CYSTIC FIBROSIS

Cystic fibrosis (CF) is the number-one life-shortening inherited disease of young people. It is a genetic disorder that particularly affects the lungs and digestive system, and it makes a child more vulnerable to repeated lung infections.

Now, thanks to high-tech medical advances in drug therapy and genetics, children born with CF can look forward to longer and more comfortable lives. In the last ten years, research into all aspects of CF has helped us to understand the illness better and to develop new therapies. In the future, more research may help us find a cure.

Cystic fibrosis makes children sick by disrupting the normal function of epithelial cells - cells that make up the sweat glands in the skin and that also line passageways inside the lungs, liver, pancreas, and digestive and reproductive systems. In CF, the inherited CF gene directs the body's epithelial cells to produce a defective form of a protein called CFTR. When the CFTR protein is defective, epithelial cells can't regulate the way chloride (part of the salt called "sodium chloride") passes across cell membranes. This disrupts the essential balance of salt and water that is needed to maintain a normal thin coating of fluid and mucus inside the lungs, pancreas, and passageways in other organs. The mucus becomes thick, sticky, and hard to move.

Normally, mucus in the lungs traps germs, which are then cleared out of the lungs. But in CF, the thick, sticky mucus and the germs it has trapped remain in the lungs, and the lungs become infected.

In the pancreas, thick mucus blocks the channels that would normally carry important enzymes to the intestines to digest foods. When this happens, the child's body can't process or absorb nutrients properly, especially fats. The child has problems gaining weight, even with a normal diet and a good appetite.

A family's risk for CF

Of all ethnic groups, Caucasians have the highest inherited risk for CF, and Asian Americans have the lowest. In the U.S. today, about one of every 3,000 Caucasian children is born with CF. This compares with one of every 17,000 African Americans and only one of every 90,000 Asian Americans. Although the chances of inherited risk may vary, CF has been described in every geographic area of the world among every ethnic population.

It takes two copies of a CF gene, one inherited from each parent, for a child to show symptoms of CF. Persons born with only one CF gene (inherited from only one parent) and one normal gene are CF carriers. CF carriers do not show CF symptoms themselves, but can pass the problem CF gene to their children. Scientists estimate that about 12 million Americans are currently CF carriers. If two CF carriers have a child, there is a one in four chance that the child will have CF.

The CF gene is found on chromosome number 7 (humans have 23 pairs of chromosomes made of the inherited genetic chemical called "DNA"). Right now, scientists have identified at least 600 different mutations in the CF gene that are capable of causing symptoms of CF. Some mutations cause milder symptoms than others. The most common mutation, called the Delta F508, causes about 90% of cases of CF and can be detected by genetic testing. This testing can be done in children, both before and after birth, and in adults who are thinking about starting or enlarging their family.

How CF affects children

The diagnosis of CF is usually made before an affected child is three years old. However, about 15% of those with CF are diagnosed later in life (even adulthood). Symptoms usually center around the lungs and digestive organs, and can be more or less severe.

A few children with CF begin having symptoms at birth. Some are born with a condition called "meconium ileus." While all newborns have meconium, the thick, dark, putty-like substance that usually passes in the first few days of a baby's life, in CF the meconium can be too thick and sticky to pass and can completely block the intestines. More commonly, though, babies born with CF do not gain weight as expected. They fail to thrive in spite of a normal diet and a good appetite. In these children, mucus blocks the passageways of the pancreas and prevents pancreatic digestive juices from entering the child's intestines. Without these digestive juices, the intestines cannot absorb fats and proteins completely, so nutrients pass out of the body unused rather than helping the child's body grow. Poor fat absorption makes the child's stools appear oily and bulky and increases his risk for deficiencies of the fat-soluble vitamins (vitamins A, D, E, and K). Unabsorbed fats may also cause excessive intestinal "gas," an abnormally swollen belly, and abdominal pain or discomfort.

Since CF also affects epithelial cells in the skin's sweat glands, children with CF may have a salty "frosting" on their skin or taste "salty" when their parents kiss them. They may also lose abnormally large amounts of body salt when they sweat on hot days.

