Pleural line slope in point of care ultrasound assessment of paediatric wheeze may reflect respiratory effort.

AIM: Asthma scoring systems rely on physical examination findings. Point of care ultrasound may provide an objective means to document improvement in the work of breathing in paediatric lower airway obstruction. METHODS: Thirty children with wheeze on physical examination (cases) and 15 children presenting with abdominal pain (controls) were studied. Using point-of-care ultrasound, m-mode tracing of lung was recorded above the right hemidiaphragm at the midclavicular line. Pleural line slope and excursion were measured before and after treatment. RESULTS: Twenty patients had a final slope measurement under 20°, and only three were admitted-one for hypoxia that resolved prior to ascending to the ward and another for poor compliance. Average decrease in pleural line slope after treatment was 43% and average decrease in pleural line excursion was 32%. Of the 10 children admitted, 8 had measurements over 25°. The correlation coefficient between pleural slope and pleural excursion was 0.67. All controls had a horizontal m-mode tracing at the pleural line. CONCLUSION: Oscillation of the m-mode line at the pleura is seen in children with lower airway obstruction and is absent in controls. There appears to be a correlation between beta-agonist therapy and decreased pleural line slope and excursion.

Increasing Vitamin D Serum Levels Is Associated With Reduced Pulmonary Exacerbations in Patients With Cystic Fibrosis.

CONTEXT: In 2012, The North American Cystic Fibrosis Foundation (NACFF) published new guidelines for the treatment of vitamin D deficiency in individuals with cystic fibrosis (CF). OBJECTIVE: The objectives of our study were to assess the efficacy of these guidelines, and to test the effect of increasing vitamin D dosage on pulmonary function and exacerbations. DESIGN: Pulmonary function tests and serum concentrations of 25-hydroxyvitamin D [25(OH)D] were measured 1 year before increasing vitamin D dosage according to the guidelines and at least 1 year later. In addition, days of hospitalization and pulmonary exacerbations were counted and an average per year (average number of days of hospitalization and average number of pulmonary exacerbations [PEA], respectively) was calculated. SETTING AND PARTICIPANTS: A total of 90 patients from The Cystic Fibrosis Clinic at Hadassah Mount-Scopus Hospital, Jerusalem, Israel. RESULTS: The mean serum concentration of vitamin D increased significantly from 20.97 ng/mL (52.34 nmol/L) at baseline to 25.41 ng/mL (63.42 nmol/L) at the end of follow-up (P < 0.001). The number of PEA decreased significantly from 2.79 ±â€Š3.96 to 2.15 ±â€Š2.91 (P = 0.007). The change in vitamin D levels was correlated with a decrease in PEA (correlation coefficient = -0.318, P = 0.002). CONCLUSIONS: The NACFF guidelines for management of vitamin D deficiency improve vitamin D levels in patients with CF but did not reach the normal values in most patients. The increase in vitamin D serum levels was, however, associated with a decrease in number of pulmonary exacerbations.

[DIAGNOSIS AND TREATMENT OF BRONCHIECTASIS: POSITION PAPER OF THE ISRAELI PULMONOLOGY SOCIETY AND THE ISRAELI PEDIATRIC PULMONOLOGY SOCIETY].

INTRODUCTION: Bronchiectasis is anatomically defined by irreversible distortion of the bronchi. Clinically, its manifestations are cough with sputum production and a predisposition to pulmonary infections. Unlike asthma and COPD, where ample clinical data are present regarding the course and effective treatment, knowledge of bronchiectasis has yet to evolve. Lately, bronchiectasis is gaining renewed attention among the medical community, with growing basic and clinical research-based data. In Israel, no registered treatments exist for bronchiectasis, which makes it difficult to treat these patients. This paper is a summary of the position of the Israeli Pulmonology Association and the Israeli Pediatric Pulmonology Association for diagnosis and treatment of bronchiectasis.

Comparison of Nasal Potential Difference and Intestinal Current Measurements as Surrogate Markers for CFTR Function.

