spirometry and pulmonary exacerbation rates 6 months after SARS-CoV-2 infection. METHODS: This multicentre prospective study was based on pwCF enrolled between October, 2020 and June, 2021 in the DECO COVID-19 project. PwCF complaining of COVID-like symptoms were tested with real-time polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab. Mean changes in respiratory function indicators and time to first episode of pulmonary exacerbation were compared in RT-PCR-positive and RT-PCR-negative patients. Regression models were used to adjust for baseline percent predicted forced expiratory volume in one second (ppFEV1) values, number of comorbidities, and initiation of CFTR modulator therapy during the follow-up. RESULTS: We enrolled 26 pwCF with RT-PCR-confirmed infection and 42 with a RT-PCR-negative test. After 6 months of follow-up, mean ppFEV1 changes were not significantly different between groups (+0.3% in positive vs. +0.2% in negative patients, p = 0.19). The 6-month cumulative probabilities of a first episode of pulmonary exacerbation were: 0.425 among RT-PCR-negative patients and 0.465 among those with a positive test (adjusted hazard ratio: 0.88, 95% CI: 0.44-1.75). CONCLUSIONS: COVID-19 did not appear to negatively influence respiratory outcomes of pwCF at 6 months from infection.

Immunogenicity of BNT162b2 mRNA-Based Vaccine against SARS-CoV-2 in People with Cystic Fibrosis According to Disease Characteristics and Maintenance Therapies.

During the SARS-CoV-2 vaccination campaign, people with CF (pwCF) were considered a clinically vulnerable population. However, data on the immunogenicity of anti-SARS-CoV-2 vaccines in pwCF are lacking. We conducted a prospective study enrolling all patients aged > 12 and who were followed-up in our CF center and received two doses of the BNT162b2 vaccine in the period of March−October 2021. Blood samples were taken from them for the quantification of antibodies to the SARS-CoV-2 spike protein receptor binding domain immediately before receiving the first dose and 3 and 6 months after the second dose. We enrolled 143 patients (median age: 21 years, range: 13−38), 16 of whom had had a previous infection. Geometric mean antibody titer (GMT) 3 months after vaccination was 1355 U/mL (95% CI: 1165−1575) and decreased to 954 U/mL (95% CI: 819−1111) after 6 months (p < 0.0001). GMT was higher among previously infected patients as compared to those naïve to SARS-CoV-2 (6707 vs. 1119 U/mL at 3 months and 4299 vs. 796 U/mL at 6 months, p < 0.0001) with no significant differences in the rate of decline over time (p = 0.135). All pwCF mounted an antibody response after two doses of the BNT162b2 vaccine, which waned at 6 months from vaccination. Age ≥ 30 years and the use of inhaled corticosteroids were associated with a lower humoral response. Between the second and the third doses, nine episodes of vaccine breakthrough infections were observed.

A successful treatment of a lobar atelectasis in a patient with cystic fibrosis.

Lobar atelectasis may be a complication of pulmonary exacerbations in cystic fibrosis (CF). There are no established guidelines on the management of this condition in patients with CF. Therapeutic bronchoscopy with recombinant human deoxyribonuclease (rhDNase) instillation has been described to be successful in patients not responding to conservative measures. We describe a case of a young man with CF, with previously mild impaired lung function, presenting with cough, desaturation, and worsening dyspnea, persisting for over 6 weeks, despite conservative therapy. Thoracic imaging showed right lower lobe atelectasis, which was successfully treated with bronchoscopy and instillation of rhDNase. Long-term resolution of the atelectasis was confirmed with chest magnetic resonance imaging follow-up.

Immunological profiles of children with recurrent otitis media with or without spontaneous tympanic membrane perforation and of children with recurrent respiratory infections.

