Aryl Hydrocarbon Receptor Agonism Antagonizes the Hypoxia-driven Inflammation in Cystic Fibrosis.

Hypoxia contributes to the exaggerated yet ineffective airway inflammation that fails to oppose infections in cystic fibrosis (CF). However, the potential for impairment of essential immune functions by HIF-1α (hypoxia-inducible factor 1α) inhibition demands a better comprehension of downstream hypoxia-dependent pathways that are amenable for manipulation. We assessed here whether hypoxia may interfere with the activity of AhR (aryl hydrocarbon receptor), a versatile environmental sensor highly expressed in the lungs, where it plays a homeostatic role. We used murine models of Aspergillus fumigatus infection in vivo and human cells in vitro to define the functional role of AhR in CF, evaluate the impact of hypoxia on AhR expression and activity, and assess whether AhR agonism may antagonize hypoxia-driven inflammation. We demonstrated that there is an important interferential cross-talk between the AhR and HIF-1α signaling pathways in murine and human CF, in that HIF-1α induction squelched the normal AhR response through an impaired formation of the AhR:ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF-1ß heterodimer. However, functional studies and analysis of the AhR genetic variability in patients with CF proved that AhR agonism could prevent hypoxia-driven inflammation, restore immune homeostasis, and improve lung function. This study emphasizes the contribution of environmental factors, such as infections, in CF disease progression and suggests the exploitation of hypoxia:xenobiotic receptor cross-talk for antiinflammatory therapy in CF.

A Prospective Study of Hematologic Complications and Long-Term Survival of Italian Patients Affected by Shwachman-Diamond Syndrome.

OBJECTIVE: To describe the hematologic outcome and long-term survival of patients enrolled in the Shwachman-Diamond syndrome Italian Registry. STUDY DESIGN: A retrospective and prospective study of patients recorded in the Shwachman-Diamond syndrome Italian Registry. RESULTS: The study population included 121 patients, 69 males and 52 females, diagnosed between 1999 and 2018. All patients had the clinical diagnosis confirmed by mutational analysis on the SBDS gene. During the study period, the incidence of SDS was 1 in 153 000 births. The median age of patients with SDS at diagnosis was 1.3 years (range, 0-35.6 years). At the first hematologic assessment, severe neutropenia was present in 25.8%, thrombocytopenia in 25.5%, and anemia in 4.6% of patients. A normal karyotype was found in 40 of 79 patients, assessed whereas the most frequent cytogenetic abnormalities were isochromosome 7 and interstitial deletion of the long arm of chromosome 20. The cumulative incidence of severe neutropenia, thrombocytopenia, and anemia at 30 years of age were 59.9%, 66.8%, and 20.2%, respectively. The 20-year cumulative incidence of myelodysplastic syndrome/leukemia and of bone marrow failure/severe cytopenia was 9.8% and 9.9%, respectively. Fifteen of 121 patients (12.4%) underwent allogeneic stem cell transplantation. Fifteen patients (12.4%) died; the probability of overall survival at 10 and 20 years was 95.7% and 87.4%, respectively. CONCLUSIONS: Despite an improvement in survival, hematologic complications still cause death in patients with SDS. Further studies are needed to optimize type and modality of hematopoietic stem cell transplantation and to assess the long-term outcome in nontransplanted patients.

Extensive molecular analysis suggested the strong genetic heterogeneity of idiopathic chronic pancreatitis.

Rationale: Genetic features of Chronic Pancreatitis (CP) have been extensively investigated mainly testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. Objectives: 80 patients with Idiopathic CP were investigated using Next Generation Sequencing approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen; modifier genes of Cystic Fibrosis phenotype; pancreatic secretion and ion homeostasis; Calcium signalling and zymogen granules exocytosis; autophagy; autoimmune pancreatitis related genes. Results: We detected mutations in 34 out of 70 genes examined; 64/80 patients (80.0%) were positive for mutations in one or more genes, 16/80 patients (20.0%) had no mutations. Mutations in CFTR were detected in 32/80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38/64 patients positive for mutations showed variants in two or more genes (59.3%). Conclusions: Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in chronic pancreatitis and that trans-heterozygosity may predispose to the idiopathic CP phenotype.

Lung clearance index short-term variability in cystic fibrosis: a pre-post pulmonary exacerbation study.

