Cystic fibrosis in children

Cystic fibrosis is a hereditary disease that affects the exocrine glands, primarily those of the gastrointestinal tract and respiratory system. It results in COPD, exocrine pancreatic insufficiency, and abnormally high electrolyte levels in sweat. Diagnosis is made by sweat testing or by identifying two mutations that cause cystic fibrosis in patients with characteristic symptoms. Treatment of cystic fibrosis is supportive, with the mandatory participation of physicians specializing in various fields of medicine, nurses, psychologists, and social workers.

ICD-10 code

• E84 Cystic fibrosis.
• E84.0 Cystic fibrosis with pulmonary manifestations.
• E84.1 Cystic fibrosis with intestinal manifestations.
• E84.8 Cystic fibrosis with other manifestations.
• E84.9 Cystic fibrosis, unspecified.

Epidemiology of cystic fibrosis

Cystic fibrosis is inherited in an autosomal recessive manner. If both parents are heterozygous for the abnormal CFTR gene, the probability of having a sick child is 25% with each pregnancy. The incidence of cystic fibrosis is 1 in 10,000-12,000 newborns. In most countries of Europe and North America, it affects 1:2,000 to 1:4,000 newborns. The prevalence of cystic fibrosis in Ukraine is 1:9,000 newborns. Every year in the USA - 2,000, in France, England, Germany - from 500 to 800, and worldwide - more than 45,000 children with cystic fibrosis.

The CFTR (cystic fibrosis transmembrane conductance regulator) gene is located on the long arm of chromosome 7 in the q31 region, is approximately 250,000 base pairs long, and includes 27 exons. CFTR belongs to the superfamily of ATP-binding proteins. It is a transmembrane protein located on the surface of most epithelial cells, functioning as a cAMP-dependent chloride channel. CFTR is also involved in the regulation of other ion channels and membrane transport. Currently, about 1,200 mutations of the CFTR gene are known, the most common mutation is AF508, the second most common is CFTR dele 2.3.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ]

Causes of Cystic Fibrosis

Cystic fibrosis is the most common life-shortening genetic disorder in the white population. In the United States, the disease occurs in approximately 1/3,300 white births, 1/15,300 black births, and 1/32,000 Asian births. With improved treatment and increased life expectancy, 40% of patients are adults.

Approximately 3% of the white population are heterozygous carriers of the cystic fibrosis gene, which is inherited in an autosomal recessive pattern. The gene responsible for the development of cystic fibrosis is localized on the long arm of chromosome 7 (7q). It codes for a membrane protein called the cystic fibrosis transmembrane regulator (CFTR). The most common mutation in this gene is called deltaF508, and its frequency is about 70% among patients with cystic fibrosis. This mutation results in the loss of one amino acid residue, phenylalanine, at position 508 of CFTR. More than 1,200 less common mutations make up the remaining 30%. Although the exact function of CFTR is unknown, it is believed to be part of the cAMP-dependent chloride channel, which regulates the transport of sodium and chloride across the cell membrane. Heterozygous carriers may exhibit minor disturbances in electrolyte transport in epithelial cells, but there are no clinical manifestations.

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Symptoms of Cystic Fibrosis

In the neonatal period, cystic fibrosis is accompanied by signs of intestinal obstruction ( meconium ileus ), in some cases peritonitis associated with perforation of the intestinal wall.

Meconium ileus, due to blockage of the ileum by viscous thick meconium, may be the earliest manifestation and is observed in 15-20% of newborns with cystic fibrosis. Meconium ileus is often accompanied by intestinal volvulus, perforation, or atresia of the intestine, and, with rare exceptions, other symptoms of cystic fibrosis develop later. Also, with cystic fibrosis, late passage of meconium and meconium impaction syndrome (a transient form of low intestinal obstruction that develops due to the formation of one or more dense meconium plugs in the anus or large intestine) may be observed.

In infants who have not shown signs of meconium ileus, the onset of the disease may be characterized by a longer recovery of initial body weight and inadequate weight gain at 4-6 weeks of age.

