Internal Medicine Pulmonology

Cystic Fibrosis

Cystic Fibrosis (CF)

Introduction – Cystic Fibrosis

Cystic fibrosis (CF) is one of the most common genetic diseases in the Caucasian population. Incidence varies within different continents of the world. The highest incidence, about 1: 2,500, is seen in the Anglo-Saxon population. The disease is passed down in an autosomal recessive manner.

The mutation 

  • The CF mutation was discovered in 1989 and localized to a gene on the long arm of chromosome 7. The gene encodes a chloride channel and is named cystic fibrosis transmembrane regulator (CFTR).
     
  • Currently, there are more than 2000 known different mutations that can cause CF. Only a few of them occur at a higher frequency than 1%.
     
  • The most common mutation is called delta F508.
     
  • Depending on where the mutation is located on the gene and what it means for the expression of the gene product, the result may be different:

    – No expression of mRNA or CFTR (class I)
    – Defective configuration of the protein (class II)
    – Defective function of the protein (class III)
    – Impaired function of the protein (class IV)
    – Fewer CFTRs are expressed on the apical membrane (class V)
     
  • The type of mutation determines whether the patient has a residual pancreatic function (type IV and V). These are called mild mutations (about 15% of patients have such a mutation, see below).

Causes

The function of the chloride channel CFTR is primarily to transport chloride ions, but also bicarbonate and ATP, across the cell membrane. CFTR is expressed in: 

  • Epithelial cells in both upper and lower airways
  • Submucous glands in the lungs
  • Sweat glands
  • Pancreas
  • Liver
  • Vas deferens
  • Cervix

It is believed that the non-functioning chloride channel at CF contributes to a thicker secretion or mucus that affects the organ in question, for example, through blockage of the output ducts (pancreas).

There is substantial evidence that CFTR lowers the height of the fluid layer in the lungs surrounding the airway cilia (airway surface liquid – ASL). It is believed that this affects the movement of the cilia and thus their ability to transport mucus. The risk of chronic and recurring lung infections then increases.

In addition, it appears that both the adaptive and innate immune systems are affected in different ways by CF with an up-regulation of the inflammatory response. The chronic infection/inflammation gradually destroys the lung parenchyma. Respiratory insufficiency is the most common cause of death in CF (95%).

CFTR is expressed in the pancreatic drainage ducts, causing a worse outflow of pancreatic juice and sodium bicarbonate, as well as progressive destruction of the pancreas. In many cases, the pancreatic function is severely impaired as early as in the neonatal period, while in other patients it decreases during the first year of life.

About 10-15% of patients have a “mild” or atypical CF defined by some residual function of the pancreas (class IV or V mutation). They later suffer from lung infections and are often diagnosed only in adolescence or adulthood, and they do not get pancreatic insufficiency leading to poor weight gain. The prognosis for this group is better.


Symptoms – Cystic Fibrosis

Common new onset of disease symptoms are: 

  • Meconium ileus during the first 24 hours of life (10-15%)
  • Diarrhea or large, loose, smelly stools
  • Poor weight gain
  • Rectal prolapse
  • Hepatic effects
  • Recurring or chronic respiratory tract infections
  • Chronic cough
  • Recurring otitis or sinusitis
  • Nasal polyps
  • Bronchiectasis
  • Pancreatitis (possibly recurring)
  • Azoospermia in adults

For one or more of the above symptoms, CF should be ruled out. It is important to remember that patients with CF may be undiagnosed and that everyone does not have lung symptoms or poor weight development.


Diagnosis

For diagnosis, two sweat tests are required which are pathological and/or detection of two known mutations, as well as symptoms of CF. When CF suspicion exists, it is advisable to start with a sweat test. If this is in the “gray zone” (40-60 mmol chloride/l) it should be redone. Alternatively, the patient is referred to (or discussed with) a CF center. If the sweat test is positive ( >60 mmol chloride/l), the patient should always be referred directly to a CF center to have the diagnosis confirmed.

If loose stools or poor weight development is present, it is good to supplement the diagnostics with feces elastase. A normal fecal elastase does not exclude CF but indicates that the patient probably does not have pancreatic insufficiency.

Diagnostic criteria 

  • One or more typical symptoms, or family history (eg siblings)

    plus
     
  • Pathological sweat test as a sign that CFTR is not functioning properly

    or
     
  • Two known mutations in genotyping

The median age at diagnosis is 10 months. In many countries in Europe, Australia and the US, there is now neonatal screening for CF, and the diagnosis can then be made already at 1-2 months of age, usually before the onset of symptoms and established lung injury.

Despite screening, some patients will be missed, especially those with a milder illness, so there must be knowledge that the disease may still be relevant as a differential diagnosis in pediatric clinics, health centers, and lung clinics. In addition, there will be patients born before the introduction of the screening who have not yet received a CF diagnosis.


Treatment – Cystic Fibrosis

The majority of patients are checked at regional CF centers every 4-6 weeks. At each center, there are physicians (pediatricians and pulmonologists), physiotherapists, nurses, dietitians, and psychologists.

The others are checked at their local hospital, where attempts are made to concentrate the admissions to 1-2 doctors as the management of CF patients requires a lot of experience. It is important that the physiotherapist and nurse also have CF experience. All patients should be checked at a CF center at least annually (more often if needed). 

  • Meconium ileus is treated with enema and/or surgery.
     
  • Pancreatic insufficiency mainly causes malabsorption of fat and fat-soluble vitamins (A, D, E, and K). The treatment consists of substitution with pancreatic enzymes for every meal that contains fat, as well as daily intake of fat-soluble vitamins. The goal is to enrich the food with fat up to about 40% to increase energy intake.

