M. Gorky Donetsk National Medical University Department No. 2 of Pediatrics Head of the Department Dr. Churilina A. V., Ph. D. Cystic Fibrosis in children icon

M. Gorky Donetsk National Medical University Department No. 2 of Pediatrics Head of the Department Dr. Churilina A. V., Ph. D. Cystic Fibrosis in children




НазваM. Gorky Donetsk National Medical University Department No. 2 of Pediatrics Head of the Department Dr. Churilina A. V., Ph. D. Cystic Fibrosis in children
Дата19.09.2012
Розмір445 b.
ТипДокументи


M.Gorky Donetsk National Medical University Department No. 2 of Pediatrics Head of the Department Dr. Churilina A.V., Ph.D. Cystic Fibrosis in children

  • Associated professor Masyuta D.I.


CYSTIC FIBROSIS

  • Cystic fibrosis (CF) is an inherited multisystem disorder of children and adults, characterized chiefly by chronic obstruction and infection of airways and by maldigestion and its consequences.

  • It is the most common life-threatening recessive genetic trait among whites. A dysfunction of the exocrine glands is the predominant pathogenetic feature and is responsible for a broad, variable, and sometimes confusing array of presenting manifestations and complications.



CF is the major cause of severe chronic lung disease of children and is responsible for most exocrine pancreatic insufficiency during early life.

  • CF is the major cause of severe chronic lung disease of children and is responsible for most exocrine pancreatic insufficiency during early life.

  • It is also responsible for many cases of nasal polyposis, pansinusitis, rectal prolapse, pancreatitis, cholelithiasis, and insulin-dependent hyperglycemia.

  • CF may present as failure to thrive and occasionally as cirrhosis or other forms of hepatic dysfunction. Therefore, this disorder enters into the differential diagnosis of many pediatric conditions.



GENETICS

  • CF is inherited as an autosomal recessive trait. With the cloning of the CF gene, it is clear that all of the more than 400 gene mutations that contribute to the CF syndrome occur at a single locus on the long arm of chromosome 7.

  • The CF gene codes for a protein of 1480 amino acids, called the CF transmembrane regulator (CFTR). CFTR is expressed largely in epithelial cells of airways, the gastrointestinal tract (including pancreas and biliary system), the sweat glands, and the genitourinary system.

  • CFTR has ion channel and regulatory functions that are perturbed to some extent by the different mutations.



PATHOGENESIS

  • Four long-standing observations are of fundamental pathophysiologic importance:

    • failure to clear mucous secretions,
    • a paucity of water in mucous secretions,
    • an elevated salt content of sweat and other serous secretions, and
    • chronic infection limited to the respiratory tract.








PATHOGENESIS

  • Subsequent studies demonstrated that the apical membranes of CF epithelial cells are unable to secrete chloride ions in response to cAMP-mediated signals, and that, at least in the respiratory tract, excessive amounts of sodium are absorbed through these membranes.

  • The postulated epithelial pathophysiology in airways involves an inability to secrete salt and secondarily secrete water in the face of excessive reabsorption of salt and water.



PATHOGENESIS

  • The proposed outcome is insufficient water on the airway surface to hydrate secretions.

  • Desiccated secretions become more viscous and elastic (rubbery) and are harder to clear by mucociliary and other mechanisms.

  • These secretions are retained and obstruct airways, starting with those of the smallest caliber, the bronchioles.

  • Airflow obstruction at the level of small airways is the earliest observable physiologic abnormality of the respiratory system.



PATHOGENESIS

  • Based on evidence for inadequate water secretion by the pancreas, it is likely that similar pathophysiologic events take place in the pancreatic and biliary ducts (and in the vas deferens), leading to desiccation of proteinaceous secretions and obstruction.

  • Because the function of sweat gland duct cells is to absorb rather than secrete chloride, salt is not retrieved from the isotonic primary sweat as it is transported to the skin surface; chloride and sodium levels consequently are elevated.



PATHOGENESIS

  • Chronic infection in CF is limited to the endobronchial spaces of the airways. The most likely explanation for infection is a sequence of events starting with failure to promptly clear inhaled bacteria and then proceeding to persistent colonization and an inflammatory response in airway walls.

