pediatrics
Cystic Fibrosis
Treatment of Cystic Fibrosis
Comprehensive, multidisciplinary support Antibiotics, inhaled medications to thin airway secretions, and physical maneuvers to clear airway secretions Inhaled bronchodilators and sometimes corticosteroids for responders Usually pancreatic enzyme and vitamin supplementation High-calorie diet (sometimes requiring supplemental enteral tube feedings) In patients with specific variants, CFTR modulators consisting of a CFTR potentiator or combination of CFTR correctors and a CFTR potentiator Comprehensive and intensive therapy should be directed by an experienced physician working with a multidisciplinary team that includes other physicians, nurses, dietitians, physical and respiratory therapists, mental health professionals, pharmacists, and social workers. The goals of therapy are maintenance of normal nutritional status, prevention or aggressive treatment of pulmonary and other complications, encouragement of physical activity, and provision of psychosocial support. The treatment regimen is complex and may take up to 2 hours each day. With appropriate support, most patients can make an age-appropriate adjustment at home and school. (See also the Cystic Fibrosis Foundation'scomprehensive treatment guidelines for all age groups.) Treatment of pulmonary manifestations centers on prevention of airway obstruction and prophylaxis against and control of pulmonary infections. Prophylaxis against pulmonary infections includes maintenance of Diphtheria-Tetanus-Pertussis Vaccine , (recombinant human deoxyribonuclease) or with 7% hypertonic saline is recommended ( Treatment references ) and has been shown to slow the rate of decline in pulmonary function and to decrease the frequency of respiratory tract exacerbations ( Airway clearance measures consisting of postural drainage, percussion, vibration, and assisted coughing ( Chest Physiotherapy ) are recommended at the time of diagnosis and should be done on a regular basis. In older patients, alternative airway clearance measures, such as active cycle of breathing, autogenic drainage, positive expiratory pressure devices, and vest therapy (high-frequency chest wall oscillation), may be effective. Regular aerobic exercise is recommended; it may also help airway clearance. For patients with obstructive sleep apnea, For patients with reversible airway obstruction, bronchodilators may be given by inhalation. Corticosteroids by inhalation usually are not effective. Oxygen therapy is indicated for patients with severe pulmonary insufficiency and hypoxemia. Mechanical ventilation or extracorporeal membrane oxygenation (ECMO) is typically not indicated for chronic Overview of Respiratory Failure . Their use is typically restricted to patients with good baseline status in whom acute reversible respiratory complications develop, in association with pulmonary surgery, or to patients in whom lung transplantation is imminent. Oral expectorants are sometimes used, but few data support their efficacy. Cough suppressants should be discouraged. Pneumothorax can be treated with closed chest How To Do Tube and Catheter Thoracostomy drainage. Open thoracotomy or thoracoscopy with resection of pleural blebs and mechanical abrasion of the pleural surfaces is effective in treating recurrent Mild to moderate Hemoptysis is treated with antibiotics (oral/aerosol or IV depending on severity of hemoptysis and severity of infection) and airway clearance. Massive or recurrent hemoptysis is treated by bronchial artery embolization or rarely by focal lung resection. Oral corticosteroids are indicated in infants with prolonged Bronchiolitis and in patients with refractory bronchospasm, Allergic bronchopulmonary aspergillosis is also treated with systemic corticosteroids and an oral antifungal medication. Ibuprofen, when given over several years at a dose sufficient to achieve a peak plasma concentration between 50 and 100 mcg/mL (242.4 and 484.8 micromol/L), has been shown to slow the rate of decline in pulmonary function, especially in children 5 to 13 years of age. The appropriate dose must be individualized based on pharmacokinetic studies. Chronic rhinosinusitis is very common. Treatment options include nasal saline irrigation, low-pressure isotonic nasal irrigation, intranasaldornase alfanebulization, and sinonasal topical antibiotics. Sinus surgery may be helpful in cases refractory to medical management. An intranasal corticosteroid spray is recommended to treat allergic rhinitis. CFTR corrector and potentiator medications are indicated for about 90% of the variants carried by patients