BACKGROUND: Multiple Breath washout (MBW) represents an important tool to detect early a possible pulmonary exacerbation especially in Cystic Fibrosis (CF) disease. Lung clearance index (LCI) is the most commonly reported multiple breath washout (MBW) index and in the last years was used as management measure for evaluation. Our aim was to analyze clinical utility of LCI index variability in pulmonary exacerbation in CF after intravenous (IV) antibiotic therapy. METHODS: A single-center study was conducted at CF Unit of Bambino Gesù Children's Hospital among hospitalized > 3 years patients for pulmonary exacerbations and treated with antibiotic IV treatment for 14 days. MBW and spirometry were evaluated within 72 h of admission to hospital and at the end of hospitalization. Descriptive analysis was conducted and correlations between quantitative variables were investigated. RESULTS: Fifty-seven patients (M22/F35) with an average age 18.56 (± 8.54) years were enrolled. LCI2.5 was significantly reduced at the end of antibiotic treatment in both pediatric and adult populations with an average reduction of -6,99%; 37/57 patients denoted an improvement, 20/57 are stable or worsened in LCI2.5 values and 4/57 (7.02%) had a significant deterioration (> 15%) at end of treatment. On the contrary a significative elevation of FEV1 and FVC were found, respectively of + 7,30% and of + 5,46%. A positive good correlection among LCI 2.5 and Scond (rho = + 0,615, p = 0.000) and LCI 2.5 and Sacin (rho = + 0,649, p = 0.000) and a negative strong correlation between FEV1 and LCI 2.5 were found in post treatment period. A similar modification of LCI 2.5 and FEV1 was noticed in both adult and pediatric population. CONCLUSIONS: LCI may have a role in the routine clinical care of both adult and pediatric CF patients as a good tool to assess response to IV antibiotic end-therapy in the same way as FEV1.

Longitudinal Effects of Elexacaftor/Tezacaftor/Ivacaftor: Multidimensional Assessment of Neuropsychological Side Effects and Physical and Mental Health Outcomes in Adolescents and Adults.

BACKGROUND: Italy initiated elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (pwCF) in July 2021. It has led to dramatic improvements in lung function, BMI, sweat chloride, and respiratory symptoms. However, few data are available on side effects or effects on a broad range of outcomes. RESEARCH QUESTION: How does ETI affect mental health, cognitive processing, neuropsychological side effects, GI symptoms, and health-related quality of life over time? STUDY DESIGN AND METHODS: This was a prospective, "real-world" longitudinal study. Participants were recruited consecutively and evaluated at initiation (T0) and after 1 month, 3 months, and 6 months of starting treatment. Assessments included depression (nine-item Patient Health Questionnaire), anxiety (seven-item Generalized Anxiety Disorder), cognition (Symbol Digit Modalities Test), GI Symptom Tracker, and health-related quality of life (Cystic Fibrosis Questionnaire-Revised). Based on literature, an ad hoc questionnaire was developed to assess side effects: insomnia, headache, memory problems, "brain fog," and concentration problems. Following descriptive analyses, longitudinal data were analyzed by using mixed models for repeated measures, controlling for age and sex when appropriate. RESULTS: Ninety-two consecutive pwCF (female/male, 46/46; mean age, 25.4 years) participated. FEV1 increased initially and then remained stable. BMI also increased significantly from T0 to 6 months (P < .01). Depression improved from T0 to 1 month (P < .001); however, no changes in anxiety were found. Cognitive processing improved from T0 to subsequent assessments. Positive changes were reported on the GI Symptom Tracker for stools and adherence challenges, although no changes were found for abdominal pain and digestion. Side effects occurred in 10% to 29%, with no reduction over time; insomnia increased significantly across time. Female participants reported more side effects than male participants (ie, insomnia, headache, concentration problems, brain fog). INTERPRETATION: This prospective study evaluated the effects of ETI using multiple measures. Significant improvements were found in many domains; however, side effects were reported by a substantial proportion of pwCF, with no improvements over time. Female participants reported more side effects than male participants. pwCF should be followed up systematically to assess the frequency of side effects after starting this new modulator.

An inflammatory Signature of Glucose Impairment in Cystic Fibrosis.