In children who are artificially fed with soy formula or cow's milk, hypoproteinemia with edema and anemia may develop as a result of impaired protein absorption.

In 50% of patients with cystic fibrosis, the first manifestations of the disease are pulmonary manifestations. Recurrent and chronic infections are common, manifested by cough and wheezing. The most disturbing is the persistent cough with difficult to separate sputum, often accompanied by vomiting and sleep disturbances. As the disease progresses, there is retraction of the intercostal spaces, involvement of the accessory muscles in the act of breathing, a barrel-shaped chest, clubbing of the fingers and cyanosis. Damage to the upper respiratory tract is usually manifested by nasal polyposis and chronic or recurrent sinusitis. Adolescents may experience delayed physical development, late onset of puberty, and decreased tolerance to physical activity.

Pancreatic insufficiency is clinically present in 85-90% of children, usually in the early stages, and may have a progressive course. Clinical manifestations include frequent, plentiful, fatty stools with a foul odor, abdominal distension, and delayed physical development with a decrease in subcutaneous fat and a decrease in muscle mass, despite normal or increased appetite. Rectal prolapse is observed in 20% of children under 1-2 years of age who do not receive treatment. Manifestations of deficiency of fat-soluble vitamins may also join.

Excessive sweating in hot weather or with fever may lead to episodes of hypotonic dehydration and circulatory collapse. In dry climates, infants may develop chronic metabolic alkalosis. The formation of salt crystals and a salty taste of the skin are characteristic of CF and make the diagnosis highly probable.

In patients aged 13 years and older, 17% develop type 1 diabetes mellitus, and 5-6% develop multilobular biliary cirrhosis with esophageal varices and portal hypertension. Chronic or recurrent abdominal pain may be due to intussusception, peptic ulceration, periappendiceal abscess, pancreatitis, gastroesophageal reflux, esophagitis, gallbladder disease, or episodes of partial intestinal obstruction due to abnormally viscous and thick stools. Complications of cystic fibrosis also include osteopenia/osteoporosis and intermittent arthralgia/arthritis.

Pulmonary manifestations of cystic fibrosis

As a rule, the lungs have a normal histological structure at birth. Lung damage is initiated by diffuse obstruction of small-caliber bronchi with abnormally thick and viscous secretions. Bronchiolitis and blockage of the airways with mucopurulent plugs develop secondary to obstruction and infection. Bronchial changes are more common than parenchymatous lesions. Emphysema is not very pronounced. As the process progresses in the lungs, the bronchial wall thickens; the airways fill with purulent, viscous secretions; areas of atelectasis appear; the hilar lymph nodes enlarge. Chronic hypoxemia leads to hypertrophy of the muscular layer of the pulmonary arteries, pulmonary hypertension, and hypertrophy of the right ventricle. Most of the changes in the lungs may be the result of inflammation developing secondary to the release of proteolytic enzymes by neutrophils in the airways. Bronchoalveolar lavage fluid contains high numbers of neutrophils and elevated concentrations of free neutrophil elastase, DNA, and interleukin-8 already at a very early age.

Chronic lung disease develops in almost all patients and leads to periodic exacerbations with infectious inflammation and progressive decline in lung function. In the early stages, the main pathogen isolated from the respiratory tract is Staphylococcus aureus, but as the disease progresses, Pseudomonas aeruginosa is most often isolated. The mycoid variant of Pseudomonas is observed only in cystic fibrosis. Colonization with Burkholderia cepacia occurs in about 7% of adult patients and may be associated with a rapid decline in lung function.

Classification of cystic fibrosis

There are 3 forms of cystic fibrosis:

• mixed (75-80%);
• predominantly pulmonary (15-20%);
• mainly intestinal (5%).

Some authors also distinguish a hepatic form, characterized by cirrhosis, portal hypertension and ascites, isolated electrolyte (pseudo-Bartter syndrome), meconium ileus, atypical and latent forms of cystic fibrosis.