OBJECTIVES: Nasal potential difference (NPD) measurement is part of the diagnostic criteria for cystic fibrosis (CF) and now used routinely as an endpoint in clinical trials of correcting the basic defect in CF. Intestinal current measurement (ICM), measured ex vivo on a rectal biopsy, has been used to study cystic fibrosis transmembrane conductance regulator (CFTR) function but has not been compared to NPD in the same subject in adults and children. The aim of the study is to evaluate the potential usefulness of ICM as a marker of CFTR function for treatment studies compared NPD in patients with CF and in healthy control subjects. METHODS: ICM and NPD were performed on healthy controls and patients with CF. The healthy adults were individuals undergoing routine screening colonoscopy at the Beth Israel Deaconess Medical Center. The healthy children were undergoing colonoscopy for suspicion of inflammation in Hadassah Hebrew University Medical Center. The CF adults were recruited from Boston Children's Hospital CF Center and CF Center Worcester Mass, the children with CF from Hadassah CF Center. RESULTS: ICM measurements in healthy control subjects (n = 16) demonstrated a mean (±SE) carbachol response of 16.0 (2.2) µA/cm, histamine response of 13.2 (2.1) µA/cm and a forskolin response of 6.3 (2.0) µA/cm. Basal NPD of -15.9 (1.9) and response to Cl free + isoproterenol of -13.8 (2.0). These responses were inverted in CF subjects (n = 12) for ICM parameters with carbachol response of -3.0 (0.5) µA/cm, histamine -1.0 (0.8) µA/cm and a forskolin response of 0.5 (0.3) and also for NPD parameters; basal NPD of -42.2 (4.3) and response to Cl free + isoproterenol of 4.3 (0.7). Pearson correlation test showed the comparability of ICM and NPD in assessing CFTR function. CONCLUSIONS: ICM is equivalent to NPD in the ability to distinguish patients with CF from controls and could be used as surrogate markers of CFTR activity in treatment protocols.

Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by several distinct defects in genes responsible for ciliary beating, leading to defective mucociliary clearance often associated with randomization of left/right body asymmetry. Individuals with PCD caused by defective radial spoke (RS) heads are difficult to diagnose owing to lack of gross ultrastructural defects and absence of situs inversus. Thus far, most mutations identified in human radial spoke genes (RSPH) are loss-of-function mutations, and missense variants have been rarely described. We studied the consequences of different RSPH9, RSPH4A, and RSPH1 mutations on the assembly of the RS complex to improve diagnostics in PCD. We report 21 individuals with PCD (16 families) with biallelic mutations in RSPH9, RSPH4A, and RSPH1, including seven novel mutations comprising missense variants, and performed high-resolution immunofluorescence analysis of human respiratory cilia. Missense variants are frequent genetic defects in PCD with RS defects. Absence of RSPH4A due to mutations in RSPH4A results in deficient axonemal assembly of the RS head components RSPH1 and RSPH9. RSPH1 mutant cilia, lacking RSPH1, fail to assemble RSPH9, whereas RSPH9 mutations result in axonemal absence of RSPH9, but do not affect the assembly of the other head proteins, RSPH1 and RSPH4A. Interestingly, our results were identical in individuals carrying loss-of-function mutations, missense variants, or one amino acid deletion. Immunofluorescence analysis can improve diagnosis of PCD in patients with loss-of-function mutations as well as missense variants. RSPH4A is the core protein of the RS head.

Implementation of a Policy Change: Replacement of Nebulizers by Spacers for the Treatment of Asthma in Children.