OBJECTIVES: The primary aim of this study was to compare the immunological profiles of children affected by recurrent acute otitis media (rAOM) with and without spontaneous tympanic membrane perforation (STMP). The secondary aim was to compare immunological features of children without parameters outside the normal range and affected by either rAOM or recurrent respiratory tract infections (rRTI). METHODS: In this study, otherwise healthy children (<10 years of age) with rAOM or rRTI were included. Data on perinatal history, vaccination status, presence of risk factors for rAOM or rRTI (including personal or family history of allergy) and number of infectious episodes in the previous 12 months were retrospectively obtained. Furthermore, data on immunological profile (blood cell count, circulating IgA, IgG, IgM and total IgE, IgG subclasses and lymphocyte subpopulations) were collected. The immune profile of children affected by rAOM with and without STMP were compared. Among children with parameters within normal range, we compared the levels of the immunological parameters of children affected by rAOM (with and without STMP) and rRTI. RESULTS: The study involved a total of 751 children: 566 (75.3%) with rAOM and 185 (24.7%) with rRTI. Among the 566 children with rAOM, 39.7% had uncomplicated rAOM and 60.3% had rAOM with STMP. The mean age of the study population was 34.9 (SD 20.5) months. The frequency of children with parameters outside the normal range was similar among children with rAOM with (4.9%) and without STMP (6.1%). Among subjects without parameters outside the normal range, children with uncomplicated rAOM had significantly lower serum IgG, lymphocyte CD8+ and CD19+ and significantly higher IgG2 levels than children affected by rAOM with STMP. Finally, children with rAOM had lower levels of IgA, IgM and IgG2 and higher levels of IgG, lymphocyte CD19+ and CD16/56+ compared to children with rRTI. CONCLUSIONS: A low (<6.5%) percentage of children with rAOM with or without STMP present parameters outside the normal range. Among subjects without parameters outside the normal range, children with uncomplicated rAOM have a different immune profile as compared to those with STMP and rRTI. New prospective studies are needed to further explore the immune features of children affected by rAOM with and without STMP.

SARS-CoV-2 antibodies among people with cystic fibrosis prior to the vaccination campaign: A seroprevalence study in two specialized centres in Northern Italy.

The prevalence of anti-SARS-CoV-2 antibodies in people with cystic fibrosis (CF) is largely unknown. We carried out a cross-sectional study between March and June 2021 with the aim of estimating the seroprevalence of anti-SARS-CoV-2 antibodies in two CF centres in Northern Italy. Total serum anti-SARS-CoV-2 (spike) antibodies levels were measured and values ≥0.8 U/mL were considered positive. Among 434 patients aged >12 years, 64 patients had a positive result (14.7%, 95% CI: 11.5-18.4), 36 (56.3%) without experiencing any COVID-19-related symptoms. Three out of 49 transplanted patients tested positive with an odds ratio for a positive result among transplanted as compared to non-transplanted patients of 0.35 (95% CI: 0.07-1.14). No significant differences were observed between sexes, age groups, socioeconomic status and lung disease severity. In conclusion, SARS-CoV-2 has infected a relatively high proportion of our patients but in most cases the infection was asymptomatic.

Cytokine storm syndrome in a young patient with cystic fibrosis.

We report the case of a patient with cystic fibrosis (CF) presenting with a full-blown cytokine storm syndrome probably triggered by infection. This condition is rare and the diagnosis can be particularly difficult in patients with a complex chronic disease such as CF. However, timely recognition and appropriate treatment in the early stages are key to avoiding a potentially fatal course.

Steroid Pulse Therapy for Severe Central Nervous System Involvement in Shiga Toxin-Producing Escherichia coli-Related Hemolytic Uremic Syndrome.

We report on the case of a 7-year-old boy with Shiga toxin-producing Escherichia coli-related hemolytic uremic syndrome (STEC-HUS), initially presenting with abdominal pain as the only clinical feature and thus requiring differential diagnosis with a surgical emergency. Diagnosis of STEC-HUS was made with the appearance of bloody diarrhea and renal function impairment, and the clinical picture rapidly progressed to multiorgan failure. Relatively late and severe central nervous system (CNS) involvement was present, characterized by subacute encephalitis progressing to coma, which became apparent when the acute phase of thrombotic microangiopathy was resolving. Therefore, neurologic manifestations were thought to be related to reperfusion damage to the CNS and high-dose IV steroid pulse therapy was empirically administered. Following this therapeutic scheme, neurologic involvement resolved with no sequelae. This case offers several points of discussion on the clinical presentation and the diagnostic approach to STEC-HUS, on the related neurologic complications, and on a novel approach to their management.

Role of ocular cytology in vernal keratoconjunctivitis.