Phase and activity of the process:

• remission phase:
  • low activity;
  • average activity;
• exacerbation phase:
  • bronchitis;
  • pneumonia.

Almost all exocrine glands are affected to varying degrees and distribution. The glands may:

• obstruction of the lumen of their excretory ducts by viscous or thick eosinophilic material may develop (pancreas, intestinal glands, intrahepatic bile ducts, gallbladder, submandibular glands);
• histological changes and hyperproduction of secretions (tracheobronchial and Brunner's glands) are noted;
• there will be no histological changes, but there will be increased secretion of sodium and chlorine (sweat, parotid and minor salivary glands).

Infertility occurs in 98% of adult males secondary to underdevelopment of the vas deferens or other forms of obstructive azoospermia. In women, fertility is reduced due to the production of thick cervical secretions, although many women with cystic fibrosis carry pregnancies to term. At the same time, the incidence of maternal complications and premature births is increased.

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Diagnosis of cystic fibrosis

Diagnosis is suggested by characteristic clinical features and confirmed by sweat testing or identification of two known mutations responsible for cystic fibrosis. Diagnosis is usually confirmed in the first year of life or early in life, but approximately 10% of patients are not diagnosed until adolescence or young adulthood.

The only reliable sweat test is the quantitative pilocarpine electrophoresis test: local sweating is stimulated by pilocarpine; the amount of sweat fluid is measured and the chloride concentration in it is determined. In patients with typical clinical manifestations or a family history of cystic fibrosis, a chloride concentration in sweat fluid of more than 60 mEq/L confirms the diagnosis. In children in the first year of life, a chloride concentration of more than 30 mEq/L indicates a high probability of cystic fibrosis. False-negative results are rare (about 1:1000 patients with cystic fibrosis have a chloride content in sweat fluid less than 50 mEq/L), but can be observed in the presence of edema and hypoproteinemia or with an insufficient volume of sweat fluid. False-positive results are usually the result of technical errors. Transient increase in sweat chlorine concentration may occur due to psychosocial deprivation (child abuse, hypo-care) and in patients with nervous anorexia. Although the results are reliable from the second day of life, a sufficient sample volume (more than 75 mg on filter paper or more than 15 µl in a capillary tube) can be difficult to obtain before the child is 3-4 weeks old. Regardless of the fact that the sweat chlorine concentration increases slightly with age, the test remains reliable in adults.

A small proportion of patients have so-called atypical cystic fibrosis, which manifests itself as chronic bronchitis with persistent Pseudomonas, normal pancreatic function, and normal or upper normal sweat chloride levels. Normal pancreatic function is observed in patients with 1 or 2 “mild” mutations of the cystic fibrosis gene, while pancreatic insufficiency develops only in patients with 2 “severe” mutations. Gene diagnostics is indicated for patients with the clinical picture of cystic fibrosis with normal or upper normal sweat chloride levels.

In patients with one or more phenotypic features typical of cystic fibrosis, or in the presence of cystic fibrosis in siblings, the diagnosis can also be confirmed by identifying 2 known mutations in the cystic fibrosis gene.

In patients with cystic fibrosis, an elevated transepithelial potential difference can be detected in the nose due to increased sodium reabsorption by epithelium that is relatively impermeable to chloride. This finding may be diagnostically significant when sweat chloride concentrations are normal or at the upper limit of normal and when two mutations in the cystic fibrosis gene have not been identified.

Serum concentration of immunoreactive trypsin is increased in infants with cystic fibrosis. Determination of the concentration of this enzyme in combination with gene diagnostics and sweat testing is the basis of neonatal screening programs conducted in many countries around the world.

In couples in which both partners are carriers of cystic fibrosis (usually identified at birth or through preconception or antenatal screening programs), gene testing may be performed to perform preimplantation or prenatal diagnosis. It is now recommended in the United States that screening for cystic fibrosis gene carriers be performed routinely as part of preconception or prenatal obstetric programs. Also, echogenic (hyperechoic) bowel may be seen on fetal ultrasound, indicating an increased risk of cystic fibrosis; in such cases, gene testing should be offered.

