Early Diagnosis Of Cystic Fibrosis Research Articles

Meconium Peritonitis in the Newborn with Cystic Fibrosis and Negative Neonatal Screening for Immunoreactive Trypsinogen: Clinical Case

Background. Meconium ileus is one of the manifestations of cystic fibrosis. It is characterized by intestinal obstruction with viscous meconium leading to perforation and peritonitis. The issues of early diagnosis of cystic fibrosis, management of newborns with meconium ileus and negative neonatal screening for immunoreactive trypsinogen (IRT), as well as IRT decrease causes and mechanisms in patients with meconium ileus require further study. Clinical case description. Routine ultrasound examination at the 33rd week of gestation has shown signs of colon obstruction and meconium peritonitis in the intrauterine child. Surgical treatment of peritonitis was performed urgently on the 1st day after birth. The child was on mechanical ventilation from the 1st day of life. The child has shown signs of intrahepatic cholestasis with direct hyperbilirubinemia (up to 100 μmol/L) and signs of hemorrhagic syndrome (bleeding from injection sites) on the 8th day of life. Negative IRT blood test was received (21.6 ng/mL, normal value < 70 ng/mL) on the 10th day. The fecal elastase concentration was 45 μg/g (normal value > 200 μg/g) (on the same day). Sweat tests were performed on the 21st and 23rd days of life. They have shown high levels of sweat chlorides (112 mmol/L in both samples, normal value — 30–59 mmol/L). The diagnosis of «cystic fibrosis» was established, thus, dornase alfa (dosage — 2.5 mg/day) was added to the therapy. Conclusion. Meconium ileus is one of the specific intestinal manifestations of cystic fibrosis and it commonly can be complicated with intestinal perforation in the intrauterine child with further peritonitis. Children with meconium ileus require sweat tests regardless the neonatal screening results.

CFTR pharmacological modulators: A great advance in cystic fibrosis management

Cystic fibrosis is a severe monogenic disease that affects around 7400 patients in France. More than 2100 mutations in the cystic fibrosis conductance transmembrane regulator (CFTR), the gene encoding for an epithelial ion channel that normally transports chloride and bicarbonate, lead to mucus dehydration and impaired bronchial clearance. Systematic neonatal screening in France since 2002 has enabled early diagnosis of cystic fibrosis. Although highly demanding, supportive treatments including daily chest physiotherapy, inhaled aerosol therapy, frequent antibiotic courses, nutritional and pancreatic extracts have improved the prognosis. Median age at death is now beyond 30 years. Ivacaftor was the first CFTR modulator found to both reduce sweat chloride concentration and improve pulmonary function in the rare CFTR gating mutations. Combinations of modulators such as lumacaftor + ivacaftor or tezacaftor + ivacaftor were found to improve pulmonary function both in patients homozygous for the F508del mutation characterized by the lack of CFTR protein and those heterozygous for F508del with minimal CFTR activity. The triple combination of ivacaftor + tezacaftor + elexacaftor was recently shown to significantly improve pulmonary function and quality of life, to normalize sweat chloride concentration, and to reduce the need for antibiotic therapy in patients with at least one F508del mutation (83% in France). These impressive data, however, need to be confirmed in the long term. Nevertheless, it is encouraging to hear treated patients testify about their markedly improved quality of life and to observe that the number of lung transplants for cystic fibrosis decreased dramatically in France after 2020, despite the COVID pandemic, with no increase in deaths without lung transplant.

