Cystic fibrosis in children

Cystic fibrosis is a hereditary disease that affects the exocrine glands, mainly the gastrointestinal tract and the respiratory system. As a result, COPD, deficiency of the exocrine part of the pancreas and an abnormally high content of electrolytes in the sweat develop. The diagnosis is based on a swallowing test or identification of 2 mutations causing cystic fibrosis in patients with characteristic symptoms. Treatment of cystic fibrosis is supportive with the obligatory participation of doctors specializing in different 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 by autosomal recessive type. If both parents are heterozygous for the abnormal CFTR gene , the probability of producing a sick child is 25% for each pregnancy. The incidence of cystic fibrosis 1 per 10 000-12 000 newborns. In most countries in Europe and North America, they fall ill from 1: 2000 to 1: 4,000 newborns. The prevalence of cystic fibrosis in Ukraine is 1: 9000 newborns. Annually in the USA - 2000, in France, England, Germany - from 500 to 800, and in the whole world - more than 45 000 children, suffering from cystic fibrosis.

The CFTR gene (cysticfibrosis transmembrane conductance regulator) is located on the long arm of chromosome 7 in the q31 region , has an extent of about 250,000 nucleotide pairs and includes 27 exons. CFTR is assigned 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 chlorine channel. CFTR is also involved in the regulation of other ion channels and membrane transport. Currently, about 1200 mutations of the CFTR gene are known , the most common mutation is AF508, the second most frequent is CFTR dele 2,3.

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

Causes of cystic fibrosis

Cystic fibrosis is the most common shortening of the life expectancy of a genetic disease in the white population. In the US, this disease occurs at a frequency of about 1/3300 births among the white population, 1/15 300 among blacks and 1/32 000 in Asian populations. Thanks to improved treatment and an increase in life expectancy 40% of patients are adults.

Approximately 3% of the white population is heterozygous carriers of the cystic fibrosis gene, which has an autosomal recessive type of inheritance. The gene responsible for the development of cystic fibrosis is located on the long arm of the 7th chromosome (7q). It encodes a membrane protein called the transmembrane cystic fibrosis regulator (MBTP). The most common mutation of this gene is called deltaF508, its frequency is about 70% among patients with cystic fibrosis. With this mutation, one amino acid residue, phenylalanine, is lost at position 508 CFTR. More than 1200 less common mutations make up the remaining 30%. Although the CFTR function is not known exactly, it is believed that it is part of the cAMP-dependent chloride channel regulating the transport of sodium and chlorine through the cell membrane. In heterozygous carriers there may be minor disturbances in the transport of electrolytes in epithelial cells, but there are no clinical manifestations.

[6], [7], [8]

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.

Meconial ileus due to blockage of the lumen of the ileum by viscous thick meconium may be the earliest manifestation and is noted in 15-20% of newborns suffering from cystic fibrosis. Often with meconial ileus, vomiting, perforation or atresia of the intestine are observed, and, with rare exceptions, other symptoms of cystic fibrosis subsequently develop. Also, in cystic fibrosis, later withdrawal of meconium and meconium blocking syndrome (a transitory form of low intestinal obstruction, which develops as a result of the formation of one or more dense meconial plugs in the anus or large intestine) may be noted.

In infants who have no manifestations of meconium ileus, the onset of the disease may result in a longer recovery of the initial body weight and inadequate weight gain in 4-6 weeks of life.

Children with artificial feeding of soy mixtures or cow's milk as a result of malabsorption of proteins may develop hypoproteinemia with edema and anemia.

In 50% of patients with cystic fibrosis, the first manifestations of the disease are manifestations of the lungs. Often there are recurrent and chronic infections, manifested by coughing and wheezing. Most of all, anxiety is caused by an obsessive cough with hard-to-separate sputum, often accompanied by vomiting and sleep disturbance. With the progression of the disease, there are intercostal spaces, the involvement of ancillary muscles in the act of breathing, a barrel chest, fingers in the form of "drumsticks" and cyanosis. The defeat of the upper respiratory tract is usually manifested by polyposis of the nose and chronic or recurrent sinusitis. In adolescents, there may be a delay in physical development, late onset of puberty, decreasing tolerance to physical exertion.

Pancreatic insufficiency is clinically present in 85-90% of children, usually in early periods, and may have a progressive course. Clinical manifestations include a frequent, plentiful, fatty stool with a fetid odor, an increase in the abdomen and a delay in physical development with a decrease in subcutaneous fat and a reduction in muscle mass, despite a normal or increased appetite. Rectal prolapse is noted in 20% of children under 1-2 years who are not receiving treatment. Also manifestations of deficiency of fat-soluble vitamins can be added.