In patients with pancreatic insufficiency, the duodenal contents are abnormally viscous, with absent or markedly decreased enzyme activity and decreased HCO3 concentrations; trypsin and chymotrypsin are absent or markedly decreased in the stool. The secretin-pancreosimin stimulation test is the gold standard for assessing exocrine pancreatic function; however, it is an invasive, technically difficult test. Noninvasive, indirect assessment of pancreatic function is achieved by measuring 72-hour stool fat excretion or by determining the concentration of human pancreatic elastase in the stool. The latter test is reliable even in the presence of exogenous pancreatic enzymes. About 40% of older patients with cystic fibrosis develop impaired glucose tolerance, characteristic of diabetes mellitus; impaired glucose tolerance develops due to decreased or delayed insulin secretion, and insulin-dependent diabetes mellitus develops in 17%.

Chest radiography and high-resolution CT may demonstrate hyperinflation and thickening of the bronchial wall in the early stages. Later, areas of infiltration, atelectasis, and hilar lymph node reaction appear. As the disease progresses, segmental or lobar atelectasis, cyst formation, bronchiectasis, and enlargement of the pulmonary artery and right ventricle develop. Branching and finger-like opacities are characteristic, reflecting the accumulation of mucus in the dilated bronchi. In almost all cases, radiography and CT show opacification of the paranasal sinuses.

Pulmonary function tests reveal hypoxemia; decreased forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), mean expiratory flow rate between 25 and 75% (MEF25-75), FEV1/FVC ratio - Tiffeneau index; increased residual volume of the lungs (RVL) and the ratio of residual volume to total lung capacity. 50% of patients show signs of reversible airway obstruction - improvement in functional indicators after inhalation of bronchodilator aerosol.

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Treatment of cystic fibrosis

Compulsory and intensive therapy should be prescribed by an experienced specialist working in a team with other doctors, nurses, dietitians, physiotherapists, counsellors, pharmacists and social workers. The goals of therapy are to maintain adequate nutritional status, prevent or aggressively treat pulmonary and other complications, educate about the need for physical activity and provide adequate psychosocial support. With proper support, most patients can lead age-appropriate lives at home and at school. Despite the enormous number of challenges, the occupational success of patients with cystic fibrosis is impressive.

Treatment of pulmonary problems focuses on preventing airway obstruction and preventing and controlling respiratory tract infections. Infection prevention includes maintaining immunity against whooping cough, Haemophilus influenzae, varicella, Streptococcus pneumoniae, and measles, and annual influenza vaccinations. Patients who have been in contact with someone with influenza are given a neuraminidase inhibitor prophylactically. Palivizumab has been shown to be safe for the prevention of respiratory syncytial virus infection in children with cystic fibrosis, but its effectiveness has not been proven.

Physiotherapy, including postural drainage, percussion, vibration massage, and cough facilitation, is indicated at the first signs of lung damage. In older patients, alternative airway clearance techniques such as active breathing, autogenic drainage, devices creating positive expiratory pressure, and high-frequency chest compressions using a vest may be effective. In reversible bronchial obstruction, bronchodilators can be used orally or by inflation and glucocorticoids by inhalation. 02 therapy is indicated for patients with severe respiratory failure and hypoxemia.

Mechanical ventilation is generally not indicated in chronic respiratory failure. Its use should be limited to patients with good baseline parameters who develop acute reversible pulmonary complications, who are undergoing pulmonary surgery, or who are about to undergo lung transplantation. Noninvasive positive expiratory flow techniques, either nasally or by mask, may also be used. Intermittent positive airway pressure devices should not be used because of the risk of pneumothorax. Oral expectorants are widely used, but there is little evidence to support their effectiveness. It is recommended not to use antitussives. Long-term daily dornase alfa (recombinant human deoxyribonuclease) has been shown to reduce the rate of decline in lung function and the incidence of severe respiratory exacerbations.

