CYSTIC FIBROSIS
 
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CYSTIC FIBROSIS

 

DEFINITION:

An inherited disorder characterized primarily by progressive lung disease, pancreatic insufficiency, gastrointestinal obstruction, and an excess of sodium and chloride in the sweat.

EPIDEMIOLOGY:

  • incidence:
    • most common fatal autosomal recessive disease affecting Caucasian populations (carrier rate is 1/20)
    • incidence varies between different populations:
      • Northern Ireland - 1 in 1700 - 1900
      • USA: Caucasians - 1 in 1900 - 3700
      • England: Asian - 1 in 10,000
      • USA: Black - 1 in 17,000
    • age of onset:
      • infancy -> adolescence
    • risk factors:
      • familial - autosomal recessive
        • chrom.#: 7q31.2
        • gene: cystic fibrosis transmembrane conductance regulator (CFTR) gene

PATHOGENESIS:

1. Background

  • function of the CFTR gene is unknown and controversial:
  • 1. defective Cl channel per se
  • 2. defective Cl channel regulator - leukotriene LTC4, prostaglandin D2
  • defective transport of anions (Cl) across epithelial cells in the airways, pancreas, intestine, and sweat glands leads to chronic lung disease, pancreatic insufficiency, gastrointestinal obstruction, and increased sodium and chloride in the sweat

2. Genetic Defect

  • over 400 mutations of the CFTR gene have been identified
  • 70% of the mutations in the CFTR gene are deltaF508
    • those homozygous for this mutation tend to be pancreatic insufficient
  • genotype -> phenotype correlation studies are in progress

CLINICAL FEATURES:

1. Respiratory Manifestations

1. Early Changes

1. Upper Airway

  • chronic rhinitis/rhinorrhea
  • nasal polyps (15-20%)
  • acute/chronic sinusitis
  • middle ear effusions
  • culture + for P. aeruginosa

2. Lower Airway

  • chronic cough (earliest manifestation)
  • coarse crackles (RUL)
  • obstructive lung disease (hyperinflation, wheezing)

2. Late Changes

  • exacerbation of respiratory distress (dyspnea, cough) associated with acute respiratory infections

3. End Stage

  • hypoxemia, pulmonary hypertension, cor pulmonale, respiratory failure

4. Complications

1. Atelectasis

  • in 5%, lobar and segmental

2. Pneumothorax

  • (+/- tension) with high recurrence rate

3. Hemoptysis

  • seen with bronchiectasis, massive in 5%

4. Clubbing

  • in 100%, extent correlates with lung severity

5. Allergic Aspergillosis

  • a. fumigatus with rusty brown plugs of sputum

6. Hypertrophic Pulmonary Osteoarthropathy

  • in 8-15%, distal tibia, fibula, ulna

7. Bacterial Infections

  • S. aureus
  • H. influenzae
  • Pseudomonas aeruginosa
    • 40% of patients are colonized by 5 years of age
  • Burkholderia cepacia (formally P. cepacia)
    • different strains

2. Gastrointestinal Tract Manifestations

1. Intestinal Tract

1. Newborn

1. Meconium Ileus
  • 5-10%, diagnostic for CF
  • small intestine obstruction
2. Meconium Plug Syndrome
  • less specific for CF
  • large intestine obstruction

2. Infant/Children

1. Meconium Ileus Equivalent
  • distal intestinal obstruction syndrome
  • a partial or complete obstruction of the terminal ileum
  • occurs in 20% of patients with CF
2. Rectal Prolapse
  • 20% of CF children
3. Others
  • intussusception
  • adhesions (from previous surgury)
  • appendix (appendicitis, periappendiceal abscess diverticulosis)
  • duodenal ulcers

2. Pancreatic Disease

1. Exocrine

1. Malabsorption
  • pancreatic enzyme deficiency (blocked ducts)
  • of fats, protein, nitrogen
  • of vitamins D,E,A,K
  • fecal loss of bile acids
2. Pancreatitis
  • in <1% of adolescents or adults

2. Endocrine

1. Diabetes Mellitus
  • in 8% of CF's older than 11
  • abnormal glucose tolerance test
  • decreased number of beta cells
  • may present with symptomatic hyperglycemia but not ketoacidosis
  • will induce microvascular changes in the retina and kidneys

3. Hepatobiliary Disease

1. Biliary Cirrhosis

  • focal
  • may increase alkaline phosphatase
  • may present with conjugated hyperbilirubinemia due to intrahepatic cholestasis
  • 2-5% of CF patients present with jaundice, ascites, edema, massive hematemesis, splenomegaly