Objective and Design: Cystic fibrosis-related diabetes (CFRD) is a severe complication associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Extensive inflammatory state in CF leads to pancreas damage and insulin resistance with consequent altered glucose tolerance and CFRD development. The aim of the present study was to identify circulating levels of inflammatory markers specifically associated with impaired glucose tolerance (IGT) and overt CFRD in a sample of young adults with CF. Materials and Methods: Sixty-four CF outpatients, without evident active pulmonary exacerbation, infectious and autoimmune diseases, were enrolled in the study and the levels of 45 inflammatory serum mediators were measured through x magnetic bead panel multiplex technology. Results: Serum levels of PDGF-AA, CCL20/MIP3α, IFNα, CCL11/eotaxin, CXCL1/GROα, GMCSF, B7H1/PDL1, IL13, IL7, VEGF, and TGFα were all significantly (p<0.05) elevated in patients according to glycemic status and directly correlated with glycated hemoglobin and C-reactive protein levels. Conclusion: Our findings suggest that increased levels of specific circulating inflammatory mediators are directly associated with impaired glucose tolerance in CF patients, thus, potentially implicating them in CFRD pathogenesis and warranting larger longitudinal studies to validate their monitoring as predictor of CFRD onset.

Environmental Microbial Contamination during Cystic Fibrosis Group-Based Psychotherapy.

Living with cystic fibrosis (CF) exposes patients to the risk of developing anxiety and depression, with therapeutic compliance reduction, hospitalization increase, and quality of life and health outcomes deterioration. As pulmonary infections represent the major cause of morbidity and mortality in patients with CF, environmental contamination due to droplet dispersion and the potential transmission from environment to such patients should be prevented. Therefore, in-person contact, including group-based psychotherapy, are strongly discouraged. Nevertheless, group sharing of disease-related experiences represents a way to recover the inner resources essential for dealing with a chronic pathology. Keeping in mind the guidelines for infection control, the aim of this study is to evaluate the risk of the dissemination of microorganisms in a restricted environment where patients with CF attend group psychotherapy sessions. Five patients, selected according to their microbiological status, attended 32 group-based psychological/psychoanalytic meetings. Before each session, they were asked to observe the infection control recommendations. Microbiological environmental monitoring (MEM) has been performed to evaluate both air and surface contamination. As reported, a strict observation of standard precautions allows one to avoid environmental contamination by pathogens of the CF respiratory tract. Although infection control guidelines discourage group-based psychological/psychoanalytic interventions, our observations report the feasibility and safety of group psychotherapy when strict precautions are taken.

Maturation of spontaneous arousals in healthy infants.

OBJECTIVE: The propensity to arouse from sleep is an integrative part of the sleep structure and can have direct implications in various clinical conditions. This study was conducted to evaluate the maturation of spontaneous arousals during the first year of life in healthy infants. DESIGN: Nineteen infants were studied with nighttime polysomnography on 3 occasions: aged 2 to 3 months, 5 to 6 months, and 8 to 9 months. Ten infants with a median age of 3 weeks were added to the main study to assess the maturation of arousals from birth. The infants were born full-term, were healthy at the time of study, and had no history of apnea. Sleep-state and cardiorespiratory parameters were scored according to recommended criteria. Arousals were differentiated into subcortical activations or cortical arousals, according to the presence of autonomic and/or electroencephalographic changes. Frequencies of subcortical activations and cortical arousals were studied at different ages in both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. RESULTS: During sleep time, the frequency of total arousals, cortical arousals, and subcortical activations decreased with age. The maturation of the arousal events differed according to sleep states and types of arousals. With age, cortical arousals increased in REM sleep (P = 0.006) and decreased in NREM sleep (P = 0.01). Subcortical activations decreased with age in REM (P < 0.001) and NREM sleep (P < 0.001). CONCLUSIONS: During total sleep time, the frequency of cortical arousals and subcortical activations decreased with maturation. However, the maturation process was different between cortical arousals and subcortical activations. This finding suggests a difference in the maturational sequence of the different brain centers regulating arousals.

Metabolomic Analysis by Nuclear Magnetic Resonance Spectroscopy as a New Approach to Understanding Inflammation and Monitoring of Pharmacological Therapy in Children and Young Adults With Cystic Fibrosis.

