Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Foreign body aspiration in Israeli children during the COVID-19 pandemic.

BACKGROUND: Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, there has been a decline in pediatric emergency department visits. Our aim was to assess the pattern of pediatric foreign body aspiration (FBA) during the first year of the COVID-19 pandemic, in comparison to the prior years. METHODS: In this retrospective multicenter study, we compared the number of children who presented with FBA during the COVID-19 year (March 1, 2020 to February 28, 2021) to the annual average of the years 2016-2019. We also compared the lockdown periods to the postlockdown periods, and the percentage of missed FBA, proven FBA, and flexible bronchoscopy as the removal procedure. RESULTS: A total of 345 children with FBA from six centers were included, 276 in the pre-COVID-19 years (average 69 per year) and 69 in the COVID-19 year. There was no difference in the prevalence of FBA between the COVID-19 year and any of the prior 4 years. Examining the lockdown effect, the monthly incidence of FBA dropped from a pre-COVID-19 average of 5.75 cases to 5.1 cases during lockdown periods and increased to 6.3 cases in postlockdown periods. No difference in the percentage of missed FB or proven FB was observed. There was a significant rise in the usage of flexible bronchoscopy as the removal procedure (average of 15.4% vs. 30.4%, p = 0.001). CONCLUSION: There were fewer cases of pediatric FBA during lockdown periods, compared to post-lockdown periods, presumably related to better parental supervision, with no difference in the prevalence of FBA during the COVID-19 year.

Combining cytogenetic and genomic technologies for deciphering challenging complex chromosomal rearrangements.

Complex chromosomal rearrangements (CCRs), a class of structural variants (SVs) involving more than two chromosome breaks, were classically thought to be extremely rare. As advanced technologies become more available, it has become apparent that CCRs are more common than formerly thought, and are a substantial cause of genetic disorders. We attempted a novel approach for solving the mechanism of challenging CCRs, which involve repetitive sequences, by precisely identifying sequence-level changes and their order. Chromosomal microarray (CMA) and FISH analyses were used for interpretation of SVs detected by whole exome sequencing (WES). Breakpoint junctions were analyzed by Nanopore sequencing, a novel long-read whole genome sequencing tool. A large deletion identified by WES, encompassing the FOXF1 enhancer, was the cause of alveolar capillary dysplasia and respiratory insufficiency, resulting in perinatal death. CMA analysis of the newborn's mother revealed two duplications encompassing the deleted region in the proband, raising our hypothesis that the deletion resulted from the mother's CCR. Breakpoint junctions of complex SVs were determined at the nucleotide level using Nanopore long-read sequencing. According to sequencing results of breakpoint junctions, the CCR in the newborn was considered the consequence of at least one double-strand break during meiosis, and reassembly of DNA fragments by intra-chromosomal homologous recombination. Our comprehensive approach, combining cytogenetics and long-read sequencing, enabled delineation of the exact breakpoints in a challenging CCR, and proposal of a mechanism in which it arises. We suggest applying our integrative approach combining technologies for deciphering future challenging CCRs, enabling risk assessment in families.

Baseline Cystic fibrosis disease severity has an adverse impact on pregnancy and infant outcomes, but does not impact disease progression.

BACKGROUND: With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. AIM: To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. METHODS: A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. RESULTS: Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. CONCLUSION: Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

Supraglottoplasty for severe laryngomalacia. Can we predict success?

OBJECTIVES: Laryngomalacia is the dynamic collapse of supraglottic structures during inspiration, leading to a variable degree of airway obstruction. Clinical symptoms appear in the first months of life and are usually mild and resolve by the age of 12-18 months. In severe cases, surgical intervention may be considered. The goal of the study was to review the clinical outcome of pediatric patients who underwent supraglottoplasty for laryngomalacia. MATERIAL AND METHODS: Clinical and demographic data were retrieved from medical records of children diagnosed with laryngomalacia by laryngo-bronchoscopy between 2013 and 2019. Indications, outcome and long-term follow-up were collected from children undergoing surgery. RESULTS: During the study period, 115 children were diagnosed with laryngomalacia. The median age at diagnosis was 3 months. Synchronous airway lesions were diagnosed in 20% of patients. Ten (8.7%) children underwent surgical treatment because of significant respiratory symptoms and/or failure to thrive. Three of them had comorbidities. All otherwise healthy children had significant respiratory and nutritional improvement after surgery while those with comorbidities had less successful outcomes. CONCLUSION: We conclude that in severe cases of laryngomalacia, supraglottoplasty has an important role to play in management. In children with comorbidities, the surgical results may be less successful. Therefore, we recommend that the decision to operate should be individualized, ensuring full disclosure to the family regarding the probable benefit along with the limitations of surgery.

