Childhood Cystic Fibrosis

　　1. Etiology

　　Cystic fibrosis is an autosomal recessive genetic disease, accounting for about 70% of all cases. The disease-causing gene is located on the long arm of chromosome 7, generally more than 250kb of DNA, and is the coding gene of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is composed of 1480 amino acids. One segment has a deletion, resulting in a phenylalanine deletion at the position of △F508. In fact, it is known that about 100 different gene mutations can cause the clinical phenotype of CF. It is now possible to detect heterozygotes and perform prenatal diagnosis for individuals with △F508 deletions. This disease mainly affects epithelial tissues and affects secretion and absorption functions. The CFTR protein is mainly related to chloride ion transport, and 99% of these patients have an increased concentration of chloride ions in their sweat. However, some scholars believe that CFTR is a molecule directly or indirectly related to chloride ion permeability. How to explain the clinical symptoms of CF using abnormal chloride ion transport is not yet clear.

　　2. Pathogenesis

　　Research in the 1980s confirmed that the negative potential difference between the intracellular and extracellular spaces of the respiratory epithelium in CF patients is greater than that in normal people, and the same phenomenon is also observed in sweat gland duct epithelium. Subsequent studies found that the function of CFTR is to transport and secrete chloride ions under the stimulation of cyclic adenosine monophosphate (cAMP). However, in CF patients, this function is lacking. CF patients secrete a large amount of abnormally thick secretions from the respiratory tract, which leads to recurrent respiratory infections and irreversible lung damage. The function of CFTR is to regulate the effect of cAMP on the chloride ion channels of epithelial cells, affecting the quantity and composition of the surface liquid of the airways. The defect of CFTR alters the physiological function of the airway surface and submucosal glands, increasing the reabsorption of sodium ions, followed by a decrease in water secretion, an increase in the absorption of extracellular fluid, which can lead to dehydration of secretions, making the dry secretions more sticky and elastic, and difficult to be cleared by mucus cilia or other mechanisms. These secretions accumulate and block the airways, initially blocking the small airways, causing bronchiolitis, and obstructing the airflow in the small airways. The same pathophysiological changes also occur in the pancreas and bile ducts, causing proteinaceous secretions to dry out and block the ducts. Since the function of sweat gland ducts is to absorb chloride ions rather than secrete them, after the sweat is secreted to the skin surface, salt cannot be recovered from the isotonic sweat; therefore, the concentration of chloride and sodium on the skin surface increases. Chronic respiratory infections in CF patients are confined to the bronchi. The initial infection is caused by the inability to clear the inhaled bacteria in time, leading to long-term colonization of bacteria and inflammatory reactions in the airway wall. Some people also propose that the abnormality of CFTR causes patients to have an inflammatory state before the first infection, and the inflammatory response worsens after the first infection. Chronic bronchiolitis and bronchitis are the initial lung manifestations, but months or years later, they may evolve into bronchiectasis and bronchiectasis. As the lung lesions worsen, the infection may extend to the surrounding lung parenchyma. Some inflammatory products, including proteases, cause excessive mucus secretion in the airways, becoming a characteristic of chronic airway diseases. Staphylococcus aureus and Pseudomonas aeruginosa have a high incidence of colonization in the airways, because the airway epithelial cells of CF or the surface liquid of the airways provide a good adhesion environment for these microorganisms. Moreover, the defense function of the airway epithelium itself is damaged in CF patients. Nutritional deficiencies, including fatty acid deficiencies, are susceptible factors for respiratory infections. In 10% to 15% of CF patients with basic pancreatic function, the content of chloride in their sweat is low, green pus infection occurs later, and lung function deterioration is slower. However, nutritional status only plays a partial role, and the presence of pancreatic function cannot exclude the possibility of lung disease.

　　1, Pulmonary complications

　　Bronchiectasis, bronchitis, bronchiolitis, pneumonia, incomplete lung expansion, hemoptysis, pneumothorax, nasal polyps, sinusitis, reactive airway disease, pulmonary heart disease, respiratory failure, bronchial mucus impaction, allergic bronchopulmonary aspergillosis.

