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ClubbingCF

Image: “”Clubbing” of the fingers is a classic feature of Cystic Fibrosis, although not present in many patients.” by Jerry Nick, M.D.. License: CC BY 3.0


Definition of Cystic Fibrosis

Cystic fibrosis due to defective chloride channels

Synonyms: cystic fibrosis, fibrosa cystica, CF

The term ‘mucoviscidosis’ (lat. mucus = phlegm, viscidus = tough, sticky) refers to a metabolic disorder caused by an autosomal recessive defect associated with the CFTR gene (cystic fibrosis transmembrane conductance regulator), involving more than 1,500 known mutations.

This defect disrupts the function of the chloride channel, resulting in the production of sticky secretions by the exocrine glands. The body parts that are most affected include the epithelia of the respiratory tracts, the biliary tracts, the pancreatic duct, the small intestine, the deferent duct, and the perspiratory glands.

cystic fibrosis

Image: “Cystic fibrosis has an autosomal recessive pattern of inheritance” by Cburnett. License: CC BY-SA 3.0

Epidemiology of Cystic Fibrosis

Spread of mucoviscidosis

The incidence of mucoviscidosis is higher in Europe than in Africa or Asia. It is about 1:2,500 in Central Europe. The frequency of the heterozygous type in Germany is 1:25, with approx. 8,000 individuals currently affected in Germany, and another 3 million healthy individuals carrying gene mutations that are transmitted hereditarily.

Etiology and Pathogenesis of Cystic Fibrosis

The deletion mutation △F508 is most common in Central Europe and North America, and leads to the loss of the amino acid phenylalanine at position 508 in the CFTR gene.

Discussion

The type of mutation is crucial in determining the severity of the disease, depending on four distinct scenarios:

  1. Absence of CFTR gene expression
  2. Synthesis of CFTR channel, but without membrane incorporation or localization, as in △F508 mutation.
  3. Defective channel expression and incorporation without opening due to the mutation.
  4. Incorrect protein folding resulting in defective channel opening

As a result of the genetic defect, the chloride channel loses its ability to release chloride and bicarbonate ions from the cell. The increased sodium absorption leads to the formation and accumulation of tough bronchial mucus in the lung (mucostasis), due to the lack of osmotic water absorption from the tissue. The resulting obstipation and inflammation eventually lead to complete organ destruction and functional deficiency.

Impact of mucoviscidosis on various organ systems

  • Lung: Blockage of mucociliary clearance; obstruction of alveoli/bronchioles with an increased risk of infection because of pathogen clusters; destruction of the lung and reformation into a honeycomb lung due to chronic inflammation
  • Pancreas: Blockage of the exocrine secretion outlets, fibrotic and cystic mutations, and loss of exocrine function
  • Gall: Obstruction of bile drainage, and development of biliary cirrhosis
  • Intestines: Obstipation
  • Perspiratory glands: The CFTR channel loses the ability to reabsorb chloride ions from primary sweat, leading to high NaCI concentrations in secondary sweat.

Clinical Signs of Cystic Fibrosis

Symptoms of mucoviscidosis

Mnemonic: CF PANCREAS

C – Chronic cough
F – Failure to thrive
P – Pancreatic insufficiency (exocrine)
A – Alkalosis and hypotonic dehydration
N – Nasal polyps, neonatal dehydration
C – Clubbing of fingers (Hippocratic fingers and nails)
RRectal prolapse
E – Electrolyte elevation (sweat)
A – Atresia, absence of vas deferens
S – Sputum associated with staphylococcal or pseudomonas infection

Clubbing CF

Image: “”Clubbing” of the fingers is a classic feature of Cystic Fibrosis, although not present in many patients.” by Jerry Nick, M.D. License: CC BY 3.0

Lung and respiratory tract

Cystic Fibrosis patients suffer from chronic productive cough. The tough secretions result in recurring bouts of bronchitis and pneumonia (bacterial, especially due to Pseudomonas aeruginosa and Staphylococcus aureus).

The increasing lung insufficiency leads to anoxia and exertional dyspnea and bronchiectasis. The oxygen deficiency manifests clinically as Hippocratic fingers and nails.

Nearly 10–50% of patients develop polyposis nasi and chronic pansinusitis associated with the lower respiratory tract.

Gastrointestinal tract

meconium ileus

Image: “Lethal course of meconium ileus in preterm twins revealing a novel cystic fibrosis mutation ” by Puzik A, Morris-Rosendahl DJ, Rückauer KD, Otto C, Gessler P, Saueressig U, Hentschel R. License: CC BY 2.0

First, the disease usually manifests itself in young patients as meconium ileus, and very rarely as meconium plug syndrome. Other symptoms include icterus prolongatus, obstipation, abdominal cramps, flatulence and steatorrhea (fatty stools).