BACKGROUND: Treatment using inhaled bronchodilators for asthma with a metered dose inhaler attached to a spacer device (MDI+S) was shown to be as efficient as nebulizers. Nevertheless, nebulizers remain the treatment of choice in most hospitals. OBJECTIVES: To implement a policy change to improve asthma treatment in pediatric wards and the pediatric emergency department. METHODS: The study was performed in the emergency department and pediatric wards of a university medical center. The study group comprised all children admitted with a diagnosis of asthma necessitating treatment. The medical and nursing staff of both the pediatric emergency department and the pediatric wards was trained how to use metered dose inhalers attached to spacers on a regular basis in asthmatic pediatric patients. At a preset date nebulizers were replaced by spacers and their use was monitored by the supervising physician. Salbutamol was administered by a metered dose inhaler (100 µg/puff) attached to a spacer device. The number of puffs was determined by severity of disease according to GINA recommendations. After 2 years the outcome and cost analysis were examined. RESULTS: During 3 years since the initial policy change 92.5%, patients were treated with spacers throughout their hospital stay (emergency department and pediatric ward). Costs were reduced by an estimated 63%. CONCLUSIONS: In view of its many advantages, replacing nebulizers by MDI+S for the treatment of acute asthma.is, feasible, if performed in collaboration with the staff, hospital authority and patients.

NKp46 regulates allergic responses.

Natural killer (NK) cells are cytotoxic cells that are able to rapidly kill viruses, tumor cells, parasites, bacteria, and even cells considered "self". The activity of NK cells is controlled by a fine balance of inhibitory and activating signals mediated by a complex set of different receptors. However, the function of NK cells is not restricted only to the killing of target cells, NK cells also possess other properties such as the secretion of proangiogenic factors during pregnancy. Here, we demonstrate another unique NK-cell activity, namely the regulation of T-cell mediated allergic responses, which is dependent on the NK-cell specific receptor NKp46 (Ncr1 in mice). Using mice in which the Ncr1 gene has been replaced with a green fluorescent protein, we demonstrate reduced delayed-type hypersensitivity and airway hypersensitivity. Interestingly, we show that this reduction in airway hypersensitivity is due to differences in the stimulation of T cells resulting in an altered cytokine profile.

Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication.

Ricin, a highly potent plant-derived toxin, is considered a potential bioterrorism weapon due to its pronounced toxicity, high availability, and ease of preparation. Acute damage following pulmonary ricinosis is characterized by local cytokine storm, massive neutrophil infiltration, and edema formation, resulting in respiratory insufficiency and death. A designated equine polyclonal antibody-based (antitoxin) treatment was developed in our laboratory and proved efficacious in alleviating lung injury and increasing survival rates. Although short-term pathogenesis was thoroughly characterized in antitoxin-treated mice, the long-term damage in surviving mice was never determined. In this study, long-term consequences of ricin intoxication were evaluated 30 days post-exposure in mice that survived antitoxin treatment. Significant pulmonary sequelae were demonstrated in surviving antitoxin-treated mice, as reflected by prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance. The presented data highlight, for the first time to our knowledge, the possibility of long-term damage development in mice that survived lethal-dose pulmonary exposure to ricin due to antitoxin treatment.

Oxidized cellulose binding to allergens with a carbohydrate-binding module attenuates allergic reactions.

Grass and mite allergens are of the main causes of allergy and asthma. A carbohydrate-binding module (CBM) represents a common motif to groups I (ß-expansin) and II/III (expansin-like) grass allergens and is suggested to mediate allergen-IgE binding. House dust mite group II allergen (Der p 2 and Der f 2) structures bear strong similarity to expansin's CBM, suggesting their ability to bind carbohydrates. Thus, this study proposes the design of a carbohydrate-based treatment in which allergen binding to carbohydrate particles will promote allergen airway clearance and prevent allergic reactions. The aim of the study was to identify a polysaccharide with high allergen-binding capacities and to explore its ability to prevent allergy. Oxidized cellulose (OC) demonstrated allergen-binding capacities toward grass and mite allergens that surpassed those of any other polysaccharide examined in this study. Furthermore, inhalant preparations of OC microparticles attenuated allergic lung inflammation in rye grass-sensitized Brown Norway rats and OVA-sensitized BALB/c mice. Fluorescently labeled OC efficiently cleared from the mouse airways and body organs. Moreover, long-term administration of OC inhalant to Wistar rats did not result in toxicity. In conclusion, many allergens, such as grass and dust mite, contain a common CBM motif. OC demonstrates a strong and relatively specific allergen-binding capacity to CBM-containing allergens. OC's ability to attenuate allergic inflammation, together with its documented safety record, forms a firm basis for its application as an alternative treatment for prevention and relief of allergy and asthma.