Ibuprofen does not prevent postbronchoscopy fever in children undergoing broncho-alveolar lavage.

BACKGROUND: Fiber-optic bronchoscopy (FOB) of the lower airways is a routine examination performed for investigating varying respiratory complaints in children. A common side effect is a transient high fever on the day of the FOB. Such episodes are usually unrelated to an infectious process but may cause clinical uncertainty and parental anxiety. We have previously shown that a single dose of systemic dexamethasone significantly reduces the rate of fever postbronchoscopy (FPB). RESEARCH QUESTION: To prospectively analyze the effect of a prophylactic dose of ibuprofen upon the FPB. STUDY DESIGN AND METHODS: Children presenting for elective FOB and broncho-alveolar lavage (BAL) were randomized, in a double-blind fashion, to receive a single dose of ibuprofen syrup 10 mg/kg or placebo prior to the procedure. Parents were contacted the next day to record the presence or absence of fever. RESULTS: Sixty-one children were included in the final analysis. Thirty-one children were in the treatment group and 30 in the placebo group. FPB occurred in 40 children (65%). There was no difference in the rate of FPB between placebo (63%) and treatment (67%) groups (P = .717). Fifty (82%) children had a positive BAL culture. Among them, 38 had FPB (76%) compared with only 2 of 11 (18%) of those with negative culture (P = .00026, relative risk 4.18). About 80% of positive cultures grew Haemophilus influenza. There was no significant difference between the number of BALs with a positive culture between the treatment and placebo groups (87% vs 77%, P = .35). CONCLUSION: FPB occurs in around twothirds of children when BAL is performed. Fever occurred significantly more frequently when BAL culture is positive. A single standard dose of the nonsteroidal anti-inflammatory drug ibuprofen administered before a FOB does not prevent FPB.

Pleural-Based Intrathoracic Cystic Lymphangioma in an Infant Mimicking a Pneumonia.

Cystic lymphangioma is an uncommon benign tumor that occurs primarily in children in the cervical region. We report the first case of a pleural-based cystic lymphangioma in an infant. The patient was admitted for RUL pneumonia. Because of the persistence of the radiographic findings despite clinical improvement, a computed tomography (CT) and a magnetic resonance imaging (MRI) scan were performed. They showed a multiloculated cystic lesion in the superior posterior right hemithorax. A surgical procedure was performed with complete resection of the tumor. Histopathological examination showed a pleural-based intrathoracic multicystic lymphangioma. One year after the surgery, the patient feels well without any sign of recurrence.

The correlation of adenosine challenge test results with subsequent clinical course among young children with suspected asthma: a retrospective cohort study.

AIM: Our aim was to evaluate the correlation of Adenosine monophosphate challenge test (AMP-PCW) results with the patients' subsequent clinical course. METHODS: We performed a 6-year retrospective cohort study of young children with suspected asthma who underwent AMP-PCW test. RESULTS: Fifty four children were included in the study (median age, 50.5 months; range, 26-90). AMP-PCW was positive in 35 (65%) children. During the 3-year follow-up period, among 22 of 35 patients in the positive AMP-PCW group and among 17 of 19 in the negative AMP-PCW group-prophylactic therapy was not changed. Prophylactic therapy was initiated or its dose was escalated in 12 of 13 (92.3%) of the children with a positive AMP-PCW test compared to none of the children with a negative challenge test (P < 0.001). Prophylactic therapy was discontinued in only one (7.6%) of the children with a positive test as compared to two (100%) of the children with a negative test (P < 0.001). There were significantly fewer severe asthma exacerbations during a 3-year follow-up period after the challenge test as compared to the preceding 3-year period both in children with a positive (from 34 to 9 total events, P = 0.01) or a negative challenge test (from 16 to 0 events P = 0.01). The severity of airway hyper responsiveness was found to associate with the number of severe asthma exacerbations (P = 0.04) and with a diagnosis of asthma during the following 3 years (P = 0.02). CONCLUSIONS: AMP-PCW test results correlates with the subsequent clinical course of young children with suspected asthma performing the test.