Tough stool can cause rectal prolapse. The manifestation of exocrine pancreatic insufficiency leads to malabsorption of nutrients and liposoluble vitamins.

Due to the lack of digestive enzymes, the body is deprived of macro- and micronutrients that are absorbed with food. Malabsorption, in turn, leads to failure to thrive (dystrophy), despite the increased energy demand.

Genital organs and reproduction

Male teenagers affected by CF can experience obstructive azoospermia and infertility because of bilateral aplasia and atresia of the deferent duct.

cystic Fibrosis

Image: “Cystic Fibrosis” by BruceBlaus. License: CC BY 3.0

Complications of Cystic Fibrosis

Exacerbation of pulmonary disease Severe cough, sputum production, clinical pulmonary report: rhonchus ↑, rale ↑, dyspnea, lung function ↓, use of accessory respiratory muscles ↑, appetite ↓, weight ↓, fever, exhaustion
Spontaneous pneumothorax  Risk of spontaneous pneumothorax with increased lung destruction
Chronic germ population (Evidence of single germ in at least three sputum cultures in at least six months) Toddlers: Staphylococcus infection, Haemophilus influenzae

Children and teenagers: Pseudomonas aeruginosa (biofilm formation), Stenotrophomonas maltophilia

Allergic bronchopulmonary aspergillosis (ABPA) Anamnesis: poor general condition, irritation of the throat ↑, chest pain ↑, fever, subfebrile temperature
Biliary cirrhosis Bile duct obstruction in adults
Endocrine pancreatic insufficiency Development of diabetes mellitus including the destruction of the islets of Langerhans in adulthood
Hemoptysis Hemorrhage of pulmonary arteries, with potentially lethal outcome if blood loss more than 0.5 L in 24 hours

Diagnosis of Cystic Fibrosis

Initial diagnosis of mucoviscidosis

The diagnosis of mucoviscidosis is initially based on clinical symptoms, which is then confirmed by further tests and procedures.

Sweat test
The sweat test is considered as the gold standard of diagnosis and entails determination of NaCl concentration by stimulating sweat using pilocarpine iontophoresis. The chloride ion concentration in the sweat must be > 60 mmol/L in two recordings.

Genetic mutation analysis
In case of borderline values, the sweat test should be repeated along with genotyping. The genetic mutation analysis captures almost 90% of those affected. Mucoviscidosis is already diagnosed prenatally via CFTR genotype analysis prior to birth.

This procedure is indicated for siblings of index patients and those diagnosed with mucoviscidosis, contemplating pregnancy and child birth.

Transepithelial potential difference
In case of clinical suspicion without evidence of CFTR mutations, the transepithelial potential difference can be detected in the Using chamber (using tissue of the nasal and rectal mucosae). Pathological levels range from -100 mV to 60 mV.

Pancreatic elastase
Pancreatic insufficiency can be detected when screening the stool for pancreatic elastase, which is reduced in CF patients.

Neonatal screening
In case of suspected mucoviscidosis, a blood test for immunoreactive trypsin is performed as part of neonatal screening. It is, however, not a standard routine procedure.

Diagnostic parameters

Clinical

  • Chronic (> 3 months) cough, sputum production, whistling breath, Hippocratic fingers
  • Hyperkyphosis with chicken or funnel breast due to pulmonary hyperinflation
  • Chronic rhinosinusitis with/without nasal polyps, often exacerbating during childhood and adolescence
  • Nutritional status: dystrophy, hypoproteinemia, and edemas

Lab

  • Electrolytes (Na+, K+, and Ca2+)
  • Liver parameter (GOT, GPT)
  • Cholestasis (liver-specific alkali phosphatase)
  • Pancreatic function (lipase, P-amylase)
  • Breakdown of liposoluble vitamins
  • CRP

Medical imaging

  • Upper abdominal sonography
  • Thoracic X-ray: persistent pulmonary image findings: bronchiectasis, atelectasis, infiltrates, hyperinflation, enlarged hilar lymph nodes; late-stage: pulmonary heart disease
  • Thoracic CT: possibility of abscesses, aspergillum infection

Microbiology

  • Persistent detection of staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa and Burkholderia cepacia in respiratory secretion and sputum.