PECULIARITIES OF CYSTIC FIBROSIS IN NEWBORN ON THE EXAMPLE OF A CLINICAL CASE

Cystic fibrosis is a severe genetic disease, which is inherited in an autosomal recessive manner and is characterized by a polyorganic clinical presentation with predominantly exocrine, respiratory and digestive gland involvement. Every year more than 45 000 children are born worldwide with this genetic disease. According to official statistics, 674 children with cystic fibrosis are registered in Ukraine, 25 of them in the Vinnytsia region. The disease is caused by a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The F508del mutation is most common in the paediatric population (19-34%). The most common clinical manifestations of cystic fibrosis in newborns are disorders of the gastrointestinal tract, pancreas, hepatobiliary system and respiratory system. In 20% of newborns, one of the earliest manifestations of cystic fibrosis is meconial ileus, which may pose a risk of complications such as meconium peritonitis, sputum, gangrene or intestinal necrosis. Early diagnosis with neonatal screening, improved care for the neonatal manifestations of meconial ileus and adequate medical follow-up by a multidisciplinary team of specialists, and improved lifelong replacement fermentation therapy have a significant impact on the life expectancy of patients with cystic fibrosis.This article presents a clinical case of early diagnosis of cystic fibrosis in a newborn. When meconial ileus is present and cysticfibrosis is suspected in a newborn, early genetic diagnosis is mandatory, in addition to timely and correctly performed neonatal screening. Comprehensive and timely treatment leads to improvement in cystic fibrosis patients and slows down the development of pathological changes in the bronchopulmonary and hepatobiliary systems.Conclusions. Prevention of a severe course of cystic fibrosis is in early detection of the disease during neonatal screening, indiagnosis at the first signs of the disease and early start of pathogenetic treatment, which improves the quality of life of patients.

Is There any Association between Fecal Calprotectin Levels and Cystic Fibrosis?

Background: Early diagnosis of cystic fibrosis (CF) and hence the initiation of symptomatic and prophylactic treatment can help improve the outcomes of CF patients. Fecal calprotectin (FC) is a marker of inflammation in the intestinal tract that is elevated in several gastrointestinal inflammatory diseases, but little is known about its value in CF. Objectives: This study, therefore, aimed to survey the associations of FC among CF patients and its correlation with the clinical manifestations of CF. Methods: This descriptive cross-sectional study was performed on 52 children with CF visiting the Children’s Hospital of Tabriz, Iran, during 2018-2019, selected through the census sampling method. The calprotectin values of <50 μg/g were considered normal. Results: There was no clinically relevant association among FC levels concerning pancreatic insufficiency, diabetes, and airway colonization with Pseudomonas. In a comparison of the number of exacerbations and Forced Expiratory Volume in the first second (FEV1), the levels of electrolytes showed no significant difference between patients with normal calprotectin and elevated FC. The results of the performed analysis indicated no significant difference between the low-fecal elastase and the FC levels in patients with CF (P=0.53). Conclusion: Demographic and clinical parameters, such as age, gender, FEV1, or Body Mass Index, had no clinically significant relationship with FC. However, serial and longitudinal calprotectin levels should also be checked, which may have clinical relevance during symptomatic episodes.

Modern Approaches in Management of Children with Cystic fibrosis

The problem of timely diagnosis and proper management of patients with cystic fibrosis is crucial not only in our country, but throughout the world. Experts of the Union of Pediatricians of Russia have considered various issues of etiology, pathogenesis, epidemiology, diagnosis, and treatment of this genetic disease in a modern light. Particular attention was paid to screening methods for early diagnosis of cystic fibrosis. The principles of complex therapy were justified, including rational use of antibacterial and mucolytic drugs and enzyme replacement therapy that significantly determine the disease prognosis.

Suspected Cystic Fibrosis in Infantile Onset Pneumonias: A Case Series and Review of Literature

Pneumonias are common in infancy and infections remain the most common aetiology especially in developing countries. A case- series of 14 children (9 males and 5 females) with cystic fibrosis is presented who came with persistent/recurrent pneumonia. Most children had infantile onset of symptoms (mean age 4.6±4.2 months). Despite multiple medical consultations in infancy a severe delay in diagnosis (mean age of diagnosis 75.5±65.1 months) and presentation was observed. The youngest child in this series was diagnosed at 2 months of age. Most common manifestations were respiratory, gastrointestinal, and failure to thrive (100%). Sweat chloride test was done in 12/14 children and was elevated in 100%. Genetic mutation was reported in 5 children only. Complications included computed tomography diagnosed bronchiectasis in (7/14;50%), pseudomonas infections (6/14,42.9%; other infections (7/14%, 50%), pulmonary hypertension (3/14,21.4%), gastroesophageal reflux (2/14; 14%). There was a high (5/14,35.7%) mortality in this series, as most of them presented late. Lack of awareness and meager diagnostic facilities are major limitations in early diagnosis of cystic fibrosis and may lead to increased morbidity and mortality among these children.