15-F2t-Isoprostane, a reliable biomarker of oxidative stress, has been found elevated in exhaled breath condensate (EBC), a non-invasive technique for sampling of airway secretions, in patients with cystic fibrosis (CF). Azithromycin has antioxidant properties in experimental models of CF, but its effects on oxidative stress in CF patients are largely unknown. Primary objective of this pilot, proof-of-concept, prospective, parallel group, pharmacological study, was investigating the potential antioxidant effects of azithromycin in CF patients as reflected by EBC 15-F2t-isoprostane. Secondary objectives included studying the effect of azithromycin on EBC and serum metabolic profiles, and on serum 15-F2t-isoprostane. In CF patients who were on maintenance treatment with oral vitamin E (200 UI once daily), treatment with oral azithromycin (250 or 500 mg depending on body weight) plus vitamin E (400 UI once daily) (group A) (n = 24) or oral vitamin E alone (400 UI once daily) (group B) (n = 21) was not associated with changes in EBC 15-F2t-isoprostane concentrations compared with baseline values after 8-weeks treatment or 2 weeks after treatment suspension. There was no between-group difference in post-treatment EBC 15-F2t-isoprostane. Likewise, no within- or between-group differences in serum 15-F2t-isoprostane concentrations were observed in either study group. NMR spectroscopy-based metabolomics of EBC shows that suspension of both azithromycin plus vitamin E and vitamin E alone has a striking effect on metabolic profiles in EBC. Between-group comparisons show that EBC metabolite distribution after treatment and 2 weeks after treatment suspension is different. Quantitative differences in ethanol, saturated fatty acids, acetate, acetoin/acetone, and methanol are responsible for these differences. Our study was unable to show antioxidant effect of azithromycin as add-on treatment with doubling the dose of oral vitamin E as reflected by 15-F2t-isoprostane concentrations in EBC. Add-on therapy with azithromycin itself does not induce EBC metabolite changes, but its suspension is associated with EBC metabolic profiles that are different from those observed after vitamin E suspension. The pathophysiological and therapeutic implications of these findings in patients with stable CF are unknown and require further research. Preliminary data suggest that EBC NMR-based metabolomics might be used for assessing the effects of pharmacological treatment suspension in stable CF patients.

Spontaneous arousability in prone and supine position in healthy infants.

STUDY OBJECTIVE: Compared with control infants, those who will be future victims of sudden infant death syndrome (SIDS) show a decreased arousability during sleep, with fewer cortical arousals and more-frequent subcortical activations. These findings suggest an incomplete arousal process in victims of SIDS. Prone sleep position, a major risk factor for SIDS, has been reported to reduce arousal responses during sleep. The present study was undertaken to evaluate whether the prone sleep position impairs the arousal process in healthy infants. METHODS: Twenty-four healthy infants were studied polygraphically during 1 night; 12 infants regularly slept supine and 12 infants regularly slept prone. Infants were matched for sex, gestational age, and age at recording. Arousals were differentiated into subcortical activations or cortical arousals, according to the presence of autonomic and/or electroencephalographic changes. Frequencies of subcortical activations and cortical arousals were compared in the prone- and the supine-sleeping infants. RESULTS: Compared with supine sleepers, prone sleepers had significantly fewer cortical arousals during rapid eye movement (REM) sleep (p = .043). There were no significant differences in cortical arousals between the 2 groups during non-REM sleep. No significant differences were seen in the frequencies of subcortical activations during both REM and non-REM sleep between supine and prone sleepers. The ratio of cortical arousal to subcortical activation showed no significant differences between the prone and the supine sleepers. CONCLUSIONS: Prone sleep position decreased the frequency of cortical arousals but did not change the frequency of subcortical activations, as has been previously found in SIDS victims. These results suggest specific pathways for impairment of the arousal process in SIDS victims.

NREM sleep instability is reduced in children with attention-deficit/hyperactivity disorder.

STUDY OBJECTIVES: To evaluate non-rapid eye movement sleep instability (NREM), as measured by the cyclic alternating pattern (CAP), in a cohort of children with attention-deficit/hyperactivity disorder (ADHD) and normal controls. DESIGN: Prospective study. SETTINGS: Sleep laboratory. PARTICIPANTS: Twenty consecutive outpatients with ADHD (18 boys and 2 girls; age range 6-13 years, mean age 9.3 years) and 20 normal children matched for age and socioeconomic status underwent polysomnographic recordings for 2 consecutive nights in a standard laboratory setting. Sleep was visually scored for sleep macrostructure and CAP, according to standard criteria. MEASUREMENTS AND RESULTS: Children with ADHD showed significantly reduced sleep duration and increased rate of stage shifts. All children with ADHD had an apnea-hypopnea index less than 1. Those with ADHD presented lower total CAP rates and lower CAP rates during sleep stage 2 than did normal controls. Moreover, in children with ADHD, we found a lower number of CAP sequences and a reduced total A1 index, mainly in light sleep (sleep stages 1 and 2). We did not find differences in A subtype percentages, but there was a longer duration of A1 subtypes in children with ADHD. CONCLUSIONS: Children with ADHD showed a lower CAP rate and a lower number of CAP sequences; this supports the hypothesis of the existence of a hypoarousal state in these patients.