BACKGROUND: Children with vernal keratoconjunctivitis (VKC) present symptoms that are similar to other ocular allergies, but more pronounced, and are controlled using topical steroids. To avoid excessive and prolonged use of topical steroid eye drops, over the past 20 years galenic eye drops of cyclosporine with a concentration of 1% to 2% and tacrolimus with a concentration of 0.1% have been introduced as a treatment for the severe and unresponsive forms. The main symptoms of VKC occur most frequently during the spring and tend to get worse during the summer, meaning that affected children tend to avoid exposure to sunlight. The aim of this study was to assess the most common cell types present in the conjunctiva of children with VKC, how ocular treatment can influence them, and whether affected children express a typical conjunctival pattern, which could be useful as a pathognomonic pattern of VKC, allowing us to study this rare eye disease. METHOD: This was a cohort study of 56 children, of whom 17 were not receiving any treatment at the time of testing, 14 were using steroid eye drops or had taken them in the previous 10 days, and 25 were treated with cyclosporine eye drops or tacrolimus eye drops 0.1%. RESULT: Children in group 1 (no topical therapy) express more epithelial cells, neutrophils, mast cells, eosinophils, and lymphocytes than the other two groups. CONCLUSION: Given the ease of performance, when conducting further longitudinal studies, the conjunctival cytology examination could be used, on the one hand, to diagnose VKC, especially when the clinical diagnosis is uncertain, and, on the other, to follow disease evolution and monitor the response to topical treatment.

Phenotype Profiling and Allergy in Otitis-Prone Children.

Background: Otitis-prone children can present some distinctive clinical patterns and although a number of known risk factors for recurrent acute otitis media (RAOM) are known, no dedicated epidemiological models have been developed to explain clinical heterogeneity. Methods: A preliminary retrospective pilot study was planned to evaluate the possible effect of allergic disease in the development of different disease phenotypes in otitis-prone children aged 3-10 years, particularly the absence (simple RAOM), or presence of episodes of otitis media with effusion between acute infections (RAOM with OME). Results: Analysis was based on the data contained in 153 charts (55.6% males, mean age of 59.4 ± 16.4 months). 75.8% of children had a simple RAOM and 24.2% a RAOM with OME. Atopy or allergy were documented in respectively 47.7 and 41.3% of children considered as a whole. The prevalence of atopy or allergy was significantly higher in the children with a RAOM with OME (atopy: 73.0 vs. 39.5%, p < 0.001; allergy: 60.0 vs. 36.1%, p = 0.049), who also more frequently showed adenoidal hypertrophy (p = 0.016), chronic adenoiditis (p = 0.007), conductive hearing loss (p = 0.004), and impaired tympanometry (p < 0.001). Conclusions: These data suggest that children with a RAOM with OME are clinically different from children with simple RAOM, as they have a more complex clinical presentation that includes not only adenoidal disease and audiological impairment, but also an underlying allergy or atopy. The possibility that the factors mentioned above may be differently involved in the heterogeneous clinical manifestations occurring in otitis-prone children needs to be further investigated in ad hoc epidemiological studies.

Impact of adenotonsillectomy on pediatric quality of life: review of the literature.

Adenotonsillectomy (ADT) is one of the most widely used procedures in the treatment of paediatric recurrent acute tonsillitis (RAT) and obstructive sleep apnoea syndrome (OSAS), both of which have significant repercussions on the patients' quality of life (QoL). The purpose of our review of literature was to highlight the great variety of tools that are currently used to evaluate QoL in children, to examine data available on their efficacy and the feasibility of their use in daily clinical practice, and to determine possible limitations related to an indirect and subjective assessment of QoL in children.Although the use of different parameters makes it difficult to compare the published studies, an analysis of the evidence currently available in the literature suggests that ADT has a generally positive impact on the QoL (especially in case of OSAS). It also highlights the importance of combining tonsillectomy and adenoidectomy in the treatment of OSAS, and documents the comparability of tonsillectomy and tonsillotomy in improving obstructive symptoms. In conclusion, our findings suggest that literature supports that ADT is associated with positive changes in QOL; however further studies using comparable standardised criteria are necessary to confirm the size and duration of this benefit.

Inhaled Antibiotic Therapy for the Treatment of Upper Respiratory Tract Infections.

