Lupus flare or infection? This is the question that puzzles physicians like Meggan Mackay, M.D., M.S., of the Feinstein Institute for Medical Research, when their patients present symptoms that could be attributed to either an infection or a lupus flare.
Being a physician and a researcher, Dr. Mackay knows that shortening the time it takes doctors to accurately diagnose what's going on with their patients is critical. The longer it takes to begin appropriate therapies, the more damage is done to healthy tissue.
This is why differentiating between infection and lupus activity (also known as flares) is the aim of her research, which began with an Alliance for Lupus Research (ALR) pilot research grant in 2008.
Before delving into the specifics of her investigation, Dr. Mackay offered some insights into lupus itself. "Lupus is an illness that is caused by an over-active immune system. When most people think of the immune system, it is in regard to its primary function to ward off infection, which it does. It also fights other diseases and acts as a constant surveillance system for viruses, bacteria and cancer cells that shouldn't be there," she explained.
In lupus there are a lot of abnormal immune cells, so the immune system does not work as it should. "It's over-reactive to self, both attacking the body and not providing the normal level of immune surveillance to protect against infection," said Dr. Mackay.
For this reason, lupus patients are particularly susceptible to infections, such as "encapsulated" organisms like streptococcus. "Patients come in with a fever, which turns out to be due to a strep infection. Then we may find they actually have lupus," Dr. Mackay said.
Complicating matters is the fact that the medications used to treat lupus also make patients more susceptible to infections.
Lupus patients are most commonly treated with steroids because they are the fastest working, most powerful anti-inflammatory medications currently available. "Within hours, steroids can shut down the production of pro-inflammatory proteins that cause lupus flares," said Dr. Mackay. "But steroids also shut down proteins that protect the body against infection."
"It has taken time but our study did find definite differences between lupus patients who flared and lupus patients who were infected."
Dr. Meggan Mackay
Unfortunately, for lupus patients, steroids aren't the only culprits. Many of the medications used in lupus are immunosuppressive — especially those used to treat serious lupus activity that affects major organs, including the kidney, brain, cardiovascular system, and lungs. These medications also decrease the immune response, making patients much more likely to get infections.
When confronted with a lupus patient who feels ill and has a fever it is usually very difficult to distinguish between lupus flare and infection since both often have similar symptoms. Dr. Mackay explains that "We frequently need to treat for both lupus flare and infection, even when treating lupus may make it more difficult for an infection to respond to antibiotics and may increase the risk of additional infections, but we have to take that risk." It's all a matter of timing, because it can take days for culture results to determine if a patient is infected or for blood tests that may suggest a lupus flare — and during that time, untreated lupus and/or infection can wreak havoc on healthy tissue.
The ALR funding she received allowed Dr. Mackay to write a protocol that looks for a way to differentiate between lupus flare and infection. With the help of a geneticist — Peter K. Gregersen, M.D., also from the Feinstein Institute, — Dr. Mackay set out to see what kinds of genes were being expressed in the blood of lupus patients who are sick and have a fever to identify differences in those who had infections and those who had flares. "It has taken time but our study did find definite differences in gene expression between lupus patients who flared and lupus patients who were infected," said Dr. Mackay.
Today Dr. Mackay is looking to replicate this work in a much larger group. The idea would be to develop a test that could be done at the bedside to differentiate between infection and lupus flare. "Knowing means we could tailor the treatment faster, reducing the risk of complications and death," she said.
Dr. Mackay is enthusiastic about the ALR: "The organization is vital to lupus research. Without this kind of support for pilot projects, many investigations would never get off the ground. To young scientists coming up in the field, that's really important. And the ALR is also essential to established investigators who may be looking to study a novel or unconventional line of inquiry."
Dr. Mackay had no personal connection to lupus, but while she was Chief Resident at Jacobi Medical Center and working in the Intensive Care Unit, she met two patients who changed the course of her career. The women were very ill and very young. Both were in their early 20s and both died from lupus complications within 24 hours of being admitted into the ICU.
Until that point, Dr. Mackay had focused on internal medicine — but these patients helped guide her to a rheumatology fellowship under the tutelage of the renowned Dr. Betty Diamond, who leads the Center for Autoimmune and Musculoskeletal Disease at the Feinstein Institute. "I've always been drawn to lupus patients," Dr. Mackay said. "They are often women, young women, and they are deeply affected by this disease. We still do not understand what causes lupus and there is a great need for better treatments. This is why I went into clinical research."
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