Investigators at the National Institutes of Health have observed that the survival rate of people with a rare immunodeficiency disease called chronic granulomatous disease (CGD) is greatly improved when even very low levels of microbe-killing molecules are present. Because production of these molecules, made by an enzyme called NADPH oxidase, can be predicted from genetic analysis, a patient's risk for severe CGD could be assessed very early in life, allowing for more personalized treatment, say the researchers.
The study was conducted at the NIH Clinical Center and led by researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, and their associated contract labs at SAIC-Frederick Inc. The study is available online in the New England Journal of Medicine.
"Advances in treatment of CGD have made it possible for people with this once-fatal disease of early childhood to survive into adulthood; however, the disease remains difficult to manage," says NIAID Director Anthony S. Fauci, M.D. "Having a marker to help predict disease prognosis will enable physicians to recommend treatment options that are more tailored to the needs of individual patients."
People with CGD have increased susceptibility to infections caused by certain bacteria, such as Staphylococcus aureus, and fungi, such as Aspergillus. They can have abscesses in the lungs, liver, spleen, bones or skin. Those with severe disease also can have tissue masses, called granulomas, which can obstruct the bowel or urinary tract. CGD affects an estimated 1,200 people in the United States and approximately 25,000 people worldwide.
The disease is caused by inherited mutations in any one of five different genes required by immune cells to make the NADPH oxidase enzyme, which in turn makes superoxide, an oxygen-derived molecule that immune cells use to destroy harmful bacteria and fungi. All CGD patients have impaired superoxide production. Some make a little superoxide, while others make none. The research team found that the level of superoxide production was linked to the type of mutation in the NADPH oxidase gene, and that the more superoxide a patient with CGD can make, the less severe the disease and the greater the life expectancy.
Until now, the severity of CGD has been linked only to how people inherit the NADPH oxidase gene mutation. If people inherit the mutation as an autosomal recessive trait, meaning that two copies of the abnormal gene, one from each parent, are present, the disease has generally been less severe than in those who inherit the mutation as an X-linked trait, meaning that the abnormal gene is located on the female sex chromosome. The majority of people with CGD inherit the mutation as an X-linked trait.
For their study, the NIH team tested the level of superoxide production by immune cells isolated from blood samples taken from 287 people with CGD, aged 1 to 64 years old, compared with superoxide production in healthy people. Some tests dated back to 1993, though patients and families affected by CGD have come to the NIH Clinical Center for treatment since the 1970s.
The NIH researchers used methods that could detect even trace amounts of superoxide, and grouped people with CGD based on the amount of superoxide made by the immune cells. The patients who produced the highest levels of superoxide had the highest survival rates, whereas those who produced the lowest levels of superoxide had the lowest survival rates.
"By precisely measuring superoxide production, we observed that even tiny residual amounts, at levels below what doctors paid attention to in the past, had a significant impact on patient survival," says John Gallin, M.D., director of the NIH Clinical Center, chief of the Clinical Pathophysiology Section of the NIAID Laboratory of Host Defenses, and senior author on the paper.
Treatment of CGD consists of lifelong antibiotics and antifungal medications. Some people also receive injections with interferon-gamma, a protein that can stimulate the immune cells to fight infections. For people with the most severe forms of CGD, bone marrow transplantation is a treatment option, but it carries potential complications that can make patients and their families reluctant to elect this therapy.
Based on the research team's observations, doctors should be able to use DNA gene-typing results to help identify those patients who are candidates for more aggressive treatments, including possible bone marrow transplantation. Bone marrow transplantation replaces the immune cells of people with CGD, which produce no or reduced amounts of microbe-killing superoxide, with healthy immune cells. In addition, therapies designed to promote NADPH oxidase function might reduce CGD severity. Therapies exist to stimulate NADPH oxidase but none are used to treat CGD.
"This study is a great example of the special strengths of the Clinical Center," comments Dr. Gallin. "We have worked for over three decades with patients with CGD, which at one time was almost entirely fatal, and have seen vast improvements in care and treatment. This work now gives us another tool to help individuals fight this disease."
Additional support for this research was provided by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute, also components of NIH, and SAIC-Frederick Inc.
NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.
NIDDK, a component of the NIH, conducts and supports research in diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans. For more information about NIDDK and its programs, see www.niddk.nih.gov.
NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Reference: DB Kuhns et al. Residual NADPH oxidase and survival in chronic granulomatous disease. New England Journal of Medicine. DOI: 10.1056/NEJMoa1007097 (2010).
Julie Wu | EurekAlert!
Drone vs. truck deliveries: Which create less carbon pollution?
31.05.2017 | University of Washington
New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
26.06.2017 | Life Sciences
26.06.2017 | Physics and Astronomy
26.06.2017 | Information Technology