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

In patients aged 13 years and older, type I diabetes mellitus develops in 17% of cases, and multilobular biliary cirrhosis with varicose veins of the esophagus and portal hypertension develops in 5-6%. Chronic or recurrent pain in the abdomen can be associated with intussusception, peptic ulceration, parapentricular abscess, pancreatitis, gastroesophageal reflux, esophagitis, gallbladder involvement, or episodes of partial intestinal obstruction due to abnormally viscous and thick feces. Complications of cystic fibrosis also include osteopenia / osteoporosis and periodic arthralgia / arthritis.

Pulmonary manifestations of cystic fibrosis

As a rule, at birth, the lungs have a normal histological structure. Damage to the lungs initiates diffuse bronchial obstruction of the small caliber abnormally thick and viscous secretion. Bronchiolitis and obstruction of the respiratory tract by muco-purulent plugs develops secondary to obstruction and infection. Changes in the bronchi are more common than parenchymal lesions. Emphysema is not very pronounced. With the progression of the process in the lungs, the wall of the bronchi thickens; the airways are filled with a purulent, viscous secret; there are sites of atelectasis; the basal lymph nodes increase. Chronic hypoxemia leads to hypertrophy of the muscular layer of the arteries of the lungs, pulmonary hypertension and right ventricular hypertrophy. Most of the changes in the lungs can be the result of inflammation, which develops again due to the release of proteolytic enzymes by neutrophils in the respiratory tract. The fluid obtained from bronchoalveolar lavage contains a large number of neutrophils and increased concentrations of free neutrophil elastase, DNA and interleukin8 already at a very early age.

Chronic lung disease develops in almost all patients and leads to periodic exacerbations with infectious inflammation and a progressive decrease in lung function. In the early period, the main causative agent, sown from the respiratory tract, is Staphylococcus aureus, but with the development of the disease, Pseudomonas aeruginosa is most often sown. Mycoid variant of Pseudomonas is noted only in cystic fibrosis. Colonization Burkholderia cepacia occurs in about 7% of adult patients and may be associated with a rapid decline in pulmonary 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 (pseudosyndrome Bartter), meconial obstruction, atypical and erased 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 in varying degrees and distribution. In glands can:

• develop obstruction of the lumen of their excretory ducts with a viscous or dense eosinophilic material (pancreas, intestinal glands, intrahepatic bile ducts, gallbladder, submandibular glands);
• histological changes and hyperproduction of secretion (tracheobronchial and Brunner's glands);
•  no histological changes, but the secretion of sodium and chlorine (sweat, parotid and small salivary glands) should be increased.

Infertility is noted in 98% of adult men again because of underdevelopment of the seminiferous ducts or other forms of obstructive azoospermia. In women, fertility is reduced due to the production of thick cervical secret, although many women with cystic fibrosis are pregnant and give birth on time. At the same time, the frequency of complications from the mother and premature birth has been increased.

[9], [10], [11],

Diagnosis of cystic fibrosis

The diagnosis is assumed on the basis of characteristic clinical manifestations and is confirmed by conducting a sweat test or by identifying two known mutations responsible for cystic fibrosis. As a rule, the diagnosis is confirmed in the first year of life or at an early age, but approximately 10% of patients are diagnosed only in the adolescent or young age.

The only reliable sweat test is a quantitative pilocarpine electrophoresis test: local sweating is stimulated by pilocarpine; the amount of liquid is measured and the concentration of chlorine is determined in it. In patients with characteristic clinical manifestations or the presence of cystic fibrosis in a family history, the concentration of chlorine in the fluids above 60 meq / l confirms the diagnosis. In children of the first year of life, a chlorine 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 chlorine content of less than 50 meq / L in the fluids), but may be noted if there is edema and hypoproteinemia or if the volume of the fluid is insufficient. False positive results are usually the result of technical errors. Transient increase in the concentration of chlorine in the sweat can occur due to psychosocial deprivation (child abuse, hypoopecia) and in patients with anorexia nervosa. Despite the fact that 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 up to the child's age 3-4 weeks. Regardless of the fact that with age the concentration of chlorine in the flowing liquid increases somewhat, the sample remains reliable in adults.