  • These events occur first in small airways, probably because clearance of altered secretions is more difficult from these regions.

  • Chronic bronchiolitis and bronchitis are the initial lung manifestations, but after months to years, structural changes in airway walls produce bronchiolectasis and bronchiectasis.



PATHOGENESIS

  • The agents of airway injury include neutrophil products, such as oxidative radicals and proteases, and immune reaction products.

  • With advanced lung disease, infection may extend to peribronchial lung parenchyma.

  • Several inflammatory products, including proteases, are responsible for the mucus hypersecretion that is characteristic of chronic airways disease.







^ CLINICAL MANIFESTATIONS

  • Mutational heterogeneity and environmental factors appear responsible for highly variable involvement of

    • the lung,
    • pancreas, and
    • other organs.






Respiratory Tract

  • Cough is the most constant symptom of pulmonary involvement. At first, the cough may be dry and hacking, but eventually, it becomes loose and productive. In older patients, the cough is most prominent on arising in the morning or after activity.

  • Expectorated mucus is usually purulent.

  • Some patients remain asymptomatic for long periods or seem to have only prolonged acute respiratory infections.

  • Others develop a chronic cough within the first weeks of life or they repeatedly develop pneumonia.



Respiratory Tract

  • Extensive bronchiolitis is attended by wheezing, which is a frequent symptom during the 1st years of life.

  • As lung disease progresses, exercise intolerance, shortness of breath, and failure to gain weight or grow are noted.

  • Exacerbations of lung symptoms eventually require hospitalization for effective treatment.

  • Finally, cor pulmonale, respiratory failure, and death supervene. The rate of progression of lung disease is the chief determinant of morbidity and mortality.



Respiratory Tract

  • Early physical findings include

    • increased anteroposterior diameter of the chest,
    • generalized hyper-resonance,
    • scattered or localized coarse crackles, and digital clubbing.
  • Expiratory wheezes may be heard, especially in young children.

  • Cyanosis is a late sign.



Respiratory Tract

  • Common pulmonary complications include

    • atelectasis,
    • hemoptysis,
    • pneumothorax, and
    • cor pulmonale
  • and usually appear beyond the 1st decade of life.

  • Nasal obstruction and rhinorrhea are common, caused by inflamed, swollen mucous membranes or, in some cases, nasal polyposis.

  • Nasal polyps are most troublesome between 5 and 20 yr of age.



Left-sided pneumothorax in a patient with cystic fibrosis



Cystic fibrosis. Lungs hyperinflated and right-side pleural effusion



Chest radiograph of a patient with cystic fibrosis.









Intestinal Tract

  • In 10–15% of newborn infants with CF, the ileum is completely obstructed by meconium (meconium ileus).

  • Abdominal distention, emesis, and failure to pass meconium appear within the first 24–48 hr of life.

  • Abdominal roentgenograms show dilated loops of bowel with air-fluid levels and frequently a collection of granular, "ground glass" material in the lower central abdomen.



Intestinal Tract

  • Rarely, meconium peritonitis results from intrauterine rupture of the bowel wall and can be detected roentgenographically by the presence of peritoneal or scrotal calcifications.

  • Ileal obstruction with fecal material (distal intestinal obstruction syndrome or meconium ileus equivalent) occurs in older patients, causing cramping abdominal pain and abdominal distention.



Intestinal Tract

  • More than 85% of children show evidence of maldigestion due to exocrine pancreatic insufficiency.

  • Symptoms include frequent, bulky, greasy stools and failure to gain weight even when food intake appears to be large.

  • Characteristically, stools contain readily visible droplets of fat.



Intestinal Tract

  • A protuberant abdomen, decreased muscle mass, poor growth, and delayed maturation are typical physical signs.

  • Excessive flatus may be a problem.

  • Deficiency of fat-soluble vitamins is occasionally symptomatic.



Cystic fibrosis



Cystic fibrosis (a 10-month-old child)



Cystic fibrosis (a 10-month-old child)







^ DIAGNOSIS AND ASSESSMENT

  • The diagnosis of CF has been based for many years on a positive quantitative sweat test (Cl- ≥ 60 mEq/L) in conjunction with one or more of the following:

    • typical chronic obstructive pulmonary disease,
    • documented exocrine pancreatic insufficiency, or
    • a positive family history.