[How can asthma in children be controlled?].

Asthma is a disease manifested by recurrent episodes of shortness of breath, wheezing or cough that often require treatment at the emergency department or even hospitalization. These exacerbations are caused by an increased inflammatory process in the airways. This review focuses on the various daily long term control medications used to prevent exacerbations. The pharmacotherapy used to manage asthma is based mainly on inhaled corticosteroids (ICS and leukotriene receptor antagonists. In more severe cases, other drugs can be added, such as long-acting beta 2 agonists lare used only in conjunction with ICS] as well as additional drugs such as slow release theophylline, anti-lgE monoclonal antibodies, and more. The step-up step-down approach is used to decide on the controller medication needed. If the preventive therapy fails, it is essential to assess the adherence to therapy, the technique used, the existence of aggravating factors and the possibility that the cause of the symptoms is not asthma. For proper disclosure the third author (E.K.) has received payment in the past for lectures from Asthma drug companies.

Optimizing CFTR modulator therapy management for cystic fibrosis through the ReX platform.

Background: Cystic fibrosis (CF) is a chronic multi-systemic disease that requires a complex daily treatment regimen. Therefore, there is sub-optimal adherence to CF therapies, and it was shown to impact its clinical and economic burden. Cystic fibrosis transmembrane conductance regulator modulators (CFTRm) are high-cost medications that demonstrated significant benefit in clinical trials. The aim of this study was to evaluate the safety, usability, and efficacy of the ReX platform in medication management of CFTRm for the treatment of people with CF (pwCF). Methods: ReX is a patient engagement platform consisting of a cloud-based management system and a cell-enabled handheld device intended to dispense oral medication into the patient's mouth, following a pre-programmed treatment protocol. It provides real-time adherence data to caregivers and timely, personalized reminders to patients. This is a prospective multi-center open study for pwCFs older than 12 years, who had been prescribed CFTRm [elexacaftor/tezacaftor/ivacaftor (ETI) or tezacaftor/ivacaftor (TI)], and provided consent to use ReX platform to receive CFTRm and record their health condition. Study duration was 12-24 months, with clinic visits where physical examination, body mass index (BMI), and pulmonary function tests were performed, and user experience questionnaires were filled in. Results: Ten pwCFs from two CF centers in Israel were included. The mean age was 31.5 years (range 15-74 years); eight were taking ETI and two TI. Median adherence to CFTRm was 97.5% (range 70%-100%) in the first year and 94% (range 84%-99%) in the second year, which is higher than the previously reported CFTRm adherence of ∼80%. No adverse events related to the use of the platform were reported. Patients reported ReX to be valuable to their treatment management and user friendly. Estimated mean forced expiratory volume in 1 s (FEV1%) increased from 74.4% to 80.8% (p = 0.004) over 2 years. Similarly, estimated BMI percentile increased from 53.5 to 59.0 (p < 0.001). Conclusions: Using the ReX platform in medication management of pwCF treated by CFTRm is safe, easy to use, and effective in improving the adherence to treatment and the clinical outcomes. Consequently, this device may potentially reduce costs to healthcare providers. Further larger and long-term studies are required to examine the clinical benefits of the ReX platform.

The clinical yield of bronchoscopy in the management of cystic fibrosis: A retrospective multicenter study.