Because CF produces thick mucus within the respiratory tract, a child with CF may suffer from nasal congestion, sinus problems, wheezing, and asthma-like symptoms. As CF symptoms progress, the child may develop a chronic cough that produces globs of thick, heavy, discolored mucus. They may also suffer from repeated lung infections like pneumonia and bronchiolitis.

As chronic infections reduce lung function, the person's ability to breathe often decreases. A person with CF may eventually begin to feel short of breath, even at rest. Despite aggressive medical therapy, lung disease develops in nearly all patients with CF and is a common cause of disability and shortened life span.

Identifying children with CF

By performing genetic tests during pregnancy, parents can now learn whether or not their unborn child will have CF. But even when genetic tests confirm CF, there is still no way to predict beforehand whether a specific child's CF symptoms will be severe or mild. Genetic testing can also be done on a child after birth, and can be performed on parents, siblings, and other relatives who are considering having a family.

After birth, the standard diagnostic test for CF is called the sweat test. It measures the amount of chloride in sweat that has been carefully collected from a child's forearm. Generally two sweat tests are performed in order to diagnose CF.

Several other tests serve as standard parts of the routine care used to monitor a child's CF. These tests include chest x-rays; blood tests to evaluate nutritional status; pulmonary function tests to measure the effects of CF on a child's breathing; and bacterial studies that confirm the growth of PSEUDOMONAS AERUGINOSA or STAPHYLOCOCCUS AUREUS bacteria in a child's lungs. (These bacteria are common in CF but do not affect healthy people exposed to CF.)

Treating a child with CF

When a child is first diagnosed with CF, depending on his condition, he may need to spend some time in the hospital. There he will have diagnostic tests, especially baseline measurements of his breathing (lung function), and a nutritional assessment. Before he leaves, his doctor will make sure that his lungs are clear, and that he has started a diet with digestive enzymes and vitamins that will help him to gain weight normally. Afterwards, he will probably see his doctor for follow-up visits at least once every three months.

The basic daily care program of a child with CF varies from child to child, but usually includes pulmonary therapy (treatments to improve lung function) and nutritional therapy (modified diet with vitamin and mineral supplements). Children with CF can also take doses of pancreatic enzymes by mouth to help them digest foods better. They may occasionally need oral or inhaled antibiotics to treat lung infections, and mucolytic medication (a mucus-thinning drug) to keep mucus fluid and flowing.

One of the newest treatments for CF that is still being researched is an inhaled spray containing normal copies of the CF gene. These normal genes, spliced into vectors, deliver the correct copy of the CF gene into the lungs of CF patients. Since 1993, more than 100 CF patients have been treated with CF gene therapy, and test trials are underway in at least nine different medical centers throughout the country and other centers around the world.

Another new therapy, called protein repair therapy, aims at repairing the defective CFTR protein. At least four different medicines - phenylbutyrate, milrinone, genistein, and a drug called CPX - are currently being tested.

CFTR

CFTR stands for Cystic Fibrosis Transmembrane Conductance Regulator, a protein found in cells that line the lungs, digestive tract, sweat glands, and genitourinary system.

CF gene

The CF gene is found on the "long arm" of chromosome number 7. There are at least 600 different forms of this gene that can lead to cystic fibrosis. Although scientists do not know exactly why the CF gene evolved in humans, they have some evidence to show that it helped to protect earlier generations from the bacteria that cause cholera, a severe intestinal infection.

Sweat test

The sweat test is an accurate, safe, and painless way to diagnose CF. In the sweat test, a small electric current is used to carry the chemical pilocarpine into the skin of the forearm. This stimulates sweat glands in the area to produce sweat. Over a period of 30 to 60 minutes, sweat is collected on filter paper (or gauze) and tested for chloride. A chloride reading of more than 60 mEq/L points to CF.

Pulmonary function tests

Pulmonary function tests (PFTs) are breathing tests that help measure lung reserve and degree of airflow obstruction. PFTs are done as soon as the child is old enough to be able to cooperate in the testing procedure. Infant PFTs are currently being studied.

Vectors

Right now, adenoviruses are being used as vectors to carry CF repair genes. An alternate virus, the adeno-associated virus, also is being tested. Another method, using fatty capsules called liposomes, doesn't use viruses at all and may be more acceptable to those who have concerns about inhaling adenoviruses.