FDA Clears First Test for Recent Infection With Toxoplasmosis Parasite

/PRNewswire/ -- On May 18, the U.S. Food and Drug Administration cleared the first test to help determine whether a pregnant woman or a person with swollen lymph nodes testing positive for toxoplasmosis, sometimes known as cat scratch disease, developed the infection within the past four months.

Toxoplasmosis is caused by the parasite Toxoplasma gondii. The infection can cause serious health problems in people with compromised immune systems. Women who become infected just before or during pregnancy may pass the parasite on to their unborn child, resulting in miscarriage, stillbirth, or an abnormally small or large head. Infection can also lead to vision loss, mental disability, seizures or other health problems later in life for the child.

Cats are most often associated with the parasite, but many other species of animals and birds also serve as hosts. The parasite also is found in people worldwide. Common symptoms of toxoplasmosis include swollen lymph nodes and flu-like symptoms.

Toxoplasmosis is considered to be a leading cause of death attributed to foodborne illness, according to the Centers for Disease Control and Prevention. More than 60 million people in the United States may be infected with Toxoplasma gondii. The parasite may be transmitted to people when they eat raw, undercooked or contaminated meat or come in contact with infected cat feces or litter.

The VIDAS TOXO IgG Avidity assay can be used to rule out recent Toxoplasma gondii infection. The test works by detecting how strongly IgG avidity antibodies bind to the Toxoplasma gondii antigens in the assay. IgG avidity antibodies from infections older than four months bind tightly with the antigens, while IgG avidity antibodies from infections acquired in the past four months form weaker bonds.

"Toxoplasmosis can have serious and lasting health consequences for infants that acquire the infection in the womb," said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostic Device Evaluation and Safety in FDA's Center for Devices and Radiological Health. "This test gives doctors an additional tool to determine if women with confirmed cases of toxoplasmosis acquired the infection before or during pregnancy."

The VIDAS TOXO IgG Avidity Assay test is for use in people who have been confirmed with the Toxoplasma gondii infection by using the VIDAS TOXO IgG II test and who are pregnant or have swollen lymph glands. The VIDAS TOXO IgG Avidity Assay test alone should not be used as a basis for clinical decisions.

The performance of the VIDAS TOXO IgG Avidity Assay has not been established for prenatal screening, for immunocompromised patients, or for cases of toxoplasmosis reinfection or relapse, and the FDA has not cleared or approved the VIDAS TOXO IgG Avidity Assay for blood or plasma donor screening.

The VIDAS TOXO IgG Avidity assay is manufactured by bioMerieux Inc. of Hazelwood, Mo.

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Old Drug Holds Promise Against Opportunistic Lung Bug

/PRNewswire/ -- A drug to treat inflammation plays a surprising role reducing the level of infection caused by an opportunistic bug that is deadly for AIDS and cancer patients and others with weakened immune systems.

The drug, sulfasalazine, spurs the body to get rid of the fungal evaders by enhancing the body's ability to chew them up instead of leaving the debris to litter the lungs, where it would continue to provoke an onslaught of harmful inflammation.

Besides opening a new avenue for research on Pneumocystis pneumonia or PCP, caused by the fungus Pneumocystis jirovecii, the work with mice also offers the possibility of manipulating immune cells called macrophages to improve treatment of infections.

The findings by scientists at the University of Rochester Medical Center were published August 19 in the journal PLoS Pathogens.

During a bout with Pneumocystis, the lungs become a battlefield, where the body pits an array of impressive forces against marauding microbes. But even when the body gets the upper hand, the damage is tremendous. Immune cells like neutrophils and macrophages can flood the lungs, literally suffocating the patient. And when the debris from dead microbes fills the lungs, more and more immune cells are called in to clean up the area, making matters worse. It becomes harder and harder to breathe.

"Many people assume that once the microbe is dead, patients usually start to feel better immediately. But with Pneumocystis, patients do not always undergo a rapid clinical improvement following antibiotic treatment. Even though the bug has been killed, the debris that is left in the lungs continues to promote inflammation," said corresponding author Terry Wright, Ph.D., an infectious disease specialist and associate professor of Microbiology and Immunology and of Pediatrics.

Pneumocystis is a common bug that infects nearly everyone at some point; the authors say that more than 80 percent of children have been infected by the age of 2. Most people shake off the infection without consequence, but for people with cancer, AIDS, or other diseases that compromise their immune system, the infection can be deadly. Usually there are few signs that the patient is sick until the infection is well established and the fungus is widespread in the lungs. Among cancer patients, mortality rates as high as 40 percent have been reported.

Since the body's immune response is central to how Pneumocystis kills patients, doctors use two different types of drugs in tandem to treat patients - an antibiotic to kill the bug, and steroids or another type of drug to reduce the consequent inflammation.