　　2, Gastrointestinal complications

　　Meconium ileus, meconium peritonitis, meconium ileus-like diseases (non-neonatal obstruction), anal prolapse, intussusception, volvulus, appendicitis, small bowel atresia, pancreatitis, biliary cirrhosis (portal hypertension, esophageal varices, splenomegaly with hyperfunction), neonatal obstructive jaundice, liver steatosis, gastroesophageal reflux, gallstones, inguinal hernia, growth retardation, vitamin deficiency (vitamins A, K, E, D), insulin deficiency, symptomatic hyperglycemia.

　　3, Other complications

　　Edema-hypoproteinemia, dehydration-heat exhaustion, hypertrophic osteoarticular lesions-arthritis, delayed puberty, amyloidosis.

　　1, Respiratory manifestations

　　More than 90% of children have recurrent chronic infections of the upper and lower respiratory tracts, including chronic bronchitis, atelectasis, and recurrent pneumonia. It may be accompanied by empyema, chronic sinusitis, and bronchiectasis. Pseudomonas aeruginosa and Staphylococcus aureus are common pathogens, and the positivity rate of pathological examination culture in death cases is as high as over 90%. Cough is the most common symptom, initially dry, and gradually accompanied by sputum sounds. Older patients may have worse coughing in the morning and after activity, with purulent sputum. Some patients may have no symptoms for a long time or only manifest long-term acute respiratory tract infections. Some may also manifest chronic cough or recurrent pneumonia within one week of birth. Bronchiolitis often accompanied by wheezing is most common in children under 1 year of age, and may present with cough, persistent or paroxysmal wheezing sounds, and rapid breathing. When the lung lesions progress or recur, cough persists, sputum is abundant and thick, difficult to cough out; there is intolerance to activity, shortness of breath, and growth and development lag. Due to recurrent infection fever, restlessness, and decreased appetite, the child becomes increasingly emaciated. Ultimately, pulmonary heart disease may occur, leading to death due to respiratory failure.

　　2, Gastrointestinal manifestations

　　In newborns with CF, 15% to 20% have meconium ileus and peritonitis, manifested as abdominal distension, vomiting, and delayed excretion of meconium. X-ray shows dilated intestines, liquid levels, and nodular shadows, and the lower abdomen shows opacification. Symptoms of pancreatic insufficiency are seen in 80% of children. The children have a good appetite, but despite taking an adequate amount of milk and complementary foods, their weight does not increase, and they often cry out of hunger. The stool is frequent, large, and shows marked steatorrhea with an odor. There is a sharp contrast between the emaciated limbs and the distended abdomen. There is often repeated rectal prolapse. Newborn CF patients may have cholestatic jaundice with reduced liver function. Older children may develop liver cirrhosis, portal hypertension, and hypersplenism. Fatal gastrointestinal bleeding may occur, and secondary phenomena such as hypoproteinemia, edema, malnutrition anemia, growth and development delay, liposoluble vitamin deficiency, hypolipidemia, and hypocholesterolemia may occur due to insufficient exocrine pancreatic secretion and malabsorption.

　　3, Other

　　Only 2% to 3% of patients have symptomatic bile duct sclerosis, which is manifested as jaundice, ascites, hemoptysis caused by esophageal varices, and hypersplenism. In addition to insufficient exocrine pancreatic function, there can also be hyperglycemia, diabetes, polyuria, and weight loss. Sexual development is delayed, with an average delay of 2 years. About 95% of males have azoospermia due to underdevelopment of the Wolffian duct. The incidence of inguinal hernia, hydrocele, and undescended testicles is higher than that of normal people. Women may have cervicitis. Infants may lose too much salt through sweating, resulting in 'salt frost' on the skin or an unpleasant skin odor. These children may manifest as hypochloremic alkalosis.

　　Cystic fibrosis is a genetic disease characterized by frequent respiratory tract infections, dyspnea, and ultimately causing permanent lung damage. Prenatal diagnosis of this disease is already possible, and genetic mutation detection can be performed during prenatal testing and neonatal screening. Fetal cells are obtained from amniotic fluid, and specific DNA probes are used to check for CF gene mutations (△F508), which can determine whether the fetus will have CF. If the test result is positive, the pregnancy should be terminated.

　　1. Blood gas analysis

　　The alveolar-arterial oxygen pressure difference is increased, the arterial PO2 is reduced, and CO2 retention occurs.