Novel transdermal patch for detecting Cystic fibrosis

A genetic condition, termed as cystic fibrosis (CF) affecting numerous organs, including the lungs, pancreas, colon, liver, and reproductive system, is completely dormant and intrinsic. Better treatment and control of CF are facilitated by early diagnosis. With the advent of technological and healthcare developments, there have been tremendous advancements in detecting CF rapidly and administering therapeutics. Accordingly, these short communication overviews developments related to early diagnosis of CF with dermal stickers. Apart from this, the future perspectives are also appraised.

Geographical barriers to timely diagnosis of cystic fibrosis and anxiety level of parents during newborn screening in Turkey.

Despite the availability of cystic fibrosis (CF) screening countrywide, diagnostic delay is still a crucial issue. The objectives of this study were to explore the stages of the NBS process, determine the risk factors associated with diagnostic delay and evaluate parent anxiety and experience throughout the process. This is a multicenter cross-sectional study. A questionnaire was completed by parents of newborns diagnosed with CF via NBS in 17 centers. Socio-demographic characteristics, parent knowledge and experiences related to NBS, sweat test availability in the region of residence, and time to the definitive CF diagnosis were assessed through this questionnaire. Parents' anxiety levels were evaluated through the State-Trait Anxiety Inventory scales 1 and 2. Delayed diagnosis (DD) was defined as a definite CF diagnosis beyond the 8th week of life. Predictors of delayed CF diagnosis were evaluated by univariate and multivariate analysis. A total of 220 CF patients diagnosed via NBS were enrolled; 82 (37.3%) babies had DD. Multivariable analysis indicated that residence in the Southeast Anatolia region of Turkey (OR = 10.79, 95% CI = 2.37-49.2) was associated with a higher incidence of DD compared with other regions in Turkey. Of the total, 216 (98.1%) of the caregivers regarded the NBS program as useful and 180 (82%) reported high anxiety levels. The organization of newborn screening should take into account regional and socio-cultural characteristics to improve the early diagnosis of CF and also reduce the anxiety level of parents.

The remaining barriers to normalcy in CF: Advances in assessment of CF lung disease.

Despite early diagnosis of cystic fibrosis (CF) through newborn screening, a substantial proportion of infants and young children with CF still demonstrate physiologic and structural evidence of lung disease progression, such as obstructive airway disease and bronchiectasis. The growing availability of highly effective CF transmembrane conductance regulatory modulator therapy to the vast majority of people with CF has led to the potential to alter the natural history of CF lung disease, but to assess the full impact of these therapies on CF lung disease and to help guide treatment, sensitive measures of early and mild disease are needed. Chest imaging using computed tomography or magnetic resonance imaging is one approach, but technologic barriers and/or concern about exposure to ionizing radiation may limit its use. However, advances in physiologic measurement techniques and exhaled breath analysis offer another option for assessment of CF lung disease.

Cystic fibrosis: Physiopathology and the latest pharmacological treatments

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease, caused by a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which primarily affects the lungs and digestive system. This gene encodes the CFTR protein, a distinctive membrane transporter of the ATP-binding cassette (ABC) superfamily. It functions as a chloride channel, allowing the balance and transport of chloride through the apical membrane of epithelial cells. Due to its ubiquitous location, mutations in the CFTR gene trigger multiple changes in ion transport and metabolic pathways, affecting various organs, as it will be herein explained. Pulmonary impairment is the most characteristic comorbidity of CF and respiratory failure is the main cause of death.This review presents the importance of an early diagnosis of CF to establish, as soon as possible, a primary therapy for symptomatic prevention and relief. It also mentions new therapeutic approaches that include CFTR modulators. They are correctors and/or potentiators of the deficient CFTR channel. In an attempt to overcome the disadvantages of CFTR modulators, the application of biotechnology techniques is addressed, such as gene therapy, gene editing, RNA therapy and therapeutic microRNAs. The potential of the intranasal administration route is another presented aspect.

