Cystic Fibrosis: Clinical Manifestations and Diagnosis PDF

Studiestof UpToDate bij ZSO: Het hoestende kind Versie 1 28-08-2020 Cystic fibrosis: Clinical manifestations and diagnosis (Bron: aangepast UpToDate 20-08-2020) INTRODUCTION Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disease amon...

Studiestof UpToDate bij ZSO: Het hoestende kind Versie 1 28-08-2020 Cystic fibrosis: Clinical manifestations and diagnosis (Bron: aangepast UpToDate 20-08-2020) INTRODUCTION Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disease among Caucasian populations, with a frequency of 1 in 2000 to 3000 live births. The median predicted survival for CF patients in the United States was 47.4 years (95% CI, 44.2-50.3) for those born in 2018, according to the Cystic Fibrosis Foundation 2018 Registry Report. These numbers do not take into account the potential impact of new cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs that are now widely in use. The usual presenting symptoms and signs include persistent pulmonary infection, pancreatic insufficiency, and elevated sweat chloride levels. However, many patients demonstrate mild or atypical symptoms, and clinicians should remain alert to the possibility of CF even when only a few of the usual features are present. Diagnosis of CF is based upon the finding of genetic and/or functional abnormalities of the CFTR gene. EPIDEMIOLOGY In the United States, CF occurs in approximately 1:3200 Caucasians, 1:10,000 Hispanics, 1:10,500 Native Americans, 1:15,000 African Americans, and 1:30,000 Asian Americans [3,4]. CF is increasingly recognized in non-white populations, not only in regions familiar with CF but also in South and East Asia, Africa, and Latin America, although the overall prevalence in these regions is low [4-7]. Prevalence estimates are likely to rise with increasing use of newborn screening and increasing recognition of individuals with mild disease or disease limited to one organ system. OVERVIEW OF CLINICAL FEATURES CF is caused by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a complex chloride channel and regulatory protein found in all exocrine tissues [24-26]. Deranged transport of chloride and/or other CFTR-affected ions, such as sodium and bicarbonate, leads to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract and to increased salt content in sweat gland secretions [2,25,27]. The typical CF patient develops multisystem disease involving several or all of these organs. Presentation — In the past, most patients were diagnosed with CF after presenting with symptoms. Because of the expansion of newborn screening programs during the past 20 years, there has been a dramatic increase in the number of CF cases identified before presenting with symptoms. There is evidence that individuals diagnosed prior to the onset of symptoms have better lung function and nutritional outcomes later in life. Symptomatic presentation in infants and children — Prior to the implementation of widespread newborn screening in the United States and many other countries, infants and children were typically diagnosed with CF after presenting with one or more of the following symptoms : Meconium ileus – 20 percent of patients Respiratory symptoms – 45 percent of patients Failure to thrive – 28 percent of patients For infants presenting with meconium ileus, the median age of diagnosis was two weeks. For those presenting with other symptoms, the median age of diagnosis was 14.5 months (interquartile range 4.2 to 65 months). These clinical presentations are still relevant for populations that do not undergo routine newborn screening for CF. Respiratory tract involvement — Typical respiratory manifestations of CF include a persistent productive cough, hyperinflation of the lung fields on chest radiograph, and pulmonary function tests that are consistent with obstructive airway disease. The onset of clinical symptoms varies widely due to differences in CFTR genotype and other individual factors, but pulmonary function abnormalities often are detectable even in the absence of symptoms. As an example, in a cohort of infants largely identified by newborn screening, 35 percent had respiratory symptoms (cough, wheezing, or any breathing difficulty); mean pulmonary function scores were abnormal by six weeks of age and declined during the subsequent two years. As the disease progresses, patients develop chronic bronchitis with typical organisms, as discussed below. Repeated infections, with aggregation of inflammatory cells and release of their contents, causes damage to the bronchial walls, with loss of cartilaginous support and muscular tone, eventually leading to bronchiectasis. Disease progression includes acute exacerbations with cough, tachypnea, dyspnea, increased sputum production, malaise, anorexia, and Studiestof UpToDate bij ZSO: Het hoestende kind Versie 1 28-08-2020 weight loss. These acute events are associated with acute, transient loss of lung function that improves with treatment but which lead to permanent loss of lung function over time. Digital clubbing is often seen in patients with moderate to advanced disease. Transient infection of the airway with pathogenic bacteria often occurs early in life. Eventually, over years and varying widely among individuals, chronic airway infection with either Staphylococcus aureus or gram-negative bacteria is established, often with radiographic evidence of bronchiectasis. S. aureus and nontypeable Haemophilus influenzae are common pathogens during early childhood, but Pseudomonas aeruginosa is ultimately isolated from the respiratory secretions of most patients. S. aureus, and particularly slow growing or "small colony" variants, continues to cause significant morbidity in older children and adults with CF. Other microbes to which CF patients appear susceptible to colonization and infection include Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia cepacia complex, nontuberculous mycobacteria (especially Mycobacterium avium comple and Mycobacterium abscessus), and the filamentous fungus Aspergillus fumigatus. This predisposition to P. aeruginosa infection may be in part because of impaired clearance directly induced by a defect in CFTR. NEWBORN SCREENING Newborn screening for CF is now performed routinely in all 50 of the United States. Generally, screening is based on a combination of the biochemical marker and genetic assays described below. Rationale — The rationale for newborn screening is that early detection of CF may lead to earlier intervention and improved outcomes because affected individuals are diagnosed, referred, and treated earlier in life as compared with individuals who are diagnosed after presenting with symptomatic CF. Techniques — Newborn screening typically employs two serial assays; infants with abnormal results for the first assay are retested with a second