2. Cholelithiasis

  • 12% of older patients
  • may be associated with biliary colic
  • may be intra- or extrahepatic
  • bile becomes lithogenic because of a high cholesterol content

3. Genitourinary Tract Manifestations

1. Males

1. Altered Wolfian Duct Structures

  • vas deferens, epididymis, seminal vesicles are atrophic, fibrotic, obstructed, or absent
  • pathogenesis: intrauterine obstruction of the genital tract

2. Infertility

  • only 2-3% are fertile
  • volume of ejaculate is 1/3 -> ½ of normal
  • complete absence of spermatozoa
  • a number of chemical abnormalities of the semen (due to absence of secretions from the seminal ves.)

3. Others

  • inguinal hernia, hydrocele, undescended testes
  • delay in the onset of puberty and sexual maturation

2. Females

1. Infertility

  • 10% are fertile
  • may be related to menstrual irregularities (oligomenorhea, anovulation), thick tenacious mucous plugs at the cervial os (abnormal cervial mucous), endocervicitis, polyp formation

2. Others

  • delay in the onset of puberty and sexual maturation

4. Sweat Gland Manifestations

  • failure to reabsorb Cl
  • increased Na, Cl, K in sweat (i.e., loose NaCl through sweat)
  • salty taste with salt crystals on skin
  • salt depletion can lead to:
    • profound hypochloremia, hyponatremia, alkalosis, and/or hypotension

INVESTIGATIONS

1. Pulmonary Function

1. Obstructive Lung Disease

  • seen within weeks -> months after birth
  • progresses from peripheral -> general involvement
  • characterized by:
    • decreased maximal flow rates
    • decreased FEV/FVC
    • increase a-A gradient (V/Q mismatch)
    • reactive airway disease

2. Restrictive Lung Disease

  • late stage disease
  • characterized by decreased VC and TLV

3. End Stage Disease

  • FEV1 <30% predicted
  • (PaO2 <55 mmHg, PaCO2 >50 mmHg)

2. For Malabsorption

  • see file on "Malabsorption"

3. Neonatal Screening

  • elevated level of trypsinogen in the blood of newborns

MANAGEMENT:

  • I. APPROACH
  • 1. Diagnosis
  • 2. Education
  • 3. Treatment Options
  • 4. Goals of Therapy
  • 5. Management Stategies
  • 1. Supportive
  • 2. Nonpharmalogical
  • 1. Chest Physiotherapy
  • 2. Diet
  • 1. Newborns
  • 2. Children
  • 3. Pharmalogical
  • 1. Antibiotics
  • 2. Ventolin
  • 4. Surgical
  • 1. For Complications
  • 2. Lung Transplantation
  • 5. Experimental
  • 1. Amiloride
  • 2. DNase (Pulmozyme)
  • 3. Gene Therapy

    • 1. Diagnosis

    1. Laboratory

    1. Sweat Chloride

    • Sweat Gain >100 mg
    • [NaCl] >60 mmol/L

    2. Molecular Characterization

    • as yet there is no correlation between genotype and phenotype

    2. Education

    • diagnosis, definition, epidemiology, prognosis, treatment options

    3. Treatment Options

    1. No Treatment

    • for the pancreatic-sufficient type there may be no need for pancreatic enzymes

    2. Treatment

    • management with pancreatic enzymes in the pancreatic-insufficient type
    • management of respiratory manifestations in all patients

    4. Goals of Therapy

    • no cure for cystic fibrosis and thus management goals revolve around the amelioration of the respiratory and gastrointestinal manifestations

    5. Management Strategies

    1. Supportive

    • CF is a chronic and progessive illness that needs close monitering and thus regular follow-up is important
    • the patient and family should be linked to a CF support group within the community
    • Psychological support - living with CF, dying with CF
    • funding for medical therapy is provided through the government and the distribution of medications is through regional centres throughout Canada
    • the Canadian CF Foundation works with 33 CF Clinics across Canada and 53 Chapters
    • the Paediatrician coordinates a team approach involving pharmacists, dieticians, psychologists, & physiotherapists

      1. Follow-up

      • clinical assessment every 3-6 months with sputum samples and pulmonary function tests with each visit
      • chest x-ray every 6-9 months
      • SMA11 and CBC with differential every 12 months