Выбор продуктов специализированного питания у детей с муковисцидозом, перенесших критические состояния в раннем возрасте

The article is devoted to the choice of nutritional support in children with cystic fibrosis. Timely early diagnosis of cystic fibrosis, replacement therapy with microspherical pancreatic enzymes and adequate nutritional support prevent the development of protein-energy malnutrition. A wide range of specialized food products on the market allows you to choose the optimal correction method. The main requirements for the nutritional components introduced into the child’s diet are high calorie content, ease of absorption, anti-inflammatory and immunomodulating effect on the mucous membrane of the gastrointestinal tract. The results of the use of specialized nutrition for cystic fibrosis at the stage of recovery of children with protein-energy deficiency are presented. In the State Novosibirsk Regional Clinical Hospital (Novosibirsk), as part of complex therapy in children of the first year of life suffering from cystic fibrosis, a specialized product of children’s dietary food was used. On the basis of the children’s pulmonology department of the clinic, 8 children with this pathology were treated with the use of a therapeutic mixture during the recovery period from 12 to 180 days. It was shown that during the use of the therapeutic mixture, patients achieved good results, all children had a good appetite and stable weight gain.

The pathological features of cystic fibrosis and the diagnostic techniques and treatments involved

Cystic fibrosis is a disease found predominantly in Caucasians. It is caused by an autosomal recessive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The mutation(s) lead to defective CFTR proteins, or transmembrane cyclic adenosine monophosphate (cAMP)-dependent chloride channels found on the surface of epithelial cells. The respiratory system is most impacted by this abnormal phenotype, and lung disease can bring about the majority of the various issues that a cystic fibrosis patient has to deal with. Even so, due to the excess amount of mucus that is secreted, individuals diagnosed with cystic fibrosis experience complications in other organs as well. Today, newborn screening is widely used as a means of early diagnosis of cystic fibrosis, and there are also multiple other novel technologies that aim for accurate diagnosis and prevention of the disease. In addition, while traditional treatment programs are based on curing the symptoms that the patients exhibit, new regimens are directed at correcting the error that occurred at the molecular level. With improvements made in the medical field, cystic fibrosis patients are able to live longer and have a better quality of life. This review article serves as a compilation of the current knowledge on the causes of cystic fibrosis, the physiological processes associated with the disease, the techniques for diagnosis of the disease, and finally the recent and upcoming therapeutics for the disease.

An Enzyme Immunoassay for Determining Immunoreactive Trypsinogen (IRT) in Dried Blood Spots on Filter Paper Using an Ultra-Microanalytical System.

Cystic fibrosis (CF) is a severe autosomal recessive disorder. It is caused by mutations in the CF transmembrane conductance regulator gene. Early diagnosis of CF can be carried out by determining high immunoreactive trypsinogen (IRT) blood values in newborns. A simple sandwich-type ultramicroELISA assay (UMELISA®) has been developed for the measurement of IRT in dried blood spots on filter paper. Strips coated with a high affinity monoclonal antibody directed against IRT are used as solid phase, to ensure the specificity of the assay. The assay is carried out within 20h. The useful rank of the curve is 0-500ng/mL, and the lowest detectable concentration is 4.8ng/mL. Intra- and inter-assay coefficients of variation were lower than 10%. The recovery mean value was 100.3±11.2%. Cross-reactivity with proteins structurally related to IRT (α2-macroglobulin, α1-antitrypsin, and human chymotrypsin) was lower than the detection limit of the assay. Four thousand four hundred six newborn samples from the Cuban Newborn Screening Program were analyzed, and the mean IRT concentration was 12.8ng/mL. Higher IRT values were obtained when samples were eluted overnight. Regression analysis showed a good correlation with the commercially available AutoDELFIA® Neonatal IRT kit (n = 3948, r= 0.885, ƙ = 0.976, p < 0.01). The analytical performance characteristics of our UMELISA® TIR Neonatal suggest that it can be used for the neonatal screening of CF.