^ DIAGNOSIS AND ASSESSMENT

  • A diagnosis can also be made for those with typical clinical features and a known CF genotype.

  • DNA analysis, for reasons outlined earlier, cannot alone rule out CF.

  • If sweat chloride values are normal, the documentation of mutations on both chromosomes and a compatible phenotype are sufficient to confirm a diagnosis.



TREATMENT

  • The treatment plan

    • should be comprehensive and
    • linked to close monitoring and early, aggressive intervention.


General Approach to Care

  • A period of hospitalization for accurate diagnosis, baseline assessment, initiation of treatment, clearing of the pulmonary involvement, and education of the patient and parents is recommended.

  • The patient is hospitalized for as long as is necessary to reverse pulmonary findings and to achieve steady weight gain.

  • Follow-up outpatient visits are scheduled at least every 3 mo because many aspects of the condition require careful monitoring.



General Approach to Care

  • Because CF patients do not hydrate their secretions adequately, attention in early childhood to oral hydration, especially during warm weather or with acute gastroenteritis, may prevent exacerbation of problems with clearance of mucus from airways.

  • For the same reason, intravenous therapy for dehydration should be initiated early.



General Approach to Care

  • The goal of therapy is to maintain a stable condition for prolonged periods. This can be accomplished for most patients by interval evaluation and adjustments of the home treatment program.

  • However, some patients have episodic acute or low-grade chronic lung infection that progresses. For these patients, 2 wk or more of intensive inhalation and physical therapy and intravenous antibiotics is indicated. Intravenous antibiotics may be required infrequently or as often as every 2–3 mo.

  • Significant improvement in pulmonary function and the patient's well-being is usually achieved.



Pulmonary Therapy The object is to clear secretions from airways and to control infection



^ INHALATION THERAPY

  • Aerosol therapy is used to deliver medications and water to the lower respiratory tract, usually before or after segmental postural drainage.

  • Some agents such as bronchodilators can be delivered by metered dose inhaler with or without a spacer. The mainstay is intermittent delivery using a small compressor that drives a hand-held nebulizer.

  • The basic aerosol solution is 0.45–0.9% saline. In patients with reactive airways, albuterol or other beta-agonists can be added.



^ INHALATION THERAPY

  • When the airway pathogens are resistant to oral antibiotics or when the infection is difficult to control at home, aerosolized antibiotics may reduce symptoms, especially those referable to tracheitis or bronchitis.

  • A preferred but time-consuming regimen is delivery of a bronchodilator, followed by chest physical therapy and then an antibiotic aerosol.



^ INHALATION THERAPY

  • Human recombinant DNase (2.5 mg), given as a single daily aerosol appears to improve pulmonary function, decrease numbers of pulmonary exacerbations, and promote a sense of well-being in patients who have mild to moderate disease and purulent secretions.

  • Another mucolytic agent, N-acetylcysteine, is toxic to ciliated epithelium, and repeated administration should be avoided.



^ CHEST PHYSICAL THERAPY

  • This treatment usually consists of chest percussion combined with postural drainage and derives its rationale from the idea that cough clears mucus from large airways, but that chest vibrations are required to move secretions from small airways where expiratory flow rates are low.

  • Chest physical therapy may be particularly useful for patients with CF because they first accumulate secretions in small airways, even before the onset of symptoms.

  • Chest physical therapy is recommended one to four times a day, depending on the severity of lung dysfunction.



^ CHEST PHYSICAL THERAPY

  • Cough or forced expirations are encouraged after each lung segment is "drained.«

  • Mechanical percussors have been designed to assist with therapy and may be useful, especially for adolescents.

  • Voluntary coughing, repeated forced expiratory maneuvers with and without positive expiratory pressure, and vigorous exercise have all been suggested as additional aids to mucus clearance.



^ ANTIBIOTIC THERAPY

  • Antibiotics are the mainstay of therapy designed to control progression of lung infection.

  • The goal is to reduce the intensity of endobronchial infection and to delay progressive lung damage.

  • Differentiation of colonization from infection is a recurring problem, and the usual guidelines for acute chest infections, such as fever, tachypnea, or chest pain, are often absent.