assay. The two assays used for newborn screening are serum immunoreactive trypsinogen (IRT) and DNA analysis for variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. (NB In Nederland wordt eerst getest op IRT, indien afwijkend volgt een test op Pancreatitis Associated Proteine en als deze waarde ook verhoogd is wordt DNA onderzoek ingezet). Infants with positive CF newborn screening results should undergo sweat chloride testing to determine whether they have CF. For optimal accuracy, sweat testing should be performed when the infant is at least two weeks of age and weighs >2 kg. DIAGNOSIS The diagnosis of CF is based upon compatible clinical findings with biochemical or genetic confirmation [33,117,118]. The sweat chloride test is the mainstay of laboratory confirmation. Diagnostic criteria — Both of the following criteria must be met to diagnose CF (table 1) : Clinical symptoms consistent with CF in at least one organ system, or positive newborn screen or genetic testing for siblings of patients with CF AND Evidence of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction (any of the following): Elevated sweat chloride ≥60 mmol/L Presence of two disease-causing variants in the CFTR gene, one from each parental allele Abnormal NPD Studiestof UpToDate bij ZSO: Het hoestende kind Versie 1 28-08-2020 Cystic fibrosis: Genetics and pathogenesis (Bron: aangepast UpToDate 26-03-2020) GENETICS CF is caused by pathogenic mutations in a single large gene on chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein [4-9]. Clinical disease requires pathogenic mutations in both copies of the CFTR gene. CFTR functions as a regulated chloride channel, which, in turn, may regulate the activity of other chloride and sodium channels at the cell surface [10-13]. Genetic changes in CFTR — The phenotypic expression of disease varies widely, primarily as a function of the specific mutation (or mutations) present [16-21]. The CFTR2 database lists more than 2000 different mutations in the CFTR gene with potential to cause disease. The most common pathogenic mutation is F508del (which describes the deletion of three DNA bases coding for the 508th amino acid residue phenylalanine). At least one copy of this mutation is found in approximately 90 percent of CF patients, and 50 percent are homozygotes. Certain mutations are found at higher frequency in some ethnic groups because of apparent founder effects. As an example, five mutations account for an estimated 97 percent of CF alleles in the Ashkenazi Jewish population [23. Mutations of the CFTR gene have been divided into five different. In general, mutations in classes I to III cause more severe disease than those in classes IV and V [19,27]. However, the clinical implications of a specific combination of mutations are often unclear, perhaps because of the influence of gene modifiers. Genotype-phenotype correlations are weak for pulmonary disease in CF and somewhat stronger for the pancreatic insufficiency phenotype. (See 'Gene modifiers' below.) In most cases, specific mutations should not be used to make assumptions about the severity of disease in an individual patient. Knowledge of the mutations may be useful to guide initial therapy, but clinical decisions should be guided by observable parameters of growth, lung function, and nutritional status. Some new therapies are directed at specific classes of CFTR mutation. PATHOGENESIS It appears that the physical and chemical abnormalities of CF airway secretions result in chronic infection with phenotypically unique bacteria, particularly Pseudomonas species. Other genetic factors, including polymorphisms of the tumor necrosis factor alpha (TNF-alpha) gene, may increase susceptibility to P. aeruginosa infection and contribute to the clinical manifestations of CF. Abnormal secretions CFTR malfunction in the respiratory epithelium is associated with a variety of changes in electrolyte and water transport. The mechanisms involved and ultimate electrolyte composition of airway surface fluid in CF airways is a subject of ongoing research [11-13,45-48]. The net result of these changes is an alteration in the rheology of airway secretions, which become thick and difficult to clear. An associated finding is an increased concentration of chloride in sweat secretions, which constitutes one of the methods of diagnosis of CF. Gastrointestinal effects Thickened secretions caused by CFTR malfunction cause the gastrointestinal complications of CF. Impaired flow of bile and pancreatic secretions cause maldigestion and malabsorption, as well as progressive liver and pancreatic disease, leading to CF-related diabetes. Because of thickened intestinal secretions and maldigestion, CF patients are prone to intestinal obstruction (distal intestinal obstruction syndrome or intussusception) and to rectal prolapse. Chronic lung infection The chronic airway obstruction caused by viscous secretions is followed by progressive pulmonary colonization with pathogenic bacteria, including Haemophilus influenzae, Staphylococcus aureus, and eventually P. aeruginosa and/or B. cepacia complex bacteria Once infection is established, neutrophils are unable to control the bacteria, even though there is massive infiltration of these inflammatory cells into the lung tissue. Recruited neutrophils subsequently release elastase, which overwhelms the antiproteases of the lung and contributes to tissue destruction in a process known as "prolonged endobronchial protease activity". In addition, Studiestof UpToDate bij ZSO: Het hoestende kind Versie 1 28-08-2020 large amounts of DNA and cytosol matrix proteins are released by degranulating neutrophils, contributing to the increased viscosity of the airway mucus. Inflammation has been noted prior to the development of bacterial colonization and may be triggered by viral infections. In turn, chronic infection appears to be the major stimulus for an exuberant but ultimately ineffective inflammatory response that subsequently results in bronchiectasis [54,55]. The inflammatory response itself appears to contribute to the progression of pulmonary dysfunction; this mechanism is the basis for the use of some antiinflammatory agents in treating CF lung disease [56,57]. Individuals with CF are particularly prone to chronic infection with P. aeruginosa, due in part to increased oxygen utilization by epithelial cells, which results in an abnormally decreased oxygen tension within the hyperviscous mucous layer. This local hypoxia induces the characteristic phenotypic changes in P. aeruginosa (and some other gram-negative bacteria), including alginate production and loss of motility. This phenotype is consistent with the development of bacterial macrocolonies (or "biofilms") within the hypoxic regions of the airway mucus layer. Once this occurs, eradication of the organism is almost impossible.