In a small part of patients, there is a so-called atypical cystic fibrosis, which is manifested by chronic bronchitis with persistence of Pseudomonas, normal pancreatic function and normal or at the upper limit of normal chlorine content in the pot. Normal pancreas function is indicated in patients with 1 or 2 "mild" mutations of the cystic fibrosis gene, while pancreatic insufficiency develops only in patients with 2 "heavy" mutations. Gene diagnosis is indicated for patients with a clinical picture of cystic fibrosis at normal or at the upper limit of normal chlorine content in the pot.

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

In patients with cystic fibrosis, an increased difference in the transepithelial potentials can be detected in the nose due to the increased reabsorption of sodium by the epithelium, which is relatively impermeable to chlorine. These data can be diagnostically significant at normal or at the upper limit of the norm of chlorine concentration in the sweat, and if 2 mutations of the cystic fibrosis gene were not identified.

Serum concentration of immunoreactive trypsin is increased in children of the first year of life suffering from cystic fibrosis. The determination of the concentration of this enzyme in combination with gene diagnostics and sweat breakdown is the basis of neonatal screening programs conducted in many countries of the world.

In pairs in which both partners are carriers of cystic fibrosis (usually it is determined at the birth of a sick child or when screening programs are carried out - before conception or prenatal), gene diagnostics can be performed for pre-implantation or prenatal diagnosis. Now in the United States, it is recommended that screening for the carriage of the cystic fibrosis gene be routinely performed as part of obstetric programs before conception or prenatal. Also, with ultrasound of the fetus, one can see an echogenic (hyperechoic) intestine, which indicates an increased risk of cystic fibrosis; in such cases, genetic diagnosis should be suggested.

In patients with pancreatic insufficiency, duodenal contents are anomalously viscous, it determines the absence or sharp decrease in enzyme activity and a decrease in the concentration of HCO3; in the stool there are no or sharply reduced trypsin and chymotrypsin. The stimulation test with secretin pancreosimine is the "gold standard" for evaluating the exocrine function of the pancreas; however this is an invasive technically complex test. A non-invasive, indirect assessment of pancreatic function is performed by measuring the 72-hour excretion of fats in the stool or by determining the concentration of human pancreatic elastase in the stool. This last study is reliable even in the presence of exogenous pancreatic enzymes. Approximately 40% of patients with cystic fibrosis in the elderly have a violation of glucose tolerance characteristic of diabetes mellitus; impaired glucose tolerance develops as a result of reduced or late insulin secretion, 17% develop insulin-dependent diabetes mellitus.

Chest X-ray and CG with high resolution can demonstrate at the early stages of hyperinflation and thickening of the bronchial wall. Subsequently, there are sites of infiltration, atelectasis and the reaction of the basal lymph nodes. With the progression of the disease, segmental or lobar atelectasis develops, the formation of cysts, bronchiectasis, and an increase in the pulmonary artery and right ventricle. Branching and finger-like dimming are characteristic, reflecting the accumulation of mucus in the enlarged bronchi. Practically in all cases, radiography and CT scan show a diminution of the paranasal sinuses.

In the study of lung function, hypoxemia is identified; decrease in the forced vital capacity of the lungs (FVC), forced expiratory volume in 1 s (FEV1), mean volumetric expiratory flow rate between 25 and 75% (СОС25-75), ratio FEV1 / FVC - Tiffno index; an increase in the residual lung volume (OOL) and the ratio of residual lung volume to total lung capacity. In 50% of patients there are signs of reversible airway obstruction - improvement of functional parameters after bronchodilator aerosol inhalation.

[12], [13], [14], [15]

Treatment of cystic fibrosis

Mandatory and intensive therapy should be appointed by an experienced specialist working in a team with other doctors, nurses, nutritionists, physical therapists, counselors, pharmacists and social workers. The goals of therapy are maintaining adequate nutritional status, preventing or aggressive treatment of pulmonary and other complications, explaining the need for motor activity and providing adequate psychosocial support. With proper support, most patients can live at home and at school, corresponding to their age. Despite a huge number of problems, the professional success of patients with cystic fibrosis is impressive.

Treatment of pulmonary problems focuses on preventing airway obstruction and preventing and monitoring respiratory infection. Prevention of infections includes the maintenance of immunity against pertussis, Haemophilus influenzae, chickenpox, Streptococcus pneumoniae and measles and annual vaccination against influenza. Patients who were in contact with influenza patients are prescribed a neuraminidase inhibitor for prophylactic purposes. It has been shown that the appointment of palivizumab to children with cystic fibrosis for the prevention of respiratory viral cytotoxic virus infection is safe, but the efficacy has not been proven.