Central to the study were mice in which the disease progresses in a manner very similar to AIDS patients. The remarkable strides in AIDS therapy in recent years have come with a down side for many patients, thanks to Pneumocystis: When anti-retroviral therapy kicks in, a patient's immune system often becomes stronger very quickly - and if the fungus is present, the immune system attacks it vigorously, causing a potentially deadly form of pneumonia.

Wright's team looked at the effects in mice of sulfasalazine, an anti-inflammatory drug that has proven useful in treating conditions like Crohn's disease and rheumatoid arthritis. The team found that Pneumocystis-infected mice treated with sulfasalazine developed much less severe disease than untreated mice. The sulfasalazine-treated mice had better lung function, less weight loss, and were generally healthier than untreated animals.

While some of the benefit was due to the drug's anti-inflammatory properties and was expected, the result included a big surprise: The drug also spurs the body to remove the bug more aggressively by boosting the activity of immune cells called macrophages.

"This was unexpected," said first author Jing Wang, Ph.D., research assistant professor in Pediatrics. "Since we reduced the response of the immune system, you would think the mice would get sicker. But instead, the mice treated with sulfasalazine were healthier. At first we thought it was due solely to the anti-inflammatory activity of the compound, but it turns out that sulfasalazine actually results in a reduced fungal burden. The drug helps the body clear the infection.

"We initially thought we had done something wrong, and so we repeated the experiment again and again. Then, when new technology was developed, we were able to document that the body cleared the infection more readily with sulfasalazine," added Wang.

Scientists have long known that the body's immune T cells are central to the body's response to fight off the infection. The Rochester team showed that the body's T cells spur macrophages to attack the fungus - to engulf its particles and chew them up in a process known as phagocytosis.

While scientists have long suspected that role for macrophages, the Rochester team relied on a new technology to gather the first direct evidence of macrophages engulfing fungal particles. The scientists worked closely with Timothy Bushnell, Ph.D., and others at Rochester's Flow Cytometry Resources Core, investigating new ways to use lasers to capture images of molecular events. Bushnell's team ultimately connected the team with scientists at Amnis. Together the group developed a new way to capture macrophage phagocytosis in single cells from mice infected with Pneumocystis. The technology enabled the team to capture more than 40,000 such events, compared to just a handful when using conventional microscopy.

The team showed that as macrophage activity increased, the animals' health improved and levels of fungus decreased. For example, 17 days after infection, mice treated with sulfasalazine had nine times as many macrophages that had engulfed fungal particles compared to mice that had not been treated with the compound.

"This marks a new direction in which to look for new therapies to treat Pneumocystis as well as other inflammatory diseases. Identifying modulators that can increase or decrease the action of our immune system in a precise manner is a growing area of research," said Wright. Recently researchers have come to realize that there are different kinds of macrophages, and Wright noted that the type whose activity is trigged by sulfasalazine does not contribute to inflammation.

In addition to Wang and Wright, other authors include Francis Gigliotti, M.D., professor of Pediatrics and of Microbiology and Immunology, and also chief of Infectious Disease at Golisano Children's Hospital; Samir Bhagwat, Ph.D., research assistant professor of Pediatrics; and Thaddeus George from the Amnis Corp. in Seattle. The work was funded by the National Heart Lung and Blood Institute and the Strong Children's Research Center.

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FDA Approves New Drug to Treat Psoriasis

The U.S. Food and Drug Administration today approved Stelara (ustekinumab), a biologic product for adults who have a moderate to severe form of psoriasis.

Plaque psoriasis is an immune system disorder that results in the rapid overproduction of skin cells. About 6 million people in the United States have plaque psoriasis which is characterized by thickened patches of inflamed, red skin, often covered with silvery scales.

"This approval provides an alternative treatment for people with plaque psoriasis, which can cause significant physical discomfort from pain and itching and result in poor self-image for people who are self-conscious about their appearance," said Julie Beitz, M.D., director, Office of Drug Evaluation III, in the FDA's Center for Drug Evaluation and Research.

Stelara is a monoclonal antibody, a laboratory-produced molecule that mimics the body's own antibodies that are produced as part of the immune system. The biologic treats psoriasis by blocking the action of two proteins which contribute to the overproduction of skin cells and inflammation.

Three studies of 2,266 patients evaluated the biologic's safety and effectiveness.

Since Stelara reduces the immune system's ability to fight infections, the product poses a risk of infection. Serious infections have been reported in patients receiving the product and some of them have lead to hospitalization. These infections were caused by viruses, fungi, or bacteria that have spread throughout the body. There may also be an increased risk of developing cancer.