BACKGROUND: Pulmonary disease is the leading cause of morbidity and mortality in people with cystic fibrosis (pwCF). Several studies have shown no benefit for bronchoscopy and bronchoalveolar lavage (BAL) over sputum to obtain microbiological cultures, hence the role of bronchoscopy in pwCF is unclear. AIM: To analyze how bronchoscopy results affected clinical decision-making in pwCF and assess safety. METHODS: A retrospective analysis of all charts of pwCF from three CF centers in Israel, between the years 2008 and 2019. We collected BAL culture results as well as sputum cultures obtained within 1 month of the BAL sample. A meaningful yield was defined as a decision to start antibiotics, change the antibiotic regimen, hospitalize the patient for treatment, or the resolution of the problem that led to bronchoscopy (e.g., atelectasis or hemoptysis). RESULTS: During the study years, of the 428 consecutive patient charts screened, 72 patients had 154 bronchoscopies (2.14 bronchoscopies/patient). Forty-five percent of the bronchoscopies had a meaningful clinical yield. The finding of copious sputum on bronchoscopy was strongly associated with a change in treatment (OR: 5.25, 95%CI: 2.1-13.07, p < 0.001). BAL culture results were strongly associated with a meaningful yield, specifically isolation of Aspergillus spp. (p = 0.003), Haemophilus influenza (p = 0.001). Eight minor adverse events following bronchoscopy were recorded. CONCLUSIONS: In this multicenter retrospective analysis of bronchoscopy procedures from three CF centers, we have shown that a significant proportion of bronchoscopies led to a change in treatment, with no serious adverse events. Our findings suggest that bronchoscopy is a safe procedure that may assist in guiding treatment in some pwCF. Future studies should evaluate whether BAL-guided decision-making may also lead to a change in clinical outcomes in pwCF.

Tumor suppressor death-associated protein kinase attenuates inflammatory responses in the lung.

Death-associated protein kinase (DAPk) is a tumor suppressor thought to inhibit cancer by promoting apoptosis and autophagy. Because cancer progression is linked to inflammation, we investigated the in vivo functions of DAPk in lung responses to various acute and chronic inflammatory stimuli. Lungs of DAPk knockout (KO) mice secreted higher concentrations of IL-6 and keratinocyte chemoattractant (or chemokine [C-X-C motif] ligand 1) in response to transient intranasal administrations of the Toll-like receptor-4 (TLR4) agonist LPS. In addition, DAPk-null macrophages and neutrophils were hyperresponsive to ex vivo stimulation with LPS. DAPk-null neutrophils were also hyperresponsive to activation via Fc receptor and Toll-like receptor-3, indicating that the suppressive functions of this kinase are not restricted to TLR4 pathways. Even after the reconstitution of DAPk-null lungs with DAPk-expressing leukocytes by transplanting wild-type (WT) bone marrow into lethally irradiated DAPk KO mice, the chimeric mice remained hypersensitive to both acute and chronic LPS challenges, as well as to tobacco smoke exposure. DAPk-null lungs reconstituted with WT leukocytes exhibited elevated neutrophil content and augmented cytokine secretion in the bronchoalveolar space, as well as enhanced epithelial cell injury in response to both acute and chronic inflammatory conditions. These results suggest that DAPk attenuates a variety of inflammatory responses, both in lung leukocytes and in lung epithelial cells. The DAPk-mediated suppression of lung inflammation and airway injury may contribute to the tumor-suppressor functions of this kinase in epithelial carcinogenesis.

Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life.

The survival of patients with cystic fibrosis (CF) continues to improve. The discovery and cloning of the CFTR gene more than 21 years ago led to the identification of the structure and function of the CFTR chloride channel. New therapies based on the understanding of the function of CFTR are currently under development. The better clinical status and improved survival of patients with CF is not only a result of understanding of the molecular mechanisms of CF but also a result of the development of therapeutic strategies that are based on insights into the natural course of the disease. Current CF treatments that target respiratory infections, inflammation, mucociliary clearance, and nutritional status are associated with improved pulmonary function and reduced exacerbations. Patients benefit from treatment at a specialized CF center by a multidisciplinary dedicated team with emphasis being placed on frequent visits, periodic testing, and monitoring adherence to therapy. The purpose of this review is to survey recent developments in CF care that are responsible for the improved survival and quality of life of patients with CF.