Differential Diagnosis of Cystic Fibrosis

Similar diseases to mucoviscidosis

Note: common diagnostic error: misinterpreting mucoviscidosis as a disease within the spectrum of rheumatic disorders
Asthma Allergy anamnesis, reversible lung obstruction with peribronchial thickening, hyperinflation, air-trapping, atelectasis, complications due to allergic bronchopulmonary aspergillosis
Primary ciliary dyskinesia Congenital dysfunction of the ciliated epithelium, recurring sinobronchial infections, more bland lung changes, recurring aspiration, Kartagener syndrome
Recurring aspiration Bronchiectasis (frequently involving the inferior lobe and posterior lung segments), common in neuromuscular diseases

Therapy of Cystic Fibrosis

Once diagnosed, mucoviscidosis requires multimodal treatment where possible. Antibiotic therapy is crucial to attenuate disease progression. A comprehensive overview of the particular pathogens and therapeutics is presented below.

Multimodal therapy for mucoviscidosis

Organ/Pathophysiology Therapy
Exocrine pancreatic insufficiency A dose of pancreatic enzymes with defined doses of lipase and protease administered with every meal
Failure to thrive, dystrophy High-calorie normal diet (patient-specific and rich in fat), no restriction on fat, and enteral nutrition via PEG
Vitamin deficit Prophylactic substitution of liposoluble vitamins in supranormal doses
Deficit of minerals and trace elements Substitution in case of detectable deficiency
CF-associated diabetes Dietary intake adjusted to energy demand, without restricting carbohydrates; reduction of blood sugar using oral anti-diabetic medication or insulin
Lung infections, respiratory lung insufficiency
  • Respiratory physiotherapy
  • Autogene drainage (supporting bronchial clearance)
  • Endurance sports (jogging, swimming, bicycling)
  • Inhalation of bronchodilators (β-sympathomimetics), antibiotics, mucolytics (recombinant rDNA) for secretolytic treatment
  • Antimycotics and immunosuppressors in case of bronchopulmonary aspergillosis
  • Schematized antibiotic therapy
  • External administration of oxygen, ventilatory support
  • Vaccination against all lung pathogens: pertussis, Pneumococci, influenza, Haemophilus influenzae
  • Pneumectomy indicated in case of recurring inflammation of pulmonary lobes that has a negative impact on the general condition.
  • Lung transplantation after exhausting all therapeutic measures, insufficiency of both lungs, remaining life expectancy < 2 years
Liver cirrhosis, cholestasis, portal vein pressure
  • Treatment with ursodeoxycholic acid, possibly combined with taurine
  • Portosystemic shunts
  • Sclerotization of esophageal varices
  • Operative gallstone removal
Hypotonic dehydration and hypochloremic alkalosis Under conditions of increased external temperature, sweating, fever, infections, vomiting, diarrhea, supplementation of food with NaCl.

Antibiotic therapy for mucoviscidosis

The two different types of antibiotic therapy include:

Long-term prophylactic therapy
This therapy is usually indicated for the treatment of infections due to Pseudomonas aeruginosa. It is administered regardless of symptoms or pathogenic evidence.

Exacerbation therapy
This type of therapy is linked to symptoms and is adjusted to the antibiogram and the specific pathogenic evidence.

  • Staphylococcus aureus: First- and third-generation Cephalosporine, Flucloxacillin, Piperacillin with Tacobactam, Clindamycin, Fosfomycin, Imipenem, Cotrimoxazol
  • Haemophilus influenza: Second/third generation Cephalosporine
  • Pseudomonas aeruginosa: Ciprofloxacin, Ceftazidim, Cefepim, Piperacillin with Tazobactam, Meropenem, Imipenem, Aztreonam, Tobram, Aminoglykoside
  • Burkholderia cepacia: Meropenem and Piperacillin, Ceftazidim, Trimethoprim, Sulfamethoxazole, Cotrimoxazol, Doxycyclin, Minocycline, Chloramphenicol, Ciprofloxacin, and Aminoglykoside
  • Stenotrophomonas maltophilia: Trimethoprim/Sulfamethoxazole, Cotrimoxazol, Doxycycline

Prognosis of Cystic Fibrosis

Patients diagnosed with  cystic fibrosis live to an age of 30 to 40 years when treated optimally, although 50% of patients die before age 18 from respiratory failure.

The prognosis depends on several factors:

  • Time of diagnosis (neonatal screening)
  • Population of resistant pathogens
  • Lung function
  • Complications (see above)
  • Pregnancy: Women suffering from CF are fertile, in contrast to men. The CFTR allele is passed on from the mother to the fetus. The child is therefore at a 1:50 risk of falling ill with mucoviscidosis.
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