Streptococcus pneumoniae oropharyngeal colonization in children and adolescents with cystic fibrosis.

BACKGROUND: This study was designed to evaluate Streptococcus pneumoniae (S. pneumoniae) carriage rates in patients with cystic fibrosis (CF). METHODS: An oropharyngeal swab was obtained from 212 CF children and adolescents enrolled during routine clinical visits. DNA from swabs was analyzed by real-time polymerase chain reaction. RESULTS: A total of 42 (19.8%) CF patients (mean age±standard deviation [SD], 12.0±3.3years) were colonized by S. pneumoniae. Carriage was more common in younger patients and tended to decline with age. Administration of systemic and/or inhaled antibiotics in the last 3months significantly correlated with a reduced carrier state [odds ratio (OR) 0.23, 95% confidence interval (CI) 0.07-0.69, and OR 0.26, 95% CI 0.08-0.77, respectively]. Vitamin D serum levels ≥30ng/mL were less common in carriers than that in non-carriers (OR 0.35; 95% CI 0.08-1.49). In both the vaccinated and unvaccinated subjects, serotypes 19F, 5, 4, and 9V were the most commonly carried serotypes. CONCLUSIONS: S. pneumoniae carrier state of school-age children and adolescents with CF is more prevalent than previously thought, and pneumococcal conjugate vaccination administered in the first year of life does not reduce the risk of re-colonization in later childhood and adolescence.

Ictal video-polysomnography and EEG spectral analysis in a child with severe Panayiotopoulos syndrome.

OBJECTIVE: To describe the ictal polysomnographic features of a patient with Panayiotopoulos syndrome, a peculiar epileptic syndrome characterized by infrequent, often single, prolonged, nocturnal, focal seizures comprising an unusual constellation of autonomic symptoms (malaise, nausea, pallor, tachycardia, vomiting) and unilateral deviation of the eyes at the onset of seizures. These clinical, ictal manifestations are rarely followed by post-ictal headache. In the literature, there is little information on the ictal EEG characteristics of Panayiotopoulos syndrome and, in particular, on certain autonomic manifestations, such as tachycardia, as the sole ictal phenomena at the onset of seizures. METHODS AND RESULTS: One, all-night videopolysomnography, during which one seizure was recorded. Video-EEG data were evaluated visually and by means of quantitative spectral analysis. The spectral analysis of the recorded seizure showed a complex ictal pattern of cortical involvement with focal onset in the right occipital area followed by the recruitment of widespread extra-occipital cortical regions. CONCLUSIONS: This is the first such analysis of this peculiar epileptic condition. Most of the symptoms were consistent with a diagnosis of severe Panayiotopoulos syndrome, although the patient also presented "atypical findings": a relatively high frequency of seizures, post-ictal headache, no spontaneous remission of seizures with age, and late onset of visual hallucinations; this last finding is more frequent in "Gastaut-type childhood occipital epilepsy", in which onset typically occurs later than in Panayiotopoulos syndrome. [Published with video sequences].

Glucose tolerance affects pubertal growth and final height of children with cystic fibrosis.

There are few data about the impact of cystic fibrosis-related diabetes (CFRD) on growth. We analyzed 17 children with cystic fibrosis (CF) presenting with newly diagnosed CFRD during puberty, in comparison with a matched control group of 52 CF children with normal glucose tolerance (NGT). Anthropometric evaluation showed that body mass index at CFRD diagnosis was significantly reduced in children with CFRD, in comparison with children with NGT (CFRD: -0.48 ± 1.08 vs. NGT: 0.2 ± 0.99; P=0.01), and the same difference remained evident at the end of follow up (CFRD: -0.49 ± 0.95 vs. NGT: 0.13 ± 0.89; P=0.04). Height standard deviation score (SDS) at baseline was slightly but not significantly lower in CFRD children (CFRD: -0.71 ± 0.83 vs. NGT: -0.25 ± 1.08; P=0.08), while final height SDS was significantly reduced (CFRD: -1.61 ± 1.12 vs. NGT: -0.61 ± 1.15; P=0.003). Mean final height SDS of the whole group was lower than mean target height SDS (final height SDS: -0.86 ± 1.2 vs. target height SDS: -0.3 ± 0.85; P<0.001). Target adjusted final height was lower in CFRD children, although the difference between CFRD and NGT children did not reach statistical significance (CFRD: -0.8 ± 1.03 vs. NGT: -0.47 ± 0.9; P=0.09). Pubertal growth and final height are negatively affected by CFRD. Intensive insulin treatment does not appear to be effective in normalizing growth, even when treatment is started early in the course of the disease, before the onset of clinical deterioration.