    2. Non-Pharmacologic

    1. Chest Physiotherapy

    • performed at least 3 times per day to relieve mucous obstruction in the lungs
    • postural drainage of the 17 segments may take up to 20-30 minutes per session
    • autogenic drainage - breathing at different lung volumes to increase release of mucous from the lower airways

    2. Diet

    1. Newborn
  • Goals
    • to provide 150% of normal caloric requirements
    • follow clinically - stooling pattern, abdominal distension, weight gain
  • Breast Feeding
    • encourage but may not be tolerated
    • supplement with formula (see below)
  • Formula
    • supplement formula to 27 kcals/oz. with Polycose and MTC Oil
    • if taking elemental formulas by mouth, may switch over to milk-based formula when infant gaining weight (i.e., by 6 weeks of age)
    • Elemental feeds - Alumentum or Nutramigen
  • Supplementations
    • Pancreatic Enzymes
      • Cotazym supplements needed for all breast and formula-fed infants
      • may add cotazym powder to apple sauce prior to feed
      • always wash mouth after enzymes given to prevent autodigestion
    • Vitamins
      • Poly-Vi-Sol 0.6 cc po od
      • Vitamin E 100 mg po tid for 1st year then 400 mg po od
    • 2. Children -> Adulthood
  • Meals
    • high calorie meals high in salt
  • Supplementations
    • Ensure drinks or puddings
    • Pancrelipase Preparations
      • Cotazym and Cotazym ECS
      • take as much is needed to control diarrhea and malabsorption
      • must take with each meal and snack
    • Multiple Vitamins
      • poly-vi-sol (tablets or drops)
      • vitamin E (capsules or drops)
    • NaCl
      • snacks high in salt (chips, cheezies, salt pills) particularly in hot weather

    • 3. Birth Control

    • liver function tests should be monitered carefully for hepatits in women on the birth control pill
    • lung function declines after pregnancy

    3. Pharmacologic

    1. Antibiotics

    1. Prophylaxis (Continuous)
  • Staph. aureus
    • Keflex (Cephalexin) 50-70 mg/kg/d po tid-qid
    • Cloxacillin 100 mg/kg/day po qid
  • Pseudo. aeruginosa
    • Tobramycin (Nebulized)- 2cc (80mg) tid after physiotherapy
    • 2. Acute Exacerbations - positive sputum
  • H. flu
    • Amoxicillin 25-50 mg/kg/day po tid x 2 weeks
  • P. aeruginosa
    • add Ciprofloxacin 40 mg/kg/day po bid x 2 weeks to Tobramycin therapy
  • B. cepacia
    • add Ciproflaxacin 40 mg/kg/day po bid or Septra po bid x 2 weeks to Tobramycin therapy
    • 3. Hospitalization
  • Tobramycin
    • 80 mg nebulized tid and
    • 3-3.5 mg/kg/dose IV q8h
  • Ceftazidime
    • 150 mg/kg/day IV tid (max. 2g/dose)
  • Keflex or Cloxacillin po

    • 2. Ventolin

    • by mask bid

    4. Surgery

    1. For Complications

    • pneumothorax, hemoptysis
    • meconium ileus + equivalent, meconium plug syndrome, rectal prolapse, partial or complete obstruction, appendicitis, cholethiasis, etc.

    2. For Lung Transplantation

    • for end stage lung disease (when FEV1 is <25% normal)
    • about 10% of patients reach transplantation with a 50% mortality within two years of transplant

    5. Experimental Therapies

    1. Amiloride

    1. Mechanism of Action
    • decreases NaCl and water absorption (diuretic)
    • inhibits bacterial growth (gram +)
    • enhances the activity of tobramycin
    • given by mask
    2. Trials
    • NEJM 322: 189 (1990)
    • Am. Rev. Resp. Dis. 141:605 (1990)
    • preliminary results show less of a decline in pulmonary function with amiloride

    2. DNase

    1. Mechanism of Action
    • decreases the viscosity of sputum and thins out lung secretions
    • increases mucociliary transport
    • digests the DNA released by inflammatory cells found in the lung secretions
    • given by mask bid
    2. Trials
    • 2.5 mg Pulmozyme od has a minimal effect (2-4%) on pulmonary function tests and is reported to show clinical improvement (decreases dyspnea, CF-related symptoms, and hospitalized days)
    • side effects: anaphylaxis, hemoptysis
    • disadvantages: $26,000/yr/patient

    3. Gene Transfer Therapy

    • adenovirus vectors with normal CFTR gene inserted into the genome administered to patients via an aerosol mist
    • also using liposomes

     

     

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