Physiotherapy, including postural drainage, percussion, vibrating massage and cough relief, is indicated in the first manifestations of pulmonary involvement. In older patients, alternative airway clearance techniques, such as an active breathing cycle, autogenous drainage, devices that produce positive exhalation pressure and high-frequency chest compressions with a vest, can be effective. With reversible bronchial obstruction, bronchodilators can be used orally and inflationally and glucocorticoids can be inhaled. 02Therapy is indicated in patients with severe respiratory failure and hypoxemia.

Mechanical ventilation, as a rule, is not indicated for chronic respiratory failure. Its use should be limited to patients with good baseline in the development of acute reversible pulmonary complications, combined with pulmonary surgery, or patients with prompt pulmonary transplantation. You can also use non-invasive methods to create positive breathing on exhalation - nasally or with the help of a mask. Devices for breathing with intermittent positive pressure should not be used because of the risk of developing pneumothorax. Widely used oral coughs, but their effectiveness is confirmed by a small amount of data. It is recommended not to use antitussives. It has been shown that prolonged daily use of dornase alpha (recombinant human deoxyribonuclease) reduces the rate of decrease in pulmonary function and the frequency of severe exacerbations on the part of the respiratory tract.

Pneumothorax can be treated by draining the pleural cavity by thoracostomy. Open thoracotomy or thoracoscopy with bullet resection and tampon swab cleansing is effective in the treatment of recurrent pneumothorax.

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

Oral glucocorticoids are shown to children of the first year with protracted bronchiolitis and patients with refractory bronchospasm, allergic bronchopulmonary aspergillosis, inflammatory complications (arthritis, vasculitis). Long-term use of glucocorticoids in an alternating regimen can slow the decline in lung function, but due to complications associated with glucocorticoid therapy, it is not recommended for routine use. Patients receiving glucocorticoids should be screened regularly to identify signs of altered carbohydrate metabolism and linear growth retardation.

It has been shown that ibuprofen, if used for a few years at a dose sufficient to achieve peak plasma concentrations between 50 and 100 μg / ml, slows down lung function, especially in children 5 to 13 years of age. The dose should be individual based on a study of the pharmacokinetics of the drug.

Antibiotics should be used to treat bacterial infections of the respiratory tract, taking into account seeding data and sensitivity to antibiotics if the patient has appropriate clinical manifestations. Penicillinase-resistant penicillins (cloxacillin or dicloxacillin) or cephalosporins (cephalexin) are the drugs of choice for staphylococcal infection. Erythromycin, amoxicillin-clavulonate, ampicillin, tetracycline, trimethoprim-sulfamethoxazole or rarely chloramphenicol can be used as monotherapy or in combination for long-term outpatient treatment of infections caused by a variety of pathogens. Fluoroquinolones are effective against sensitive Pseudomonas strains and have been safely used in young children. In severe exacerbations, especially when colonizing Pseudomonas, it is advised to use parenteral antibiotics, which often requires hospitalization in the hospital, but some carefully selected patients can be treated at home. Combinations of aminoglycosides (tobramycin, gentamicin) and penicillins with anti-synergic activity are administered intravenously. Typically, the 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 daily) may be required to achieve acceptable concentrations in the blood [peak level 8-10 μg / ml (11-17 μmol / l), the minimum level is less than 2 μg / ml (less than 4 μmol / l)]. Tobramycin is also effective and safe if administered once a day (10-12 mg / kg). Because of the increased excretion of certain penicillins by the kidneys, higher doses may be required to achieve a therapeutic concentration. The goal of treating pulmonary infections is a sufficient improvement in the clinical state, so there is no need for continued use of antibacterial drugs. At the same time, patients with colonization of Pseudomonas can be shown prolonged treatment with antibiotics. In individual patients, aerosol administration of tobramycin by courses repeated every other month and azithromycin 3 times a week may be effective in improving or stabilizing lung function and reducing the frequency of exacerbations.

In patients with colonization of Pseudomonas in the presence of clinical manifestations, the goal of antibacterial therapy is to improve clinical parameters and the possible reduction of the number of microorganisms in the airways. The eradication of Pseudomonas is impossible. However, it has been shown that early antibiotic therapy during primary airway colonization with non-comedogenic Pseudomonas strains may be effective in eradicating the microorganism for some time. Treatment regimens vary, but usually consist of inhalation of tobramycin or colistin, often in combination with fluoroquinolone intake.

Patients with manifested clinical right ventricular failure should receive diuretics, oxygen and restrict salt intake.

