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Discovery Science
AIDS and Its Pulmonary Threat — A Mystery Solved
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Since the 1980s, pneumocystis pneumonia, or PCP, has infected thousands of HIV/AIDS patients. For nearly three decades, Mayo Clinic internist Andrew Limper, M.D., has researched the mystifying and often fatal lung infection. Along the way, he has developed better treatments for patients and saved lives, all in his pursuit of developing a vaccine to cure the infection.
It starts with breathing difficulties, fever and a dry cough. Left unchecked, infection will spread, leading to an increase of damaged lung tissue and death. In the mid-1980s, doctors across the country were mystified as a rapid-onset lung infection caused respiratory failure and death in AIDS patients. The culprit was pneumocystis pneumonia, or PCP, and up until then it had been considered rare.
Andrew Limper, M.D., then a resident at Mayo Clinic in Rochester, Minn., had a keen interest in lung diseases at an opportune time. “There were a number of patients in the hospital who at that time had HIV/AIDS. I saw a number of those cases,” recalls Dr. Limper, who was fresh out of medical school at the University of Illinois College of Medicine at Peoria. “I got very interested.”
AIDS set off wake-up calls and launched new research. The identity of the organism that caused PCP was misunderstood: Long considered a consequence of a parasite, PCP was identified in 1988 as a fungus. In the late 1980s, the Centers for Disease Control and Prevention acknowledged PCP as the AIDS-defining moment of the human immunodeficiency virus (HIV) that underlies the disease.
Exploring PCP infections
Today, Dr. Limper, an internist, is the Walter and Leonore Annenberg Professor of Pulmonary Medicine at Mayo Clinic. He heads the lab on Lung Defense, Infection and Fibrosis. It’s his research on PCP, however, that has put him on the world’s stage. He travels to conferences to talk about the cause of the infection and to stress the urgency of early diagnosis. In 2011, he was first author on a statement issued by the American Thoracic Society on the diagnosis and treatment of fungal infections.
Dr. Limper and colleagues have been exploring PCP infections, particularly how they grow and cause damage in the lungs, in pursuit of new and safer drug treatments that neutralize the fungus without harming the host. Most of the research is being done in animals, with correlative studies in samples of PCP-infected human lung tissues. His team, he says, is perhaps three to five years away from taking an experimental vaccine into clinical trials.
The most-often used drug therapy is an antibiotic combination of trimethoprim and sulfamethoxazole, which both eliminate bacteria that cause various infections. However, less-effective antibiotics are often substituted because of high rates of allergic reactions in AIDS patients to the sulfa-based sulfamethoxazole. Patients with moderate to severe PCP likely will be given a corticosteroid in conjunction with the trimethoprim-sulfamethoxazole combination.
“PCP once was the major cause of death for people with HIV/AIDS. But now, it’s possible to prevent or treat most cases,” says Dr. Limper, a co-inventor of a rapid-use assay to diagnose the infection. “The key to surviving PCP is early treatment. It’s a pretty darned serious infection. Between 20 percent and 50 percent of people who get this infection die from it.”
Still a concern
Unfortunately, the treatment for PCP infection is not widespread among all sectors of the health care community, resulting in patients arriving at Mayo Clinic with the infection.
“We are very aware of this infection in our practices at Mayo Clinic,” Dr. Limper says. “But we oftentimes have patients referred to us from the outside who have cancer and are in chemotherapy or have had transplants and other types of problems. As they come to us they are developing this infection because they have not been placed on a prophylaxis. It’s easier to take a pill every day to avoid this infection than ending up in one of our ICUs.”
While AIDS/HIV triggered intensive research on PCP in the 1980s, it had slowly made its presence known in patients with compromised immune systems such as organ transplant patients and cancer patients undergoing chemotherapy. In AIDS patients, the infection can smolder for weeks before they become seriously ill. Cancer and transplant patients, however, experience it rapidly.
“When a patient is immunosuppressed, the lungs are likely targets for infections to occur,” he says. “The reason for that is we’re all breathing multiple times a day. If you take the lung and flatten it out, it’s a big surface area. It’s about the size of a racquetball court, about 40 feet by 20 feet. There is a lot of air coming in and going. If there are infectious agents in the air, they get in there.”
