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New Treatments for Cystic Fibrosis

Cystic fibrosis is a genetic disorder. It’s an autosomal recessive. It’s characterized by a triad of symptoms; chronic lung disease, intestinal malabsorption, and elevated sweat chloride. These kids can also have liver disease. It’s interesting that clinically most kids with CF either have bad lung disease or have bad liver disease. Most don’t have both, although obviously if you see enough CF patients it is possible to see all of those. So basically a chronic lung disease. A pancreatic insufficiency or malabsorption and an elevated sweat chloride.

The gene was discovered in 1989 and by virtue of that we now understand fairly well the pathophysiology of cystic fibrosis. Basically, the genetic mutation, which is on the long arm of chromosome 7 in cystic fibrosis, codes for a protein called the cystic fibrosis transmembrane regulator protein, or CFTR. This is a fairly large protein which is in the wall of cells and we now know that this protein is in fact the chloride channel for exocrine cells. So if we have an exocrine cell here - and of course we have an exocrine cell in the most important physiologic system, the lungs.

In the normal situation chloride is actively transported through the chloride channel, or CFTR, into the so-called sol phase of the mucociliary blanket - that is, the liquid under the mucus phase. This allows this mucus to be thin and relatively easily moved along by the mucociliary blanket. The role of mucus of course is to trap bacteria and other garbage that gets down into the lung and so it moves this out into the large airways where it can be coughed out. When chloride is transported out the chloride channel, water follows it passively. So chloride going out means that water goes out which means that this mucus is hydrated. In cystic fibrosis, the problem is that the chloride channel is abnormal - that is the protein that’s affected - and consequently chloride is not transported out of the cell.

Consequently water does not go out and therefore the mucus - that is the exocrine secretion or product of this cell - is thick, viscid and essentially dehydrated. So that occurs in exocrine cells in the lung, so that is these cells which produce bronchial mucus, produce this thick stuff. It gets stuck. It’s role is still to trap bacteria. It does that well but it does not move along out the lung, so the bacteria stay there causing chronic infection, chronic inflammation and progressive lung damage. Now this same process happens in the pancreas, in the exocrine cells.

So the problem there is that the digestive enzymes can’t leave the cell, don’t get into the tubules which go out eventually to the intestines. Since they stay in the pancreatic cells they eventually auto digest the pancreas and the pancreas gradually gets destroyed in CF over time so that diabetes mellitus, for example, is a late complication that we see in late 20-year-olds, 30-year-olds, 40-year-olds with CF. This same process also occurs in liver cells.

The opposite of this happens in sweat glands. In sweat glands, sweat passes along out here and chloride is ordinarily reabsorbed into the cells. But the same abnormal chloride channel blocks reabsorption of chloride so chloride remains in the sweat.

To kind of review the lungs in cystic fibrosis patients; with functioning chloride channels, the mucus is well hydrated, is relatively fluid, traps bacteria, moves it along, gets it out of the lung. In cystic fibrosis the chloride channel does not transport chloride out, blocks movement of water, consequently the mucus is dried out, dehydrated, viscid, traps bacteria but that bacteria.

Now, let’s talk about diagnosis of cystic fibrosis for a second. The diagnosis should certainly be suspected in infants or children who have pneumonia, especially more than one. Pneumonia is not normal in children. The otherwise healthy child might have one pneumonia. He really shouldn’t have two or more. So any child who has had two or more pneumonias really needs a diagnostic evaluation to see if there is some underlying chronic lung disease as that cause of that. So pneumonia, especially more than one, especially in a Caucasian, one should think cystic fibrosis. Wheezing or chronic asthma, especially if it is unresponsive to therapy. Again, about six months ago we had a child referred to us here from Bakersfield by very good pediatricians who had been treating this child for asthma, but actually very astutely noticed.

I didn’t mention the frequency, by the way. It’s in your handout. In Caucasians CF is unfortunately very common. It’s 1 in about 2,000 Caucasians. It’s 1 in about 10,000 Hispanics, 1 in about 17,000 blacks and 1 in about 90,000 Asians.

Pulmonary disease in cystic fibrosis; again, it’s caused by the thickened mucous secretions, which is the primary abnormality. These prevent mucociliary clearance and trap bacteria in the airways. Chronic infection causes progressive lung damage. In some states that have newborn screening, or in some families in whom there has been a previous child with CF - so once subsequent children are born, we test them as a matter of course - abnormal lung function is already detectable in infancy. Even when you make the diagnosis in an otherwise asymptomatic child. Therefore we institute treatment as soon as the diagnosis is made.

Pulmonary infections in CF; Pseudomonas aeruginosa is the most common cause of lung infection in CF, and we now know that this can occur and does occur even in infancy. Pseudomonas, or actually Burkolderia cepacia is the new name for this, may be associated with a poorer prognosis, primarily because it’s resistant to more antibiotics. Pseudomonas, once present, really is probably never cleared from the lungs of CF patients. So we really use antibiotics in a suppressive sort of fashion. That is, Pseudomonas is always there. When they get sick we treat them with antibiotics to try and reduce the Pseudomonas load. Recent advances include a TOBI.

So treatment for pulmonary disease in CF is to facilitate the removal of thickened, infected mucous secretions. Aerosolized bronchodilators and chest physiotherapy are started as soon as the diagnosis is made. There are a number of ways that one can give chest physiotherapy. They are all, frankly, about equally effective. It doesn’t make much difference which one they do.