Factors Associated with Positive Adenosine Challenge Test in Young Children with Suspected Asthma.

Background: To investigate the predictive factors associated with positive adenosine monophosphate challenge using the auscultation method (AMP-PCW) test results. Methods: This is a prospective study of young children with suspected asthma who underwent AMP-PCW test. Patients with a positive AMP-PCW test were compared with those with a negative AMP-PCW. A multivariate logistic regression model was performed to identify the independent determinants of positive AMP-PCW. Results: A total of 159 patients completed the AMP-PCW test. The median age was 53 months. In total, 54.0% of patients had a positive AMP-PCW. The prevalence of atopic dermatitis and family history of asthma and allergy were significantly higher among the positive AMP-PCW group (P = 0.04, P = 0.02, and P = 0.007, respectively), as were the prevalences of elevated immunoglobulin E (IgE), peripheral blood eosinophils percentage (P = 0.003, P < 0.001, respectively), and number of emergency department (ED) visits/hospitalizations before AMP-PCW test (P = 0.006). A significant inverse correlation exists between peripheral blood eosinophils percentage and serum IgE levels with the AMP end-point concentrations (r = -0.302, P = 0.001, and r = -0.312, P = 0.001, respectively). In multivariate logistic regression model, peripheral blood eosinophils percentage, IgE levels, and the number of ED visits/hospitalizations before the AMP-PCW test were found as independent predictors for positive AMP-PCW test result. Conclusions: Our results suggest that bronchial responsiveness to AMP-PCW is related to proxy markers of airway inflammation (elevated eosinophils and IgE levels) and clinical exacerbation of asthma before the test. This may support the role of AMP-PCW in detecting inflammatory changes and monitoring their trend among young children with suspected asthma.

Failure to conceive in women with CF is associated with pancreatic insufficiency and advancing age.

OBJECTIVE: The causes of subfertility in women with CF though multifactorial are not well described. Our aim in this study was to determine the prevalence and factors associated with female subfertility among women with CF. METHODS: A retrospective multinational study from 11 CF centers in 5 countries (Israel, France, Spain, Italy, UK) including women with CF was undertaken. Sub/infertility was defined as not achieving a spontaneous pregnancy after one year of unprotected sexual intercourse. Data including genetics, pancreatic insufficiency (PI), prevalence of diabetes (CFRD), lung function, nutritional status measured by body mass index (BMI), sputum bacterial colonization, and rate of pulmonary exacerbations were collected from patients' files. RESULTS: Out of 605 women, 241 attempted pregnancy. Of these, 84 (35%) had subfertility, and 67 of them eventually became pregnant. Females attempting conception were older but had better pulmonary function and nutrition compared to those who did not. In a multivariate analysis, PI (OR 1.9 [1.03-3.5], p = .04) and older age (OR 3.9 [2.1-7.3] p < .0001) were associated with subfertility. Lung function, BMI, CFRD, Presence of two class I-III mutations and number of exacerbations in the year prior to fertility attempts were not associated with subfertility. CONCLUSIONS: The prevalence of subfertility among women with CF (35%) is higher than the expected 5-15% subfertility in the general population. Older age and pancreatic insufficiency are associated with subfertility in women with CF.

Sex-linked difference in blood oxygen saturation.

