Helping to Fight Infant Respiratory Disease

In the early 1960s, 50,000 babies a year died because they were born without a chemical substance necessary for proper lung function. Today, thanks to one Harvard researcher, such infants' chances for survival have more than doubled.

Mary Ellen Avery, Rotch professor of pediatrics at Harvard Medical School, was awarded a National Medal of Science in September for her work with pulmonary surfactant, the chemical substance lining the air spaces in the lungs and preventing their collapse.

The medal, presented by President Bush, is considered the most prestigious science award in the country.

During her career, Avery has worked to understand and come up with treatments for infants with respiratory ailments.

The neonatologist's first paper on the subject, co-written by Harvard colleague Jere Mead '43, was published in 1959. In the paper, the authors studied the surface tension of lung extracts prepared from babies with hyaline membrane disease, which causes respiratory distress syndrome (RDS) and often leads to death.

The researchers found that the surface tension of these extracts was consistently higher than that of extracts prepared from infants without the disease.

Avery and Mead concluded that something which regulates surface tension in the lung must be absent in those babies with hyaline membrane disease. If unregulated, surface tension causes alveoli--the air-carrying sacs of lungs--to collapse, followed by the collapse of the lungs.

At this point, scientists began investigating the differences in the infants' lungs, and specifically what in their composition might be affecting surface tension, says Avery.

This interest was sparked, she says, by the high death rate of premature infants with RDS.

"The first breath is the most difficult breath you ever take," she says. The differences in air pressure between the atmosphere and the newly born infant's lung, which is airless, create this difficulty. In infants with RDS, breathing is even harder.

Normally, says Avery, the lung contains a constant residue of oxygen, even on exhaling. But in infants with RDS, the lung does not contain this residue, and breathing remains difficult.

With further study, Avery discovered that these premature infants did not have normal amounts of the chemical surfactant. By 1980, the genetic process involved in producing the substance as well as the cell production sites in the lung had been isolated.

These findings, as well as work that Avery performed showing that administration of surfactant in the lamb fetus accelerated lung growth, set the stage for clinical trails of the substance.

Tetsoro Fujiwara, a Japanese researcher, began surfactant replacement therapy in infants, the results of which were reported in 1980. Fujiwara was able to achieve success in this therapy through the use of calf-lung surfactant administered as a liquid into the trachea.

Clinical trials sponsored by the National Institutes of Health, as well as two U.S. drug companies, Ross Laboratories and Burroughs Wellcome, have resulted in two Food and Drug Administration approved surfactants as of this fall.

Avery says that thanks to this new therapy, the U.S. infant mortality rate has been cut by 50 percent, and RDS is no longer the leading cause of death in premature infants.

Current Treatments

Currently, two methods of treatment are in use. In surfactant replacement therapy, surfactant is administered to the infant's lungs and then stimulates the lungs to produce their own.

Surfactant production can also be stimulated by the delivery of glucocorticoid, a steroid, to pregnant women. The fetus secretes surfactant into the amniotic fluid, which can then be tested by doctors in amniocentesis to determine whether or not the newborn will have RDS.

Part of the success of surfactant therapy has been the efficiency of liquid administration, says Avery. With infusion down the trachea, 20 times the amount of the substance reaches the lungs as compared with aerosol treatment, which was previously the standard method of administration of pulmonary drugs.

This may open doors for treatment of other diseases, says the neonatologist.

"We may be able to use surfactant to distribute other drugs into the lungs," she says. Such applications could be used for adults as well as infants.

Because of its inherent low surface tension, surfactant can move easily through the lung, distributing very evenly, Avery says.

In a paper published this year, Avery and other researchers found that surfactant is an effective vehicle for delivery of drugs into the lungs of hamsters. One of the drugs tested, pentamidine, may be of use in combatting a form of pneumonia which often proves deadly to AIDS patients.

Surfactant and Diabetes

In the past, says Avery, high numbers of mothers with poorly controlled diabetes resulting in stillborn infants caused many obstetricians to utilize Caeserian sections in delivery.

What happened, however, was that many of these infants were born with immature lungs that did not produce enough surfactant. By performing autopsies on a large number of stillborn infants as well as those who died of RDS after delivery, Avery found that the lack of surfactant was due to the high blood glucose of these infants.

Because of this high level of glucose passed through the placenta by the mother, a large amount of insulin will be produced by the non-diabetic fetus.

Insulin opposes the action of enzymes necessary to make surfactant, says Avery, and thus leads to immature lung formation.

With induction of the steroid glucocorticoid into the mother and surfactant replacement therapy, many stillborns are now avoided, she says.

Colleagues Praise Avery

Researchers and Avery's colleagues say that she has pioneered some of the most important work in her field.

"She's a fantastic woman who's accomplished a great deal," says Joseph D. Brain, Drinker professor of environmental physiology at the Harvard School of Public Health. "She's a really spectacular scientist, and a great role model."

Brian says that Avery has pioneered good medical management of premature babies in addition to her other work.

"She's really helped usher in the age of the neonatal intensive care unit," he says. "She and others have seen the number of infant deaths fall."

H. William Taeusch, a researcher who worked with Avery for more than 20 years, says that Avery's research with surfactant has influenced neonatal care around the globe.

"Most premature babies around the world are now treated with surfactant," he says. In addition, she has trained people in neonatal units all over the world, he says.

"She is a world leader in pediatrics," says Taeusch. "I was lucky to work with her."