The FDA is requiring a risk evaluation and mitigation strategy or REMS for Stelara that includes a communication plan targeted to healthcare providers and a medication guide for patients.

Stelara is manufactured by Centocor Ortho Biotech Inc. of Horsham, Pa., a wholly-owned subsidiary of Johnson & Johnson of New Brunswick, N.J.

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Kidney Transplant Survival can be Long-Term for People with HIV

A Johns Hopkins study finds that HIV-positive kidney transplant recipients could have the same one-year survival rates for themselves and their donor organs as those without HIV, provided certain risk factors for transplant failure are recognized and tightly managed.

“Kidney transplantation is a viable and necessary option for HIV-positive patients with chronic kidney disease, especially since kidney disease is taking such a large toll on this group,” says Jayme Locke, M.D., a resident in the Department of Surgery at Johns Hopkins University School of Medicine, and lead researcher of the study described in the January issue of the Archives of Surgery.

Traditionally, HIV patients were not considered transplant candidates because survival rates after transplantation were thought to be greatly compromised by the disease, which cripples the body’s immune system. Transplant patients also take drugs that suppress their immune systems in order to prevent organ rejection, a regimen thought to further threaten their already fragile immune systems.

Locke says their study results are in part a reflection of newer antiretroviral therapies that have reduced HIV death rates by 80 percent. Indeed, people with HIV now die like most other people, of chronic diseases, rather than from the opportunistic infections that once took a grave toll. Kidney disease, for example, accounts for more than 10 percent of HIV-related deaths.

For the study, Locke and her team looked at the one-year kidney survival rates and one-year patient survival rates of 36,492 HIV-negative and 100 HIV-positive kidney transplant recipients listed on the United Organ Sharing Network (UNOS) list who received transplants between January 2004 and June 2006. They excluded those under 18 and anyone who had multi-organ transplantation.

The chances of survival were the same in both groups. However, kidney survival rates in these two groups showed that HIV-negative recipients had a 94.6 percent survival rate, compared to 87.9 percent in people with HIV. (People can survive on dialysis even if their transplanted kidney fails.)

However, when the investigators broke down the results into subgroups, they learned that some of the kidneys transplanted into HIV-positive recipients were relatively late getting to full function. This so-called delayed graft function (DGF) reduced kidney survival by 30 percent. When this group was removed from the rate comparison, both HIV-positive and HIV-negative groups had equal kidney and patient survival rates, says Locke.

According to Locke, this is significant because DGF can be avoided by controlling certain negative risk factors such as advanced organ donor age, deceased-donor kidneys (vs. live-donor kidneys) and long cold ischemic times (the time the kidney is without blood flow before transplant).

Other researchers who contributed to this study from Johns Hopkins University School of Medicine include Robert Montgomery, M.D., Ph.D.; Daniel S. Warren, Ph.D.; and Dorry Segev, M.D., of the Department of Surgery; and Aruna Subramanian, M.D., of the Department of Medicine.

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FDA Approves Updated Labeling for Psoriasis Drug Raptiva

The U.S. Food and Drug Administration today announced labeling changes, including a Boxed Warning, to highlight the risks of life-threatening infections, including progressive multifocal leukoencephalopathy (PML), with the use of Raptiva (efalizumab). The labeling changes are based on the FDA's post-market surveillance. The FDA is also requiring the submission of a Risk Evaluation and Mitigation Strategy (REMS), which will include a Medication Guide for patients and a timetable for assessment of the REMS.

Raptiva is a once-weekly injection approved for adults with moderate to severe plaque psoriasis who are candidates for systemic (whole body) therapy or phototherapy to control their psoriasis.

The FDA's Office of Surveillance and Epidemiology, charged by the Agency with monitoring drugs once approved for the marketplace, has received reports of serious infections leading to hospitalizations, and deaths in some cases, in patients using Raptiva.

The now-required Boxed Warning will highlight the risk of bacterial sepsis, viral meningitis, invasive fungal disease, progressive multifocal leukoencephalopathy and other opportunistic infections.

Additionally, Raptiva's label will be updated to include data from juvenile animal studies in mice (age equivalent to a 1-14 year old human). These data indicate a potential risk for the permanent suppression of the immune system with repeat administration of Raptiva in this age group. Raptiva is not approved for children under 18 years of age.

"As part of FDA's monitoring of the life-cycle of approved products, the agency received reports of serious infections in some patients taking Raptiva. These reports led to our decision to highlight these risks in the drugs labeling," said Janet Woodcock, the FDA's director of the Center for Drug Evaluation and Research. "Doctors and other prescribers should carefully evaluate and weigh the risk/benefit profile of Raptiva for patients who would be more susceptible to these risks."