Ethical Dilemma: Elexacaftor-Tezacaftor-Ivacaftor or Lung Transplantation in Cystic Fibrosis and End-Stage Lung Disease?

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of this disease. We present an ethical dilemma involving an 11-year-old child with CF and end-stage lung disease. Shortly after starting treatment with elexacaftor-tezacaftor-ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other are limited. A survey of CF center team members was conducted for the purpose of this article. Ethical principles that may guide us in these situations are discussed. Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared with other team members, are more likely to provide a specific recommendation vs presenting the information to the family and letting them decide (OR, 4.0; 95% CI, 1.2-12.8; P = .021). A shared decision-making model, stressing our moral obligation as physicians to respect autonomy by appreciating family values, while offering to participate in the decision-making process and ensuring nonmaleficence, is presented. In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. The current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making, which is focused on respecting autonomy, is our preferred approach in these situations.

Respiratory physiotherapy in patients with cystic fibrosis and upper limb deep vein thrombosis.

We report physiotherapy management of two patients with severe cystic fibrosis (CF) lung disease and upper limb deep vein thrombosis (DVT). These patients were admitted due to a pulmonary exacerbation. Following peripherally inserted central catheters, they were diagnosed with an upper limb DVT. Due to their underlying lung disease, physiotherapy was mandatory for improvement. However, the DVT and anticoagulation treatment raised concerns for pulmonary emboli and hemoptysis. A framework for physiotherapy management in these patients, using a set of precautions and restrictions to maintain airway clearance while minimizing the risk for pulmonary emboli and hemoptysis, was established. Using this set of instructions, the patients experienced no major adverse events while maintaining sufficient airway clearance to allow respiratory improvement. These precautions were continued until the upper limb DVTs were resolved. To our knowledge, there are currently no guidelines or expert opinions available. Therefore, this framework can help guide physiotherapy management.

Manual external chest compression reverses respiratory failure in children with severe air trapping.

We report manual external chest compression (MECC) as an effective treatment for acute respiratory failure due to severe air trapping. In this retrospective study, we describe our experience with MECC administered to five children suffering from severe air trapping as a consequence of severe asthma or bronchiolitis. These children were admitted to the Pediatric Intensive Care Unit (PICU) with clinical and blood gases parameters compatible with acute respiratory failure. Before intubation MECC was performed. The results of blood gasses before, during, and after MECC showed gradual changes in PCO2 over time indicating the improvement in tidal volume and ventilation. Respiratory failure resolved in all five children within 4 h with no complications. The need for intubation and mechanical ventilation was avoided, and all children were discharged from the PICU within 48 h.

Betamethasone versus dexamethasone for inpatient preschool wheezing-A case-control study.

BACKGROUND AND OBJECTIVES: Wheezing is one of the most common reasons for the presentation of children to primary care or the emergency ward, before 7 years of age. Current guidelines recommend a short course of oral corticosteroids (OCS) for those children with a wheezing attack severe enough to require hospitalization. However, the optimal choice of therapy is controversial. We aimed to compare the efficacy of betamethasone to that of dexamethasone in achieving clinical response in preschool children requiring hospitalization for an acute wheezing attack. METHODS: This was a retrospective study. Medical records of healthy children without significant comorbidities between 1 and 7 years of age (n = 234) admitted with a moderate-severity acute wheezing attack to two pediatric wards between 2014 and 2018 were included. All children were treated with either betamethasone or dexamethasone exclusively during the hospitalization. The primary outcome of interest was the length of hospital stay (LOS). RESULTS: The demographic parameters and the clinical severity of wheezing episodes were similar in the two study groups, as was the LOS. However, the dexamethasone cumulative dose used during hospitalization was significantly larger than the betamethasone cumulative dose (3.76 (1.88-5.64) vs. 1.86 (1.24-3.1) mg/kg of prednisone-equivalent dose, p < .001). CONCLUSION: In preschool children with acute wheezing requiring hospitalization, betamethasone achieved a similar clinical response when compared to dexamethasone, with a lower cumulative steroid dose. Further studies are needed to understand the additional benefits of betamethasone over other steroids or placebo.