Neonatal intestinal obstruction can sometimes be alleviated by enemas with hyperosmolar or isoosmolar radiopaque material; in other cases, surgical intervention, enterostomy, may be necessary to wash the viscous meconium in the lumen of the intestine. After the neonatal period, episodes of partial intestinal obstruction (the syndrome of distal intestinal obstruction) can be treated with enemas with a hyperosmolar or isoosmolar radiopaque substance or acetylcysteine or ingestion of a balanced solution for intestinal lavage. To prevent such episodes, you can use lactulose or sodium dioctyl sulfosuccinate.

Substitution therapy with pancreatic enzymes should be performed with each major and non-essential food intake. The most effective enzyme preparations contain pancreatic lipase in the pH of sensitive microsphere coated microspheres or microtablets. Children of the first year of life are prescribed 1000-2000 units of lipase per every 120 ml of the mixture or each breast-feeding. After a year, dosing is applied for 1 kg of body weight, starting with 1000 units of lipase / (kg of food intake) for children under 4 years and 500 El lipases / (kg for meals) for children over 4 years old. Usually half of the standard dose is given with light meals (snacks). Doses above 2500 U lipase / (kg per meal) or 10,000 U lipase / (kg day) should be avoided, since high doses of enzymes are associated with the development of fibrosing colonopathy. In patients with a high requirement for enzymes, the use of H blockers or proton pump inhibitors can improve the effectiveness of enzymes.

Dietotherapy includes enough calories and protein to ensure normal growth - 30-50% more than normal age norms, and also the consumption of fats should be normal or increased to increase the calorie content of food; multivitamins in double doses from age norms; additionally vitamin E in water-soluble form; additional salt during periods of temperature stress and increased sweating. Children of the first year of life who are receiving broad-spectrum antibiotics and patients with liver damage and hemoptysis should additionally be prescribed vitamin K. Children with severe pancreatic insufficiency should be better served by mixtures based on protein hydrolysis containing medium chain triglycerides instead of conventional modified cow-milk formulas. To increase the intake of calories, it is possible to use glucose polymers and medium chain triglycerides. Patients who can not maintain an adequate nutritional status, restore normal growth and stabilize lung function by enteral feeding through a nasogastric tube, gastrostomy or inostasis. It has not been proven that the use of drugs that increase appetite and / or androgens is effective, their use is not recommended.

Surgical treatment may be indicated with local bronchiectasis or atelectasis that defies conservative treatment, nasal polyps, chronic sinusitis, bleeding from varicose veins of the esophagus with portal hypertension, gallbladder involvement and intestinal obstruction due to bowel invasions or intussusception that can not be resolved conservatively . In patients with terminal hepatic insufficiency, liver transplantation is successfully performed. Bilateral pulmonary lung transplantation and lung transplantation from a living donor are successfully performed in patients with severe pulmonary-cardiac involvement.

Therapy and care for a patient with cystic fibrosis in the terminal period. The patient and his family deserve a confidential conversation about the prognosis and the preferred care and treatment, especially if the patient has an increasingly marked limitation of reserves. Most patients with cystic fibrosis in the terminal period are late and adolescent patients who are responsible for their own choice. Therefore, they must know what remains in the reserve and what can be done. A sign of respect for a patient suffering from cystic fibrosis is to make sure that he has all the information and the opportunity to make a life choice, including having a hand supporting him to determine how and when to accept death. Transplantation is often required. Thinking about transplantation, patients need to weigh the benefits of a longer graft life versus the uncertainty of getting a transplant and a permanent (but different) problem - life with a transplanted organ.

Patients with worsening of the condition need to discuss the probability of death. Patients and their families should know that often death comes quietly, without severe symptoms. Palliative care, including sufficient sedation, should be offered, if appropriate, to ensure a peaceful death. One possible way for a patient is to consider the possibility of taking part in a short-term trial of fully aggressive treatment, if necessary, but discuss in advance the parameters that will indicate the need to stop treatment and accept death.

What is the prognosis of cystic fibrosis?

Cystic fibrosis and its course is largely determined by the degree of lung damage. This defeat is irreversible, leading to exhaustion and, ultimately, death, usually as a result of a combination of respiratory failure and pulmonary heart disease. The prognosis has significantly improved over the past 5 decades, mainly due to active treatment before the development of irreversible changes in the lungs. The average life expectancy in the US is 35 years. Life expectancy is longer in patients without pancreatic insufficiency. Female gender, early colonization by mucoid Pseudomonas, lung damage in the debut, smoking and airway hyperreactivity are associated with a slightly worse prognosis. FEV1, estimated with age and gender, is the best predictor of mortality.