with CF. CFTR modulators are not available for patients with class I frameshift and nonsense mutations. Ivacaftoris a small-molecule oral medication given chronically that potentiates the CFTR ion channel in patients with specificCFTRvariants. It may be used in patients 1 month of age and older who carry at least 1 copy of a specific variant potentiated byivacaftor. Lumacaftor, tezacaftor, and elexacaftor are small-molecule oral medications that partially correct the defective CFTR protein by altering protein misfolding in patients who carry the F508del variant or other specified variants. The combination of lumacaftor andivacaftorcan be given to patients 1 year of age and older who carry 2 copies of the F508del variant. The combination of tezacaftor andivacaftorcan be given to patients 6 years of age and older who carry 2 copies of the F508del variant or other specified variants. can be given to patients 2 years of age and older who carry at least 1 copy of the F508del variant or 1 copy of certain rare variants ( Treatment references ). These medications can improve pulmonary function, increase weight, improve exocrine pancreatic function, decrease the frequency of pulmonary exacerbations and hospitalizations, improve quality of life, and reduce and sometimes normalize sweat chloride concentrations ( Treatment references ). The indications for Formild pulmonary exacerbations,a short course of oral antibiotics should be given based on culture and sensitivity testing. The medications of choice for methicillin-sensitive staphylococcus are a penicillinase-resistant penicillin (eg,dicloxacillin), a cephalosporin (eg,cephalexin), ortrimethoprim/sulfamethoxazole.Erythromycin,amoxicillin/clavulanate, atetracycline, orlinezolidmay be used. For patients colonized with methicillin-resistantS. aureus(MRSA), a course of oraltrimethoprim/sulfamethoxazole,clindamycin,linezolid, or atetracyclinemay be effective. For patients colonized withP. aeruginosa, a short course of inhaledtobramycinoraztreonam(eg, 4 weeks) and/or an oral fluoroquinolone (eg, 2 to 3 weeks) may be effective. Fluoroquinolones have been used safely in young children. Formoderate-to-severe pulmonary exacerbations,especially in patients colonized withP. aeruginosa, IV antibiotic therapy is advised. Patients often require hospital admission, but carefully selected patients can safely receive some of the therapy at home. Combinations of the aminoglycosidetobramycin(or sometimesamikacin) plus a cephalosporin, extended-spectrum penicillin, fluoroquinolone, or monobactam with antipseudomonal activity are given IV, usually for 2 weeks. Higher doses may be required to achieve acceptable serum concentrations. Because of enhanced renal clearance in patients with CF, large doses of some penicillins may be required to achieve adequate serum levels. For patients colonized with MRSA,vancomycinorlinezolidcan be added to the IV regimen. , antibiotics delivered by inhalation improve clinical parameters and possibly reduce the bacterial burden in the airways ( Treatment references ). The long-term use of alternate-month inhaled Patients who have a clinically significant nontuberculous mycobacterium infection may require long-term therapy with a combination of oral, inhaled, and IV antibiotics. Patients with Allergic Bronchopulmonary Aspergillosis (ABPA) (ABPA) or lower airways aspergillus infection may require prolonged oral or IV therapy with an antifungal azole and/or systemic corticosteroids. Neonatal intestinal obstruction can sometimes be relieved by enemas containing a hyperosmolar or iso-osmolar radiopaque contrast material; otherwise, surgical enterostomy to flush out the viscid meconium in the intestinal lumen may be necessary. After the neonatal period, episodes of partial intestinal obstruction (distal intestinal obstruction syndrome) can be treated with enemas containing a hyperosmolar or iso-osmolar radiopaque contrast material oracetylcysteine, or by oral administration of a balanced intestinal lavage solution. A stool softener such as dioctyl sodium sulfosuccinate (docusate) orlactulosemay help prevent such episodes. Ursodeoxycholic acid, a hydrophilic bile acid, is often used in patients with liver disease caused by CF, but there is little evidence to support its efficacy in preventing progression from bile stasis to cirrhosis. Pancreatic enzyme replacementshould be given with all meals and snacks to patients with pancreatic insufficiency. The most effective enzyme preparations containpancrelipasein pH-sensitive, enteric-coated microspheres or microtablets. For infants, the capsules are opened and the