Pneumothorax can be treated by draining the pleural space via thoracostomy. Open thoracotomy or thoracoscopy with resection of bullae and swab cleaning of the pleural surfaces is effective in treating recurrent pneumothorax.

Massive or recurrent hemoptysis is treated by embolization of the affected bronchial arteries.

Oral glucocorticoids are indicated for infants with protracted bronchiolitis and patients with refractory bronchospasm, allergic bronchopulmonary aspergillosis, and inflammatory complications (arthritis, vasculitis). Long-term use of glucocorticoids in an alternating regimen may slow the decline in lung function; however, due to complications associated with glucocorticoid therapy, it is not recommended for routine use. Patients receiving glucocorticoids should be regularly examined for signs of carbohydrate metabolism disorders and linear growth retardation.

Ibuprofen, when given for several years at a dose sufficient to achieve peak plasma concentrations between 50 and 100 μg/mL, has been shown to slow the decline in lung function, especially in children aged 5 to 13 years. The dose should be individualized based on pharmacokinetic studies.

Antibiotics should be used for bacterial respiratory tract infections based on culture and susceptibility data and the patient has appropriate clinical manifestations. Penicillinase-resistant penicillins (cloxacillin or dicloxacillin) or cephalosporins (cephalexin) are the drugs of choice for staphylococcal infections. Erythromycin, amoxicillin-clavulanate, ampicillin, tetracycline, trimethoprim-sulfamethoxazole, or rarely chloramphenicol may be used alone or in combination for the long-term outpatient treatment of infections caused by a variety of pathogens. Fluoroquinolones are effective against susceptible Pseudomonas strains and have been used safely in young children. For severe exacerbations, especially when colonized with Pseudomonas, parenteral antibiotics are advised, which often require hospitalization, although selected, carefully selected patients may be treated at home. Combinations of aminoglycosides (tobramycin, gentamicin) and penicillins with antipseudomonal activity are administered intravenously. The usual starting dose of tobramycin or gentamicin is 2.5-3.5 mg/kg 3 times a day, but high doses (3.5-4 mg/kg 3 times a day) may be required to achieve acceptable blood concentrations [peak level 8-10 μg/ml (11-17 μmol/l), trough level less than 2 μg/ml (less than 4 μmol/l)]. Tobramycin is also effective and safe when administered once daily (10-12 mg/kg). Because of increased renal excretion of some penicillins, higher doses may be required to achieve therapeutic concentrations. The goal of treatment of pulmonary infections is sufficient improvement of the clinical condition, so long-term use of antibacterial drugs is not necessary. However, patients with Pseudomonas colonization may benefit from long-term antibiotic treatment. In selected patients, aerosolized tobramycin in monthly courses and oral azithromycin 3 times weekly may be effective in improving or stabilizing lung function and reducing the frequency of exacerbations.

In symptomatic patients colonized with Pseudomonas, the goal of antibacterial therapy is to improve clinical parameters and possibly reduce the number of organisms in the airways. Eradication of Pseudomonas is not possible. However, it has been shown that early antibacterial therapy during primary airway colonization with nonmucoid Pseudomonas may be effective in eradicating the organism for a period of time. Treatment regimens vary but typically consist of inhaled tobramycin or colistin, often in combination with an oral fluoroquinolone.

Patients with clinically evident right ventricular failure should receive diuretics, oxygen, and salt restriction.

Neonatal intestinal obstruction can sometimes be relieved by enemas with hyperosmolar or iso-osmolar radiocontrast material; in other cases, surgical intervention with enterostomy may be necessary to flush out the viscous meconium in the intestinal lumen. After the neonatal period, episodes of partial intestinal obstruction (distal intestinal obstruction syndrome) can be treated with enemas with hyperosmolar or iso-osmolar radiocontrast material or acetylcysteine or with oral balanced bowel lavage solution. Lactulose or sodium dioctyl sulfosuccinate can be used to prevent such episodes.

