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Genomics aids diagnosis of unusual chronic meningitis case

The culprit: A bacterium more commonly linked to acne

by Tamara BhandariMay 19, 2016

Robert Boston

A patient who suffered for three years from confusion and difficulty walking was successfully treated after a research team at Washington University School of Medicine in St. Louis used an experimental technique to identify the cause of his symptoms.

The researchers sequenced tens of millions of bits of genetic material in the patient’s cerebrospinal fluid using a technique known as high-throughput metagenomic shotgun sequencing. They found that an acne-causing bacterium that normally lives harmlessly on the skin had infected the tissue surrounding his brain and spinal cord, causing chronic meningitis.

The paper is available online in the journal Transplant Infectious Diseases.

John DiPersio, MD, PhD, deputy director of the Siteman Cancer Center, Armin Ghobadi, MD, an assistant professor of oncology, and colleagues already were treating a 40-year-old patient for leukemia when he developed a persistent headache, confusion and difficulty walking. The doctors suspected an infection, but traditional microbiologic techniques failed to identify the pathogen, and multiple courses of antimicrobial drugs failed to permanently eliminate the symptoms.

In desperation, the doctors reached out to colleagues at the School of Medicine and the university’s McDonnell Genome Institute. Through work on the Human Microbiome Project and other genomics research, these scientists had developed the expertise and scientific infrastructure necessary to identify unknown microbes that are undetectable by traditional methods.

The task fell to infectious disease specialist Gregory Storch, MD, the Ruth L. Siteman Professor of Pediatrics, and Kristine Wylie, PhD, and Todd Wylie, assistant professors in pediatrics.

Using two samples of cerebrospinal fluid drawn from the patient three months apart, the researchers sequenced the genetic material and then compared the sequences to a database of known genomes to identify the organisms present.

“Lo and behold, Propionibacterium acnes dropped out,” said Storch, referring to a skin bacterium mostly known for causing acne. In both samples, about 47,000 of the millions of sequences belonged to P. acnes, five times as many as the second most common microbe.

Gregory Storch, MD, led a team that used an experimental genomics-based technique to diagnose an unusual case of meningitis.Robert Boston
Gregory Storch, MD, led a team that used an experimental genomics-based technique to diagnose an unusual case of meningitis.

The researchers also analyzed five control samples from other patients, two of whom had viral infections and three whose infections were unknown. The method correctly identified viral sequences in the two samples from known viral infections. Just a few hundred P. acnes sequences were found in the control samples, compared with the tens of thousands seen in the sample from the patient with meningitis.

“Meningitis isn’t often caused by P. acnes, but in this case, it fit the clinical picture,” Storch said. “We knew we had to have an organism of low virulence, meaning it was capable of causing disease but not severe disease that would be rapidly fatal.”

There are rare reports in medical literature of P. acnes meningitis. The cases usually involve immunocompromised patients similar to DiPersio’s and do not progress rapidly. The bacteria had been cultured from a previous sample of the patient’s, but it had been dismissed as an insignificant contaminant from the skin.

Since the technique is experimental, the researchers had to obtain permission from the Food and Drug Administration and the Washington University Institutional Review Board, which oversees studies involving human participants, before their results could be used to determine treatment for the patient.

DiPersio and a team including Merilda Blanco-Guzman, MD, and Steven Lawrence, MD, co-authors of the published report, administered a six-week course of antibiotics targeted against P. acnes. The antibiotic cleared the infection, and, after fluid that had collected in the patient’s central nervous system was drained, his neurological symptoms resolved.

Metagenomic shotgun sequencing was originally developed to identify the members of microbial communities in the environment, such as those found in soil or seawater. This study is only the third to report using this technique for clinical diagnosis.

“What’s novel about this case is that we were able to identify an organism that would otherwise be overlooked because it is not normally a pathogen, and that led to successful treatment of a patient who had a very complicated history,” Kristine Wylie said.

Current methods for diagnosing infection require technicians to grow the organism or amplify its genetic material, both of which require some knowledge of what the organism is likely to be. Shotgun sequencing requires only that the genetic material be present.

“Even an unknown organism could be identified, if it had some relationship to something in the database of microbial sequences,” Storch said. “We might be able to identify it as, say, a coronavirus, even though it might be a new species of coronavirus.”

The researchers currently are working to validate the technique in clinical cases. After the first successful diagnosis, they tried the technique on another difficult case. That time, it didn’t work.  The cause of that patient’s illness is still unknown.

“We didn’t detect anything,” Kristine Wylie said. “It could be the sample was taken at the wrong time, and the infection already was cleared. Or it might not have been an infection at all.”

The researchers have begun another study using samples from 20 difficult cases of suspected infections that resolved without the specific cause ever being identified.

The researchers want to gain insight into which kinds of cases would be the best candidates for this technique. Compared with current methods, it is slow and expensive. The meningitis case took five days to diagnose, at a cost of about $7,000.

“It’s expensive, but these difficult cases are already very expensive,” said Kristine Wylie. “In the case of this patient, he was admitted to the hospital multiple times before he was diagnosed.”

Storch agreed. “We see this as something held in reserve for very difficult cases,” he said. “It was clearly useful in this one case, but we need to get a much better handle on what kinds of patients and what kinds of diseases it would be worth trying this on.”

This work was funded by intramural funds available to John DiPersio and the university’s Division of Oncology, and by funds from the university’s Department of Pediatrics.

Wylie KM, Blanco-Guzman M, Wylie TN, Lawrence SJ, Ghobadi A, DiPersio JF and Storch GA. High-throughput sequencing of cerebrospinal fluid for diagnosis of chronic Propionibacterium acnes meningitis in an allogeneic stem cell transplant recipient. Transplant Infectious Diseases. April 2016.

Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Tamara covers infectious diseases, molecular microbiology, neurology, neuroscience, surgery, the Institute for Informatics, the Division of Physician-Scientists and the MSTP program. She holds a double bachelor's degree in molecular biophysics & biochemistry and in sociology from Yale University, a master's in public health from the University of California, Berkeley, and a PhD in biomedical science from the University of California, San Diego. She joined WashU Medicine Marketing & Communications in 2016. She has received three Robert G. Fenley writing awards from the American Association of Medical Colleges: a bronze in 2020 for "Mind’s quality control center found in long-ignored brain area," a silver in 2022 for "Mice with hallucination-like behaviors reveal insight into psychotic illness," and a bronze in 2023 for "Race of people given Alzheimer’s blood tests may affect interpretation of results." Since January of 2024, Tamara has been writing under the name Tamara Schneider.