Incidental late diagnosis of cystic fibrosis following AH1N1 influenza virus pneumonia: a case report

BackgroundCystic fibrosis is an autosomal recessive disorder characterized by chronic progressive multisystem involvement. AH1N1 virus infections caused classic influenza symptoms in the majority of cystic fibrosis patients while others experienced severe outcomes.Case presentationWe report a case of late incidental cystic fibrosis diagnosis in a young Caucasian man suffering from respiratory failure following infection due to AH1N1 influenza virus. The patient was admitted to our department with fever, cough, and dyspnea at rest unresponsive to antibioticsConclusionsLate diagnosis of cystic fibrosis in uncommon. This report highlights the importance of early cystic fibrosis diagnosis to minimize risk of occurrence of potential life-threatening complications.

Cystic Fibrosis Late Diagnosis: A Case Report

Cystic Fibrosis (CF) is an autosomal recessive disease that affects mucus and sweat producing cells involving multiple organs. CF is usually diagnosed in childhood; however, a considered number of adults are diagnosed every year. Atypical CF can be a milder form of the CF disorder, and individuals with atypical CF can remain undiagnosed for many years. Physicians should suspect of CF in adult individuals when these present recurrent pneumonia or bronchiectasis. Therefore, since early diagnosis of CF can avoid morbidities and unnecessary hospitalizations, the recognition of CF symptoms by clinicians is necessary to avoid late diagnosis.

Onset of persistent pseudomonas aeruginosa infection in children with cystic fibrosis with interval censored data.

BackgroundPersistent Pseudomonas aeruginosa (PPA) infection promotes lung function deterioration in children with cystic fibrosis (CF). Although early CF diagnosis through newborn screening (NBS) has been shown to provide nutritional/growth benefit, it is unclear whether NBS lowers the risk of PPA infection and how the effect of NBS vary with age. Modeling the onset age of PPA infection is challenging because 1) the onset age of PPA infection is interval censored in patient registry data; and 2) some risk factors such as NBS may have time-varying effects.MethodsThis problem fits into the framework of a recently developed Bayesian dynamic Cox model for interval censored data, where each regression coefficient is allowed to be time-varying to an extent determined by the data.ResultsApplication of the methodology to data from the CF Foundation Patient Registry revealed interesting findings. Compared with patients with meconium ileus or diagnosed through signs or symptoms, patients diagnosed through NBS had significantly lower risks of acquiring PPA infection between age 1 and 2 years, and the benefit in survival rate was found to last up to age 4 years. Two cohorts of five years apart were compared. Patients born in cohort 2003–2004 had significantly lower risks of the PPA infections at any age up to 4 years than those born in 1998–1999.ConclusionsThe study supports benefits of NBS on PPA infection in early childhood. In addition, our analyses demonstrate that patients in the more recent cohort had significantly lower risks of acquiring PPA infection up to age 4 years, which suggests improved CF treatment and care over time.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-016-0220-5) contains supplementary material, which is available to authorized users.

Nutritional status of adolescents with cystic fibrosis treated at a reference center in the southeast region of Brazil.

BackgroundSeveral factors can interfere with the full physical and emotional growth of adolescents, among them chronic diseases. The aim was to determine the nutritional status of adolescents and to associate it with puberty, pancreatic sufficiency, lung function and age range of Cystic Fibrosis (CF) diagnosis.MethodsAn observational, cross-sectional, retrospective and analytical study was conducted using the data of medical records. Setting: Reference center in the northeastern region of the state of São Paulo – Brazil. Patients: All adolescents with CF attended in 2010 were included. Some variables included: pancreatic sufficiency (steatocrit >2 %), pancreatic enzymes replacement (yes/no), pubertal status-Tanner criteria (prepubertal: M1/G1, pubertal: M2/G2 to M4/G4, postpubertal: M5/G5), age at CF diagnosis (<2 and ≥2 years of age), Lung function, measured as a predicted forced expiratory volume in 1 s (FEV1). Main outcome measures Nutritional indicators: body mass index for age (BMI/A) and height for age (H/A) with z-score calculated with Anthro Plus software. Cut-off reference points: ≥ z-score −3 and < z-score −2 (thinness); z-score −2 and ≤ z-score-z +1 (normal weight); >z-score +1 (overweight or obesity), and z-score <−2 (low or very low H/A). The groups were compared by the Kruskal-Wallis test. Level of significance: p < 0.05.ResultsThirty adolescents. Median (min;max) age: 14.4 (10.1;19.8) years. BMI/A and H/A z-score, respectively: early diagnosis of CF (−0.8; −1.1) or late diagnosis of CF (−0.5;-0.8); with pancreatic insufficiency (−0.7; −0.8) or without pancreatic insufficiency (−0.8; −0.5) and prepubertal (−0.8; −0.7) pubertal (−0.2; −1.5) or postpubertal (−0.7; -0.5). No significant difference (p > 0.05) was observed. Patients with and without pancreatic insufficiency, presented H/A borderline z-score (p = 0.05). Association between H/A and FEV1 was borderline (p = 0.05).ConclusionsAdolescents presented adequate nutritional status, although with slightly lower values than those of developed countries. FEV1 lower levels occurred more frequently in adolescents with low H/A.