Raptiva works by suppressing the immune system to reduce psoriasis flare-ups, however by suppressing the body's natural defense system, it can also increase the risk of serious infections and malignancies in patients.

Patients identified to begin therapy with Raptiva should have received all their age-appropriate vaccinations before starting the drug. Vaccinations should not be administered to patients taking Raptiva because immunity to the vaccination virus may not be conferred.

Patients taking Raptiva should be educated about recognizing the signs and symptoms of infection, PML (confusion, dizziness or loss of balance, difficulty talking or walking, and vision problems), anemia (dizziness upon standing, weakness or jaundice), thrombocytopenia (bruising, bleeding gums, pin-point sized red or purple dots under the skin), or the worsening of their psoriasis or arthritis. Signs of a nervous system disorder include sudden onset of numbness, tingling or weakness in the arms, legs or face.

If any of these signs appear, Raptiva patients should seek immediate medical attention. Patients with pre-existing infections or who have a compromised immune system should notify their health care professional before beginning treatment with Raptiva.

Because reports of these adverse events were received voluntarily from populations of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug's use.

One report of PML in a Raptiva-treated patient came from an ongoing post-marketing epidemiological study of patients with psoriasis.

Health care professionals should monitor patients treated with Raptiva for the signs and symptoms of these adverse events and also instruct patients to report any such signs and symptoms to them without delay.

Consumers and health care professionals can report adverse events to the FDA's MedWatch program at 800-FDA-1088, by mail at MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787, or online at www.fda.gov/medwatch/report.htm.

Raptiva was approved in 2003. It is manufactured by Genentech, Inc. of San Francisco, Calif.

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Arteries Have Unique Immune Functions

Human arteries play distinct roles in the immune system depending on their anatomical location, researchers at Emory University School of Medicine have discovered.

Their findings explain why vascular diseases affect different parts of the arterial network and could help doctors fine-tune the treatment of such diseases as atherosclerosis and vasculitis. Atherosclerosis causes heart attacks and strokes because it occurs preferentially in arteries supplying the heart and the brain.

The results were published online this week by the journal Circulation.

Arteries can play an active role in sensing foreign invasion and bodily injury, because cells embedded in the arterial walls called dendritic cells act like smoke-sensing fire alarms for the immune system, says senior author Cornelia Weyand, MD. PhD, co-director of the Kathleen B. and Mason I. Lowance Center for Human Immunology at Emory University.

"All of our major arteries have this alarm system," she says. "To our surprise, we found that the arteries of the neck, the arms, the abdomen and the legs are triggered by different infectious organisms. Thus, each artery functions in a specialized way."

Some vascular diseases attack arteries only in the abdomen or in the neck and upper extremities, and this selectivity has puzzled doctors for years, Weyand says.

To probe the differences among arteries, Weyand and her co-workers examined the activity of genes that encode Toll-like receptors in blood vessels from human donors.

Toll-like receptors are a cornerstone of the "innate" immune system, which can be activated by common features of infection-causing invaders. The capture of bacterial or viral fragments through Toll-like receptors alerts the immune system early during an infectious attack. Toll-like receptors can respond to whip-like antennas on bacteria called flagellae, parts of bacterial cell walls, or DNA and RNA that leaks from viruses or bacteria.

Each type of artery had a different set of Toll-like receptor genes turned on, the authors found. In contrast to arteries, veins could not be stimulated through Toll-like receptors.

For example, cells in the iliac arteries, located in the vicinity of the gut, respond avidly to flagellae but cells from the subclavian arteries, which transport blood to the upper body, do not.

A possible explanation is that dendritic cells from iliac arteries are better able to sense flagellae because of the abundant bacterial flora that inhabits the gut, Weyand says.

Weyand hypothesizes that the dendritic cells in arteries are mainly performing a protective, calming function. Arteries are in constant contact with blood borne infectious agents, with potentially dangerous consequences of damaging the vessel wall.

"It's when that protective function breaks down that we see inflammation and various vascular diseases," she says.

She says her team is now investigating how the dendritic cells in arteries move and change as they receive various signals.

The first author of the paper is research specialist Olga Pryshchep, with contributions from postdoctoral fellow Wei Ma-Krupa, PhD, Joerg Goronzy, MD, PhD, co-director of the Lowance Center, and Brian Younge, MD, of the Mayo Clinic.

The research team used samples from 37 deceased donors with an average age of 64. Only arterial samples without atherosclerotic lesions were used.

The research was funded by the National Institutes of Health, the Dana Foundation and the McIntyre Family Discovery Fund.

Reference: Vessel-specific Toll-like receptor profiles in human medium and large arteries Circulation, Sep 2008; doi:10.1161/CIRCULATIONAHA.108.789172

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