ZnT8 antibodies in patients with cystic fibrosis: an expression of secondary beta-cell damage?

Cystic Fibrosis-Related Diabetes (CFRD) is caused by a severe insulin deficiency with associated different degrees of insulin resistance. Data concerning the potential impact of autoimmunity are conflicting. Ninety subjects with cystic fibrosis (CF) were tested for glucose tolerance and autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA2) and zinc transporter 8 (Znt8A). Eighty-three subjects showed a normal glucose tolerance (92.2%), 6 subjects (6.6%) impaired glucose tolerance and 1 subject (1.1%) newly diagnosed CFRD. Four subjects were found positive for both IAA and GADA (4.4%), one subject (1.1%) for both IA2 and GADA, and one subject (1.1%) for isolated GADA. Three subjects (3.3%) showed isolated ZnT8A positivity. ZnT8A positivity in CF patients is uncommon and not associated with other autoantibodies. ZnT8A may not represent a specific indicator of a primary autoimmune beta-cell destruction, but possibly the expression of a secondary damage of the pancreatic islets with autoantigen release.

Validation of a predictive survival model in Italian patients with cystic fibrosis.

BACKGROUND: In 2001 Liou published a 5-year survival model using CFF Registry data. AIMS: To evaluate its validity in predicting survival in Italian CF patients. METHODS: In a retrospective study on 945 patients, the 9 variables selected by Liou were analyzed, vital status on December 2008 recorded and observed and expected deaths compared. To develop a new model, patients were randomly divided into a derivation (n=475) and a validation sample (n=470). RESULTS: A significant difference was found between observed and expected deaths based on Liou's model (62 vs 94), with a 34% reduction in mortality (p<0.05). A new model (based on FEV1, Staphylococcus aureus and Burkholderia cepacia complex infection, number of pulmonary exacerbations/year) was generated, that correctly predicted survival in the validation sample (31 observed vs 29 expected deaths, p=0.660). CONCLUSIONS: The Liou model did not adequately predict 5-year survival in our CF population that, compared to the one in which it was originally tested, could benefit from 10 years of improvement in treatments and practice patterns. A new generated model, based on only four variables, was more accurate in predicting 5-year survival in Italian CF patients.

Fewer spontaneous arousals in infants with apparent life-threatening event.

STUDY OBJECTIVES: A deficit in arousal process has been implicated as a mechanism of sudden infant death syndrome (SIDS). Compared with control infants, SIDS victims showed significantly more subcortical activations and fewer cortical arousals than matched control infants. Apparent life-threatening event (ALTE) is often considered as an aborted SIDS event. The aim of this study was to study the arousal characteristics of ALTE infants during the first months of life. DESIGN: 35 ALTE infants were studied with nighttime polysomnography at 2-3, 5-6, and 8-9 months of age. Eighteen of the infants had mothers who smoked. The infants were born full term and were usually supine sleepers. Sleep state and cardiorespiratory parameters were scored according to recommended criteria. Arousals were differentiated into subcortical activations or cortical arousals, according to the presence of autonomic and/or electroencephalographic changes. The results were compared with those of 19 healthy infants with nonsmoking mothers. RESULTS: During NREM sleep, the ALTE infants had fewer total arousals, cortical arousals, and subcortical activations at 2-3 and 5-6 months (P < 0.001) than control infants. ALTE infants with smoking mothers had more obstructive apnea (P = 0.009) and more subcortical activations during REM sleep at 2-3 months of age (P < 0.001) than ALTE infants with nonsmoking mothers. CONCLUSIONS: Spontaneous arousals were differently altered in ALTE infants than in SIDS infants, suggesting an entity different from SIDS. ALTE infants with smoking mothers had arousal and respiratory characteristics that were similar to future SIDS victims, suggesting some common abnormalities in brainstem dysfunction.