BACKGROUND: It is not known whether SpO2 in healthy volunteers is affected by sex. OBJECTIVE: To evaluate whether there are differences in SpO2 between young healthy adult males and females and to evaluate whether the differences are already present at birth. METHODS: We studied two cohorts of patients. The first one consisted of young adult volunteers (105 males and 102 females). In these patients, SpO2 was measured as well as selected anthropometric variables (height, weight), vital signs (respiratory rate, pulse rate and body temperature) and obtained data on menstrual cycle phase of the female participants. For the second cohort, we reanalyzed data from a previous prospective study that was performed to compare SpO2 of newborns infants born at different altitudes (sea level or 760 m above sea level). MEASUREMENTS AND MAIN RESULTS: In young male adults, mean SpO2 was 97.1% ± 1.2% versus 98.6% ± 1.0% in females (P < .001). This difference remained significant (P = .002) after correction for BMI, BSA and age, variables that were significantly different between sexes in univariate analysis. The SpO2 in females was unaffected by menstrual phase. In contrast to findings in adults, there were no significant differences in SpO2 measurements in newborn infants attributable to sex. CONCLUSIONS: Healthy young female adults have a higher (1.5%) SpO2 than their male counterparts. This difference is not yet present at birth. Further studies are needed to determine the timing of sex-differences, and to better define the mechanism(s) behind this observation.

Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening.

BACKGROUND: Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. METHODS: An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts. RESULTS: We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. CONCLUSIONS: Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis.

Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients. OBJECTIVES: To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure. METHODS: In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year. RESULTS: Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken. CONCLUSIONS: Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure.

Is obstructive sleep apnea syndrome in children season dependent?

INTRODUCTION: The most common cause of obstructive sleep apnea (OSA) in children is an enlargement of tonsils and/or adenoids. Previous studies have shown that the size of adenoids and tonsils is influenced by upper respiratory tract infections and exposure to allergens. The rate of exposure to bacteria, viruses, and allergens fluctuates from season to season. Therefore, we hypothesized that the rate of polysomnograms positive for OSA may vary according to season. OBJECTIVE: The objective of this study is to determine whether the prevalence of OSA in children, as determined by polysomnography, is affected by the season during which the study was performed. METHODS: We retrospectively reviewed polysomnography tests of 296 children, ages 0-12 years, referred for suspected OSA. We compared the Obstructive Apnea Hypopnea Index (OAHI) between the seasons and the rates of abnormal tests in each season according to the degree of severity. RESULTS: The mean OAHI did not significantly differ among the seasons (winter, 3.0 ± 5.0; spring, 3.0 ± 4.9; summer, 4.0 ± 6.3; fall, 3.4 ± 5.7, p = 0.183). When dividing the OAHI by levels of severity, no seasonality was found in moderate (winter, 13.8 %; spring, 6.7 %; summer, 11.7 %; fall, 14.1 %, p = NS) and severe OSA (winter, 8.8 %; spring, 11.2 %; summer, 10 %; fall, 7.8 %, p = NS). There was a small increase in the frequency of mild OSA diagnoses in the summer compared to the other seasons. CONCLUSION: In this study, season does not appear to affect the rate of diagnosis of significant OSA in children. Re-evaluation during a different season is unlikely to provide different results and may postpone surgery unnecessarily.

The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening.

BACKGROUND: Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. METHODS: A retrospective review of governmental databanks, the national CF registry and CF centers. RESULTS: CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. CONCLUSIONS: PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.

High-Flow Nasal Cannula Therapy for Obstructive Sleep Apnea in Children.

INTRODUCTION: Over the last decade, high-flow nasal cannula (HFNC) therapy has become an increasingly important and popular mode of noninvasive respiratory support. HFNC facilitates delivery of humidified and heated oxygen at a high flow rate and generates positive airway pressure. METHODS: We present five cases of children with OSA without adenotonsillar hypertrophy who were treated with HFNC. RESULTS: We demonstrated a statistically significant improvement in apnea-hypopnea index and nadir oxygen saturation in this small cohort. CONCLUSION: We present our successful experience of treating severe OSA with HFNC in the home setting. Further randomized controlled trials are needed to determine whether HFNC could be considered as an established alternative for CPAP in OSA in children.

[Foreign body aspiration in children].