contents are mixed with acidic food. After infancy, weight-based dosing is used. Doses>2,500 IU lipase/kg/meal or>10,000 IU lipase/kg/day should be avoided because high enzyme dosages have been associated with fibrosing colonopathy. In patients with high enzyme requirements, acid suppression with an H2 blocker or proton pump inhibitor may improve enzyme effectiveness. Diettherapy includes sufficient calories and protein to promote normal growth—30 to 50% more than the usual recommended dietary allowances may be required (see table). Diet therapy also includes a normal-to-high total fat intake to increase the caloric density of the diet, a water-miscible multivitamin supplement in double the recommended daily allowance, supplementation with vitamin D3 (cholecalciferol) in patients withvitamin Ddeficiency or insufficiency, and salt supplementation during infancy and periods of thermal stress and increased sweating. Infants receiving broad-spectrum antibiotics and patients with liver disease and hemoptysis should be given additional supplemental vitamin K. Formulas containing protein hydrolysates and medium-chain triglycerides may be used instead of modified whole-milk formulas for infants with severe malabsorption. Glucose polymers and medium-chain triglyceride supplements can be used to increase caloric intake. In patients who fail to maintain adequate nutritional status, enteral supplementation via gastrostomy or jejunostomy may improve growth and stabilize pulmonary function (see Overview of Nutritional Support ). The use of appetite stimulants to enhance growth may be helpful in some patients. Cystic fibrosis–related diabetes (CFRD)is caused byinsulininsufficiency and shares features of both type 1 and type 2 diabetes.Insulinis the only recommended treatment. Management includes aninsulinregimen, nutrition counseling, a diabetes self-management education program, and monitoring for microvascular complications. The plan should be carried out in conjunction with an endocrinologist and a dietitian with experience in treating both CF and diabetes. Patients with symptomaticright heart failureshould be treated with diuretics, salt restriction, and oxygen. Recombinant human growth hormone (rhGH)may improve pulmonary function, increase height and weight and bone mineral content, and reduce the rate of hospitalization. However, because of the added cost and inconvenience, rhGH is not commonly used. may be indicated for localized Bronchiectasis or Liver Transplantation has been done successfully in patients with end-stage liver disease. Often, discussion of Lung and Heart-Lung Transplantation is needed. In considering transplantation, patients need to weigh the merits of longer survival with a transplant against the uncertainty of getting a transplant and the ongoing (but different) burden of living with an organ transplant. Bilateral cadaveric lung and live donor lobar transplantation has been done successfully in patients with advanced pulmonary disease. Combined liver-lung transplantation has been done for patients with end-stage liver and lung disease. Bilateral lung transplantation for severe lung disease is becoming more routine and more successful with experience and improved techniques. Among adults with CF, median survival posttransplant is about 9 years. 1.Flume PA, O'Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health.Am J Respir Crit Care Med2007;176(10):957-969. doi:10.1164/rccm.200705-664OC 2.Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health.Am J Respir Crit Care Med2013;187(7):680-689. doi:10.1164/rccm.201207-1160oe 3.Stahl M, Wielpütz MO, Ricklefs I, et al. Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS). A Randomized, Double-Blind, Controlled Study.Am J Respir Crit Care Med2019;199(10):1238-1248. doi:10.1164/rccm.201807-1203OC 4.Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of theelexacaftorplustezacaftorplusivacaftorcombination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears inLancet2020 May 30;395(10238):1694].Lancet2019;394(10212):1940-1948. doi:10.1016/S0140-6736(19)32597-8 5.Middleton PG, Mall MA, Dřevínek P, et al.Elexacaftor-Tezacaftor-Ivacaftorfor Cystic Fibrosis with a Single Phe508del Allele.N Engl J Med2019;381(19):1809-1819. doi:10.1056/NEJMoa1908639 6.Taylor-Cousar JL, Robinson PD, Shteinberg M, Downey DG. CFTR modulator therapy: transforming the landscape of clinical care in cystic fibrosis.Lancet2023;402(10408):1171-1184. doi:10.1016/S0140-6736(23)01609-4 7.Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection.Ann Am Thorac Soc2014;11(10):1640-1650. doi:10.1513/AnnalsATS.201404-166OC 