Upper respiratory tract infections (URTIs), primarily acute rhinopharyngitis, tonsillitis, adenoiditis, and rhinosinusitis (RS), are major causes of morbidity in both children and adults of any age. In addition to the frequent occurrence of related medical problems and the associated socioeconomic costs, URTIs have a significant impact on the quality of life of patients and their families, and have placed an escalating financial burden on the global healthcare system. Most URTIs are caused by viruses and require only symptomatic treatment. However, a number of cases, particularly those that are severe, recurrent, or chronic, have a bacterial etiology and need appropriate antimicrobial treatment to avoid complications or frequent exacerbations. To ensure therapeutic antibiotic concentration without any significant systemic drug exposure, the direct delivery of antibiotics to the upper respiratory tract by inhalation is a potential solution. The main aim of this review is to determine if and when aerosolized antibiotics can be effectively used to treat URTIs in noncystic fibrosis (non-CF) patients. There is a lack of strong evidence for the use of nebulized antibiotics to treat URTIs in non-CF patients. The only disease for which positive results have been reported is chronic RS in adults. However, conflicting conclusions have been drawn, and many problems related to the drug of choice, dosages, duration of treatment, and the best device for administration remain unsolved. Further studies are needed to better determine when and through which treatment modalities inhaled antibiotics can positively modify the course of chronic RS.

Genetic Polymorphisms of Functional Candidate Genes and Recurrent Acute Otitis Media With or Without Tympanic Membrane Perforation.

Evaluation of the genetic contribution to the development of recurrent acute otitis media (rAOM) remains challenging. This study aimed to evaluate the potential association between single nucleotide polymorphisms (SNPs) in selected genes and rAOM and to analyze whether genetic variations might predispose to the development of complicated recurrent cases, such as those with tympanic membrane perforation (TMP).A total of 33 candidate genes and 47 SNPs were genotyped in 200 children with rAOM (116 with a history of TMP) and in 200 healthy controls.INFγ rs 12369470CT was significantly less common in the children with rAOM than in healthy controls (odds ratio [OR] 0.5, 95% confidence interval [CI] 0.25-1, P = 0.04). Although not significant, interleukin (IL)-1ß rs 1143627G and toll-like receptor (TLR)-4 rs2737191AG were less frequently detected in the children with rAOM than in controls. The opposite was true for IL-8 rs2227306CT, which was found more frequently in the children with rAOM than in healthy controls. The IL-10 rs1800896TC SNP and the IL-1α rs6746923A and AG SNPs were significantly more and less common, respectively, among children without a history of TMP than among those who suffered from this complication (OR 2.17, 95% CI 1.09-4.41, P = 0.02, and OR 0.42, 95% CI 0.21-0.84, P = 0.01).This study is the first report suggesting an association between variants in genes encoding for factors of innate or adaptive immunity and the occurrence of rAOM with or without TMP, which confirms the role of genetics in conditioning susceptibility to AOM.

Middle ear problems in children hospitalised because of lower respiratory tract infections: a comparison between two cohorts in Burundi and Italy.

OBJECTIVES: To compare the prevalence of acute otitis media (AOM) and otitis media with effusion (OME) in children hospitalized for acute lower respiratory infections (LRTIs) in Burundi and Italy. METHODS: The study, which was conducted from 1 February to 30 April 2011 at the hospital of Kiremba (Burundi, Africa) and at Paediatric Clinic 1 of the University of Milan (Italy), enrolled patients aged <5 years who were hospitalised because of LRTIs. Upon admission, the children underwent an otological examination (pneumatic otoscopy and tympanometry), and middle ear diseases were compared between the two groups. RESULTS: A total of 108 children enrolled in Burundi (44 males; median age 17 months) were compared to 108 patients enrolled in Italy (53 males; median age 19 months). About one-third of the children in Burundi (33, 30.6%) had normal middle ears. AOM was never diagnosed, whereas OME was detected in 74 children (68.5%: bilateral in 51, 68.9%, and unilateral in 23, 31.1%). The prevalence of OME decreased with increasing age: it was 86.5% in children aged <12 months, 73.7% in those aged 12-24 months, and 43.8% in those aged >24 months (p < 0.001). There was no difference in the proportion of children with OME in Burundi (68.5%) and Italy (63.9%; p = 0.47). OME was significantly more frequent in the children with pneumonia admitted in Burundi than in the children with pneumonia admitted in Italy (p = 0.004). CONCLUSIONS: In children hospitalized for lower respiratory tract infection, OME is almost as frequently seen in developing countries like Burundi, Africa, as in developed countries like Italy. Follow-up monitoring of these children might be required to assess if OME is just a transient phenomenon.