From protozoan parasite to ascomycetous fungi
PCP has probably been around for thousands of years, Dr. Limper says. Little was known about it until 1909, when Brazilian scientist Carlos Chagas isolated it in the lungs of guinea pigs being used to study sleeping sickness. Soon after, it was found in a rat colony being used for research. Dutch physicians saw it in humans in World War II. After the war, malnourished children across Europe fell victim to it.
The cause was long thought to be a protozoan parasite of the blood or a form of yeast. Finally, in 1988, a team led by Jeffrey C. Edman, M.D., at the University of California, San Francisco sequenced a small section of its RNA and classified the species as ascomycetous fungi, which produce sexual spores in sacs, as is the case in yeast.
“Scientists still don’t know what the natural reservoir is, but we know it’s probably present in the air,” Dr. Limper says. “There has been evidence that it occurs out in nature. It has been found in apple orchards and in soil. But it is believed that the fungus can only grow inside of a living mammalian host, like a human. We believe it survives because it infects all of us when we are small children and we can clear it. But if you have an immune failure you can get an infection.”
Seeking a treatment
Chances are, he says, more than 90 percent of young children are probably exposed to the fungus while playing outdoors. It perhaps triggers a brief bout of coughing and sneezing, and then goes dormant, awaiting an opportunity to emerge.
“It’s really a unique infection,” Dr. Limper says. “It’s an organism that has learned to co-exist for a long time because it infects people with normal immune systems when we are kids but it doesn’t kill us. That is probably a good survival tactic for a parasite or a fungus, but in the last couple of decades with the large number of immunosuppressed patients it has become a big problem.”
Through Dr. Limper’s efforts, scientists know a lot about the life cycle of the fungus, says Eva M. Carmona Porquera, M.D., Ph.D., his colleague of Mayo Clinic’s Department of Pulmonary and Critical Care Medicine. “His laboratory has identified and characterized many life-cycle and cell wall genes of the pneumocystis organism,” she says. “Prior to these studies, little information on pneumocystis life-cycle biology was known due to the inability to culture the organism.”
“We cannot culture the pneumocystis that comes out of human lungs,” Dr. Limper adds. “That’s one of the reasons that research has been slow. We’ve learned that we can grow pneumocystis in rats and mice. That allows us to do a lot of testing in animals much more rapidly than we could do it in humans. But we cannot do it in the culture dish.”
His lab’s research has focused on two key questions: Why and how do people die from PCP, and what can be done to prevent death? The latter, he stressed, must begin with early diagnosis.
“You have to give an anti-fungal drug to try to get rid of the fungus,” Dr. Limper says. “However, if you want to keep people off a ventilator and prevent death, we also have to suppress the inflammation. That means we have to further immunosuppress patients with medications like prednisone or other corticosteroids, and that actually reduces that inflammation that leads to lung injury and death.
“What we’ve discovered is that when you are immunosuppressed, you don’t have the normal level of white cells that can actually kill the fungus. So instead, your innate immune system kicks in,” he says. “That makes a lot of inflammation in a non-specific way to try to get rid of the fungus, but the inflammation actually destroys lung function.”
Newer treatment options
Newer treatment options, including his team’s work on a potential vaccine, have emerged from using molecular techniques employed in rodents to study the cell biology of the fungus. Dr. Limper’s team has focused on the cell wall, or plasma membrane, of the trophic form and the much larger cyst form of pneumocystis. The latter, Dr. Limper has found, consists mostly of sugary proteins known as beta glucans that are responsible for the stiffness of the cell wall during the organism’s life cycle.
Dr. Limper and colleagues were the first to identify the gene responsible for the synthesis of beta glucans — a discovery that points to potential targets to disrupt the fungal growth and spread of infection in the lungs. The beta glucans, he says, are also strong stimulants for inflammation.
Dr. Limper’s efforts are being watched closely by cancer researchers, says Edward B. Leof, Ph.D., Mayo Clinic’s Erivan K. Haub Family Professor of Cancer Research. “Dr. Limper is addressing both fundamental as well as translational questions in two distinct areas: host-pathogen interactions and responses during PCP infection, and also in lung fibrosis,” he says.
And it all started almost thirty years ago when William J. “Bill” Martin, II, M.D., who led a National Institutes of Health-funded pulmonary research laboratory at Mayo Clinic, took notice of his resident’s curiosity. “He suggested that I come into the lab and try to figure out what pneumocystis does,” Dr. Limper says. “I started in 1987, and it has become a lifelong interest and passion.”
— Jim Barlow
November 2015