　　2. Sweat chloride test

　　The sodium chloride in the patient's sweat increases. The most accurate method of collecting sweat is through pilocarpine (pilocarpine) iontophoresis. After stimulating the sweat glands, collect sweat (at least 0.1 to 0.5 ml). Then measure the chlorine by titration, and measure sodium and potassium by flame photometry. If adrenal insufficiency can be excluded, a sweat chloride value of 60 mmol/L is positive, and two positive sweat chloride tests are required.

　　3. Abnormal pancreatic function

　　The duodenal fluid is less and thick, the pH is reduced, the bicarbonate ion is low, trypsin is deficient or only a small amount, trypsin test is negative, chymotrypsin, lipase, and amylase are all low.

　　1. Eat the yam, Job's tears, and glutinous rice porridge on an empty stomach, which is beneficial to the spleen, clears the lungs, and补肾, and is also very easy to digest and absorb.

　　1. Foods rich in B vitamins: B vitamins are vitamins that work together, and the whole B group must be taken as a whole for the best effect. All B vitamins are water-soluble vitamins, which regulate metabolism, maintain the health of the skin and muscles, enhance the function of the immune system and nervous system, promote cell growth and division, including the production of red blood cells, and prevent anemia. The pallor of the face and lips is related to a lack of B vitamins.

　　1. Treatment

　　The treatment plan should be relatively perfect, closely combined with monitoring, and make early and active intervention. It is recommended to stay in the hospital for a period of time to confirm the diagnosis, perform the corresponding basic examinations and treatments, remove pulmonary lesions, and educate the patients.

　　1. Treatment of pulmonary lesions

　　The purpose is to clear respiratory tract secretions and control infection. Medications such as acetylcysteine and antibiotics can be administered through ultrasonic nebulization and bronchoalveolar lavage, inhaled bronchodilators, chest physical therapy, and postural drainage; bronchoscope aspiration and lavage can also be used, especially in cases of atelectasis and mucus obstruction; appropriate antibiotic treatment can be used when necessary. Cystic fibrosis lung lesions are prone to secondary pseudomonas aeruginosa infection, and polyvalent pseudomonas aeruginosa vaccine can be used for prevention. Recombinant deoxyribonuclease (DNA enzyme) nebulization can make secretions thin, prevent the formation of mucus plugs, and reduce infection. In addition, the treatment of pulmonary complications should also be carried out: such as atelectasis, hemoptysis, pneumothorax, allergic aspergillosis, hypertrophic pulmonary osteoarthropathy, and respiratory failure, right heart failure, and so on.

　　2. Treatment of gastrointestinal lesions

　　(1) Diet therapy: ① Supply a high-calorie diet, 30% to 50% higher than the calories calculated by age. ② Increase protein, generally 6-8g/kg per day. ③ The amount of fat should be slightly lower. ④ The diet should contain simple sugars such as fructose, glucose, and sucrose without starch, ripe bananas can be used early. ⑤ Provide a variety of vitamins, especially a large amount of vitamin A 10,000U daily, sufficient complex vitamin B and vitamin E 100-200U daily; infants and children under 2 years old and those with prolonged prothrombin time should take vitamin K. ⑥ To make up for the loss of chloride, salt should be added to the diet.

　　(2) Drug therapy: Take 2-5g of pancreatic enzyme preparation daily, the dose depending on the satisfaction of height and weight increase, which may vary from person to person. When the efficacy is satisfactory, it is manifested by the reduction of abdominal distension, improvement of digestion and absorption function, reduction in the frequency, shape, and smell of stools, normal appetite, and weight gain. Oxygen therapy should be given to severe or acute onset cases.

　　(3) Treatment of gastrointestinal complications: including meconium ileus, distal intestinal obstruction syndrome, and abdominal pain caused by other reasons, gastroesophageal reflux, rectal prolapse, liver disease, pancreatitis, and the treatment of hyperglycemia, etc.

　　3. Gene therapy

　　Recent foreign research has introduced the normal gene that can express CFTR into the airway to treat CF, which is currently in the clinical trial stage, and it will take some time before it can be used for treatment.

　　4. Other

　　Including the treatment of nasal polyps, salt loss, and hypochloremic alkalosis, etc.

　　II. Prognosis

　　Poor prognosis in patients with long course of disease, often complicated by complications. In the past, most children died of secondary infection, respiratory failure, and heart failure during infancy. Over the past 20 years, due to early diagnosis and reasonable treatment, the mortality rate of children has significantly decreased, and the survival period has been greatly extended. A considerable number of patients can survive to 30-40 years old.