The Use of Infant Pulmonary Function Tests in the Diagnosis of Neuroendocrine Cell Hyperplasia of Infancy.

BACKGROUND: Infant pulmonary function tests (iPFTs) in subjects with neuroendocrine cell hyperplasia of infancy (NEHI) have demonstrated substantial expiratory airflow obstruction and air trapping. RESEARCH QUESTION: Can indices from iPFTs be used in the diagnosis of NEHI? STUDY DESIGN AND METHODS: This is an observational case-control study evaluating iPFT results from a registry of patients assessed at the Hadassah Hebrew University Medical Center between 2008 and 2018. iPFTs results in infants with NEHI were compared to two disease control infant groups (infants evaluated for recurrent wheezing and infants evaluated due to prematurity) and a spirometry control group of infants with normal expiratory airflow, using the Kruskal-Wallis test. Receiver operating characteristic (ROC) curves were used to assess the diagnostic accuracy of iPFT indices. RESULTS: We evaluated iPFT data in 481 infants (15, NEHI; 292, wheezing; 128, premature; and 46, spirometry control group). Infants with NEHI had significantly increased trapped air volumes (median functional residual capacity measured with infant whole-body plethysmography [FRCpleth] was 199% predicted; median ratio of residual volume to total lung capacity was 59% predicted) when compared with results in all evaluated groups of infants (P < .001), including multiple pairwise comparisons. Airflow limitation was demonstrated in infants with NEHI when compared with the infants in the spirometry control group but was similar to the two disease control groups. FRCpleth had the best discriminatory ability for NEHI diagnosis, with an FRCpleth ≥ 150% predicted demonstrating a ROC of 0.91 (95% CI, 0.82-1.00), sensitivity of 86.7% (95% CI, 59.5%-98.3%), and specificity of 95.5% (95% CI, 93.2%-97.3%). INTERPRETATION: Findings on iPFTs of markedly increased air trapping, out of proportion to the degree of airflow limitation, are characteristic of infants with NEHI. iPFT results demonstrating an FRCpleth ≥ 150% predicted are highly specific for NEHI and may aid in early diagnosis. Further research is required to confirm these findings in a prospective cohort and to understand the pathophysiologic explanation for these findings.

How abnormal is the normal? Clinical characteristics of CF patients with normal FEV1.

BACKGROUND: Normal values (>80%) of Forced Expiratory Volume in one second (FEV1 ) in patients with cystic fibrosis (CF) may lead to the interpretation that there is no lung disease. This study is a comprehensive analysis of lung involvement in CF patients having normal FEV1 . METHODS: Patients were recruited from two CF centers: Hadassah Medical Center, Jerusalem and Vall d' Hebron Hospital, Barcelona. Lung disease was assessed by lung clearance index (LCI), chest CT-Brody score, respiratory cultures, number of pulmonary exacerbations (PEx), and days of antibiotic treatment in the year before the assessment. RESULTS: Of the 247 patients, 89 (36%) had FEV1 ≥80% and were included in the study (mean age, 17.6; range, 4.25-49 years). Chronic Pseudomonas aeruginosa infection was found in 21%, and 31% had at least one major PEx in the year before the study. Abnormally elevated LCI was found in 86% of patients, ranging between 7.52 and 18.97, and total Brody score (TBS) was abnormal in 92% (range, 5.0-96.5). Patients with chronic P. aeruginosa had significantly higher LCI (p = .01) and TBS (p = .02) which were associated with more major PEx (p < .01 and p = .01, respectively) and more days of intravenous (IV) antibiotic treatment in the preceding year (p = .03 and p = .001, respectively). CONCLUSIONS: Most CF patients with normal FEV1 have already physiological and structural lung abnormalities which were associated with more PEx and IV antibiotic treatment. Further studies are needed to determine if better adherence to the currently used therapies and the new cystic fibrosis transmembrane modulators will prevent the progression of lung disease.