225 Nutritional status of children with cystic fibrosis (CF) in Russia and neighboring territories

Objectives Our previous abstract failed to elucidate if early diagnosis of CF by neonatal screening which had been introduced in Russia since 2006 had a positive influence on the nutritional status of CF children. We suppose that the higher portion of patients with low z-scores is a result of early diagnose but inadequate treatment in some distant Russian regions (Caucasus). The aim of the study was to determine the nutritional status of CF children in Russian regions versus some neighboring territories and Caucasus region. Methods 61 children with CF from Moscow region (112 measurements), 64 children (141 measurements) from other Russian regions, 19 children from Ukraine, Kazakhstan and Moldova, receiving treatment in Moscow (41 measurements), and 25 children from Caucasus (40 measurements). Weight and height of CF children were recorded according to standard methods and expressed as standard deviation scores (z-score) and percentiles adjusted for age and gender using WHOAnthro- and WHOAnthroPlus programs. Results Mann–Whitney test showed statistically significant differences in z-scores: weight/age (p Conclusion Children with CF in Moscow and Russian regions have relatively good nutritional status compared with Caucasus region and Ukraine/Kazakhstan/Moldavian patients with CF, which require better primary care in these regions.

WS11.4 The significance of a neonatal screening program in the early diagnosis of cystic fibrosis

Objectives A national newborn screening (NBS) program for cystic fibrosis (CF) was introduced all over Russia in January 2007. Currently, this is the main method of CF diagnosis in the country and from 140 to 190 CF newborns are diagnosed per year. In the Moscow region NBS is carried out from June 2006. In total 134 CF patients were identified (the end 2014). Methods From the Moscow region CF Patients Register we analyzed the data of all diagnosed CF patients under 18 years old in two different periods: from 1999 to 2005 (before the introduction of NBS in Moscow – Group I) and from 2007 to 2013 (Group II). Results Before the NBS program CF was diagnosed in 83 patients. In the period 2007–2013 CF was diagnosed in 228 CF patients. The average age at diagnosis in Group I was 4.5 years (30% before 12 months), and in Group II – 1.8 years (74% before 12 months). The average age of patients at CF diagnosis in the positive NBS group was 2.3 months, in the infants with false-negative NBS results – 23 months. In Group I meconium ileus (MI) was diagnosed in 5 children (6%), and in Group II – in 27 children (12%). We assume there were much more cases of CF under-diagnosis in MI newborns in Moscow region before 2007. MI patients in Group I were diagnosed as having CF at the age of 1.4 years, and in Group II – 1.7 months. Conclusion Our findings demonstrate both the effectiveness of NBS and a greater awareness of CF nosology among physicians. At the same time, underdiagnosed CF before NBS program, false-negative NBS and sweat testing results, as well as a number of CF health care organization problems in Moscow still influence the diagnosis age of new CF patients.

Cystic fibrosis diagnosed via presentation of intussusception in childhood

The presentation of intussusception leading to the diagnosis of cystic fibrosis is rare, with only a limited number of cases previously reported in the literature. We encountered such a case which describes a unique clinical presentation of intussusception providing a broad discussion of the disease and its pathophysiology. Although statewide screening programs have been created, cystic fibrosis can still go undiagnosed until late childhood. • Intussusception can occur in older children and lead to the diagnosis of cystic fibrosis. • Statewide screening programs provide early diagnosis of cystic fibrosis. • Older children with intussusception may require further imaging modalities.