Foreign body (FB) aspiration occurs mainly in children under 3 years of age and is one of the most frequent causes of accidental death under 12 months of age. The increased risk of FB aspiration in children is due to the different structure of the pharynx and the upper airways compared to adults. In addition, children have an immature swallowing mechanism and they most commonly aspirate food stuffs. FB aspiration is usually a sudden and dramatic event when the child feels that he is suffocating or choking. After the acute event, the clinical presentation widely ranges from severe respiratory distress to the most minimal symptoms. Bronchoscopy is the best diagnostic and therapeutic modality for FB inhalation. Prevention and rapid diagnosis can be lifesaving. In 2010, the American Academy of Pediatrics published a position paper on prevention of FB aspiration. The association calls for more proactive preventative measures to protect children from FB aspiration and to prevent mortality and morbidity. These include: 1. Raising awareness of parents and caregivers to supervise children and create a safe environment for them. 2. Promoting legislation and enforcing regulations that will prevent dangerous products being sold for children. 3. Changing the design of products, especially food products and toys, that will reduce the risks of choking. In this overview we will show the principles of diagnosis of FB aspiration and a flow chart including when flexible or rigid bronchoscopy is required.

Is infection with hypermutable Pseudomonas aeruginosa clinically significant?

BACKGROUND: Hypermutable Pseudomonas aeruginosa (HPA) with high mutation rate due to defects in the DNA mismatch repair genes are frequently isolated in the sputum of cystic fibrosis (CF) patients. These isolates tend to be multidrug resistant and may be better adapted to the CF lung environment. However, the clinical significance of this infection has not been determined. METHODS: This prospective study enrolled patients with PA infection attending CF clinics in Jerusalem between 2010 and 2011. Mutation frequency of pseudomonas isolates was determined by quantification of colonies resistant to rifampicin. RESULTS: Of the 73 patients enrolled, 22 (30%) were infected with HPA. Average mutation frequency was 2.95×10(-4) in HPA and 1×10(-7) in non-HPA. Pulmonary function tests, number of pulmonary exacerbations and the response to antibiotic therapy were similar between patients infected with HPA and non-HPA isolates. The only predictors for infection with HPA were resistance to multiple antimicrobial categories (OR=4.8, 95% CI: 1.8-12.4) and previous use of inhaled colistin (OR=8.1, 95% CI: 2-30). Resistant mutant subpopulation analysis was a poor screening test for identifying HPA isolates. CONCLUSIONS: Infection with hypermutable strains represents the marked ability of PA to adapt to the lung environment, but was not associated with worse clinical outcome.

Evaluation of the intestinal current measurement method as a diagnostic test for cystic fibrosis.

BACKGROUND: The sweat test and nasal potential difference measurement are now established tools in the diagnostic work up of cystic fibrosis (CF). Intestinal current measurement (ICM) is under consideration as an aid in the diagnosis of CF especially in young children. The aim of this study is to evaluate the diagnostic reliability of ICM. METHODS: Rectal biopsies were obtained from three groups: CF patients, controls, and patients who were suspected for CF. ICMs were performed by mounting the rectal biopsy in an Ussing chamber and sequentially adding secretagogues while recording current changes. RESULTS: Twenty-one CF patients (aged 3.0 ± 3.8 years) and 16 controls (aged 15.6 ± 15.1 years) were examined and have remarkably different results (presented as µA/cm(2) ): carbachol 16.3 ± 6.9, histamine 13.2 ± 8.9, and cAMP/forskolin 4.8 ± 4.0 for control group and carbachol -1.5 ± 5.3 (P < 0.0001), histamine -1.5 ± 3.1 (P < 0.0001), and cAMP/forskolin 0.36 ± 0.67 (P < 0.0001) for the CF group. Our suggested reference values are: +5.40, +3.52, +2.19 for carbachol, histamine, and cAMP/forskolin, respectively. The combination parameter (the arithmetic sum of carbachol, histamine, and cAMP/forskolin) of +7.19 differentiates normal from abnormal (ROC curve analysis, area under the curve = 1.00, both sensitivity and specificity are 100%). This statistical model was applied to 71 patients suspected for CF and revealed that 66 patients had normal ICM results (combination >7.19) and five patients had abnormal ICM results (combination <7.19). CONCLUSION: We have shown that ICM tests may be useful to differentiate between patients suspected to have CF. These results require confirmation so that ICM may be included in diagnostic algorithms.