Pancreatic enzyme replacement therapy should be given with each main and minor meal. The most effective enzyme preparations contain pancreatic lipase in pH-sensitive, enteric-coated microspheres or microtablets. Infants under one year of age are given 1000-2000 U lipase for every 120 ml of formula or each breastfeeding. After one year, the dosage is based on 1 kg of body weight, starting with 1000 U lipase/(kg per meal) for children under 4 years of age and 500 U lipase/(kg per meal) for children over 4 years of age. Usually, half the standard dose is given with a light meal (snack). Doses above 2500 U lipase/(kg per meal) or 10,000 U lipase/(kg day) should be avoided, as high doses of enzymes have been associated with the development of fibrosing colonopathy. In patients with high enzyme requirements, the use of H blockers or proton pump inhibitors may improve enzyme efficiency.

Diet therapy includes sufficient calories and protein to ensure normal growth - 30-50% more than the usual age norms, and fat intake should be normal or increased to increase the caloric content of food; multivitamins in doses twice the age norms; additional vitamin E in water-soluble form; additional salt during periods of temperature stress and increased sweating. Children in the first year of life receiving broad-spectrum antibiotics and patients with liver damage and hemoptysis should be additionally prescribed vitamin K. Children with severe pancreatic insufficiency should be fed with protein hydrolysis formulas containing medium-chain triglycerides instead of the usual modified cow's milk-based formulas. Glucose polymers and medium-chain triglycerides can be used to increase caloric intake. In patients who fail to maintain adequate nutritional status, enteral feeding via nasogastric tube, gastrostomy, or jejunostomy may restore normal growth and stabilize lung function. The use of appetite stimulants and/or androgens has not been shown to be effective and is not recommended.

Surgical treatment may be indicated for localized bronchiectasis or atelectasis that do not respond to conservative treatment, nasal polyps, chronic sinusitis, bleeding from esophageal varices in portal hypertension, gallbladder disease, and intestinal obstruction due to volvulus or intussusception that cannot be resolved conservatively. Liver transplantation is successfully performed in patients with terminal liver failure. Bilateral cadaveric lung transplantation and living donor lung lobe transplantation are successfully performed in patients with severe pulmonary heart disease.

End-of-life care and management of patients with cystic fibrosis. The patient and family deserve a confidential discussion about the prognosis and preferred care and treatment, especially as the patient's reserves become increasingly limited. Most patients with end-of-life cystic fibrosis are in their late teens and early adulthood and are responsible for their own choices. They should therefore know what remains in reserve and what can be done. It is respectful to the patient with cystic fibrosis to ensure that he or she has the information and opportunity to make life choices, including having a supportive hand to determine how and when to die. Transplantation is often a discussion. When considering transplantation, patients need to weigh the benefits of living longer with a transplant versus the uncertainty of receiving a transplant and the ongoing (but different) challenge of living with a transplanted organ.

Patients with deteriorating conditions need to have a discussion about the possibility of death. Patients and their families need to know that death often occurs quietly, without severe symptoms. Palliative care, including adequate sedation, should be offered if appropriate to ensure a peaceful death. One option is for the patient to consider participating in a short-term trial of fully aggressive treatment if needed, but to discuss in advance the parameters that would dictate the need to stop treatment and accept death.

What is the prognosis for cystic fibrosis?

Cystic fibrosis and its clinical course are largely determined by the extent of lung damage. This damage is irreversible, leading to debilitation and ultimately death, usually from a combination of respiratory failure and cor pulmonale. Prognosis has improved significantly over the past 5 decades, largely due to aggressive treatment before irreversible lung damage develops. Average life expectancy in the United States is 35 years. Life expectancy is longer in patients without pancreatic insufficiency. Female sex, early colonization with mucoid Pseudomonas, lung involvement at presentation, smoking, and airway hyperreactivity are associated with a slightly worse prognosis. Age- and sex-adjusted FEV1 is the best predictor of mortality.