    The goal of the treatment is for the patient to have normal weight development and normal levels of fat-soluble vitamins. Treatment is monitored by following weight development, stool consistency and frequency, and the levels of fat-soluble vitamins in the blood.
     
  • Good nutrition is a prerequisite for a good immune system and is, therefore, a very important part of the basic treatment for CF.
     
  • In the case of severely impaired lung function, the energy demand is significantly increased due to increased breathing work, while the appetite is reduced. Percutaneous gastrostomy can therefore often be necessary.
     
  • The pulmonary treatment consists of inhalation of expectorant and bronchodilator drugs, usually twice a day, and then breathing gymnastics to mobilize mucus from the lung. The treatment is performed by the patient in the home, is time-consuming (1-2 hours) and varies with age, lung function and the type of infection the patient has. Physical activity or exercise that involves increased breathing frequency and deeper breathing is an important part of the treatment and the patient is therefore stimulated from childhood to be as physically active as possible.

Antibiotics

Oral antibiotics are given in virus-triggered upper respiratory tract infections to counteract secondary bacterial infections. Children are often infected with Staphylococcus aureus or Hemophilus influenza. A little further up the age spectrum, gram-negative bacteria such as Pseudomonas aeruginosaStenotrophomonas maltophilia and Burkholderia cepacia become more common.

The goal is to keep the lungs free from chronic infection. Modern lung treatment is therefore aimed at finding and eradicating the bacteria that cause infection early. Patients then often become free from chronic colonization well into old age, sometimes up to adulthood. The most common bacteria that cause chronic infection are S. aureus and P. aeruginosa.

Antibiotic treatment can be given orally, as inhalation or intravenously, depending on the type of bacteria and disease severity. Intravenous antibiotic therapy is now usually self administered by the patient or parents at home with the help of pre-filled infusion pumps (Homepump or Intermate).

Despite, or perhaps because of, more effective treatments, new pathogens that are more difficult to treat have begun to emerge. The most feared of these is Mycobacterium abscessus. Also, fungal infections have become more common, as well as allergic aspergillosis.


Complications – Cystic Fibrosis

  • Liver – Despite early treatment with ursodeoxycholic acid (Ursofalk), which makes the bile less viscid, some patients with CF develop severe biliary cirrhosis. This may result in the patient having to undergo liver transplantation in the late teens or young adulthood.
     
  • Diabetes mellitus – At age 30, about 25% of CF patients have developed insulin-requiring diabetes mellitus. The causes are considered to be decreased insulin production due to injured pancreas, as well as an increased need for insulin and a decreased insulin sensitivity due to chronic infection/inflammation. However, insulin deficiency is not complete – patients (as opposed to type 1 diabetics) do not develop ketoacidosis.
     
  • Ears, Nose and Throat – Many patients develop chronic sinusitis and recurrent nasal polyps, which can require surgical interventions. Sinus maxillaris is often filled with secretions and sinus frontalis/sphenoidalis is usually underdeveloped. Surgery (FESS) is required in many patients.
     
  • Impaired Fertility – In principle, all men with CF have impaired fertility because the ductus deferens does not have an open lumen. However, sperm production in the testicle is normal. Most men with CF who wish to become fathers can now do so with the help of IVF technology. Many women with CF can become pregnant naturally, but some may need help through fertility clinics due to thick cervical secretions.
     
  • Osteopenia and osteoporosis – Many adults with CF have a reduced bone density and an increased risk of spontaneous fractures. The cause is considered multifactorial; chronic inflammation that inhibits bone formation and stimulates degradation, cortisone therapy, low physical activity levels, and possibly deficiency of vitamin D. With effective treatment, all of these factors can be mitigated.

Prognosis – Cystic Fibrosis

Over the past 20-30 years, the life expectancy of CF patients has increased significantly. Few became adults in the 1960s and in 1986 the average life expectancy for CF patients was 26 years. The reason for the improvement is considered to be: 

  • Care has been condensed to CF centers
  • The infections are treated earlier and more effectively with new types of antibiotics
  • Nutrition is better with new “enteric-coated” pancreatic enzymes that allow the fat in the food to be absorbed more efficiently. The food can then be enriched with fat which increases the energy density of the food.
  • Physiotherapy has been developed

Future development 

  • Inhalation gene therapy. A study has been completed (2014) which was partially successful but the result showed that new more efficient carriers of the healthy gene are needed. This development is ongoing.
     
  • Several new drugs that are mutation-specific and that affect the expression of CFTR, the transport of CFTR out to the cell membrane, or activate other chloride channels in the cell membrane are currently being tested in clinical trials. Two drugs are now approved in the US and Europe, partly ivacaftor (Kalydeco) which can be prescribed to patients carrying the G551D mutation and 7 other rare gating-mutations as well as lumacaftor/ivacaftor (Orkambi) which is a combination drug for patients homozygous for dF508 and over 6 years of age. Additional drugs are currently undergoing phase III testing, which also includes patients with only a dF508 mutation, which would increase the proportion of treatable individuals up to 85% of the CF population.
     
  • Work on developing new antibiotics, as well as improving methods for inhalation of antibiotics, is ongoing.
     
  • Various types of drugs that can reduce the degree of inflammation of the lung are also under development.
     
  • When more mutation-specific drugs are approved and used, one can expect further increase in median survival while fewer patients will need lung transplantations at a young age.

Further Reading