^ ANTIBIOTIC THERAPY

  • Consequently, all aspects of the patient's history and examination, including anorexia, weight loss, and diminished activity, must be used to guide the frequency and duration of therapy.

  • Antibiotic treatment varies from intermittent short courses of one antibiotic to continuous treatment with one or more antibiotics.



^ BRONCHODILATOR THERAPY

  • Reversible airway obstruction occurs in many patients with CF, sometimes in conjunction with frank asthma or acute bronchopulmonary aspergillosis.

  • Reversible obstruction is suggested by improvement of 15% or more in flow rates after inhalation of a bronchodilator.

  • Treatment may include use of beta-adrenergic agonists by aerosol.



^ ENDOSCOPY AND LAVAGE

  • Treatment of obstructed airways sometimes includes tracheobronchial suctioning or lavage, especially if atelectasis or mucoid impaction is present.

  • Bronchopulmonary lavage may be performed by the instillation of saline or by a mucolytic agent through a fiberoptic bronchoscope.

  • Antibiotics (usually gentamicin or tobramycin) may also be directly instilled at lavage, transiently achieving a much higher endobronchial concentration than can be obtained by using intravenous therapy. There is no evidence for sustained benefit from repeated endoscopic or lavage procedures.



EXPECTORANTS

  • Systemic drugs, such as iodides and guaiphenesin, do not effectively assist with the removal of secretions from the respiratory tract.





DIET

  • Many infants at the time of diagnosis have nutritional deficits.

  • Young infants who present with wheezy breathing and are fed soy protein formulas do not utilize this protein well and may develop hypoproteinemia with anasarca.

  • Infants do well with formulas containing predigested protein and medium-chain triglycerides.

  • A low-fat, high-protein, high-caloric diet was generally recommended in the past for older children. Some children on this diet became deficient in essential fatty acids. With the advent of improved pancreatic enzyme products, normal amounts of fat in the diet are usually tolerated well.



DIET

  • Most individuals have a higher than normal caloric need because of increased work of breathing and perhaps because of increased metabolic activity related to the basic defect.

  • When anorexia of chronic infection supervenes, weight loss occurs.

  • Further encouragement to eat high-caloric foods may be useful, but weight gain generally is not realized unless lung infection is controlled.



^ PANCREATIC ENZYME REPLACEMENT

  • Extracts of animal pancreas given with ingested food reduce but do not fully correct stool fat and nitrogen losses.

  • Enzyme dosage and product should be individualized for each patient.

  • The introduction of pH-sensitive enteric-coated enzyme microspheres has been a major advance in patient care.



^ PANCREATIC ENZYME REPLACEMENT

  • Several strengths, up to 20,000 IU of lipase/capsule are available.

  • The microsphere preparations usually are sufficiently effective to permit a liberal diet, which may include homogenized milk.

  • The dose of enzymes required usually increases with age, but some teenagers and young adults may later have a decrease in their requirement.



^ VITAMIN AND MINERAL SUPPLEMENT

  • Because pancreatic insufficiency results in malabsorption of fat-soluble vitamins (A, D, E, and K), vitamin supplementation is recommended.

  • Capsules containing adequate amounts of all four vitamins for CF patients are now available.

  • Infants with zinc deficiency and rash have been reported.

  • In addition, attention should be paid to iron status; in one study almost one third of patients with CF had a low serum ferritin concentration.



^ SALT DEPLETION

  • Sweat salt losses can be high, especially in warm arid climates.

  • Children should have free access to salt, and precautions against overdressing infants should be observed.

  • Hypochloremic alkalosis should be suspected in any infant who has had gastroenteritis symptoms, and prompt fluid and electrolyte therapy should be instituted as needed.



PROGNOSIS

  • CF remains a life-limiting disorder, although survival has improved dramatically during the last 30–40 yr.

  • Infants with severe lung disease occasionally succumb, but most children survive this difficult period and are relatively healthy into adolescence or adulthood.

  • However, the slow progression of lung disease eventually reaches disabling proportions.



PROGNOSIS

  • Survival beyond 20 yr of treatment exceeds 90% if CF is diagnosed and treatment begun before substantial lung damage has occurred.

  • For the most part, children with CF have good school attendance records and do not need to be restricted in their activities.





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