Even a Brain-Eating Amoeba Can’t Hide From This Cutting-Edge Diagnosis Tech

They turned to an emerging strategy known as unbiased diagnosis. It ultimately confirmed an illness so rare and so deadly, few doctors have ever seen it: brain-eating amoeba disease. The patient’s brain had been invaded by a single-cell critter called Balamuthia mandrillaris, one of at least three types of amoebas known to infect human brains.

The unbiased approach is called metagenomic next-generation sequencing, a powerful technology that analyzes all of the genetic material in a patient’s tissue sample and as a result can screen for a wide range of disease-causing microbes in a single test. 

“This is very different than all other clinical diagnostics,” said Joseph DeRisi, a molecular biologist at UCSF and a pioneer of metagenomic sequencing. 

Dr. DeRisi was a central character in Michael Lewis’s book about Covid, “The Premonition.“ Along with colleagues at USCF, he used a precursor of metagenomics sequencing to identify a coronavirus early on as the pathogen behind the first SARS epidemic in 2003. More recently, metagenomics has been instrumental in efforts at UCSF and other centers to track the coronavirus behind the Covid pandemic.

The conventional search for the cause of an infection involves examining patient tissue under a microscope or culturing samples in a petri dish to see if bacteria or other microbes grow. But doctors have to be looking for a particular bug to find it. Such tests are typically ordered after doctors weigh the details of a case and form a hunch about the cause of the infection—a biased approach.

Dr. DeRisi and other proponents of metagenomic sequencing say it is poised to transform how doctors tackle one of medicine’s toughest challenges—the diagnosis of major infections that are often lethal and extremely costly to treat unless they are quickly identified. Dr. DeRisi foresees metagenomic testing for infectious disease eventually rolling out across medicine. 

Metagenomics is the future of medical diagnostics, said

Eric Topol,

director of Scripps Research Translational Institute, La Jolla, Calif. “It should be the present,” he said, but not many hospitals are equipped to do it.

A metagenomics test spells out the order of the four letters that make up the genetic code in all the DNA and RNA in a patient sample and compares the result against human and nonhuman genome sequences stored in databases such as the National Institutes of Health’s GenBank. 

A typical sample might yield 100 million snippets of genetic material, Dr. DeRisi said. Some 99% would be human. Those sequences are computationally stripped away and the remaining 1 million pieces are screened against all the sequences in GenBank in an effort to find a match.  

“Hundreds of things“ can give you a brain infection, said Dr. DeRisi, who is also president of Chan Zuckerberg Biohub, San Francisco. Conventional testing typically looks for one type of bug at a time. A metagenomics test “doesn’t care if it’s bacteria, a fungus or a parasitic worm or a virus. They all have RNA or DNA.”

A biased diagnosis can be likened to the card game Go Fish, said Natasha Spottiswoode, an infectious disease physician at UCSF who has overseen care of the Balamuthia patient. A player holding a green fish card asks another, “Do you have any green fish?” If the answer is no, the question on the next turn may be, “Do you have any red fish?” 

For an unbiased query, “What you really want to ask is, ‘Do you have any fish at all?’” Dr. Spottiswoode said. “And then figure out what color they are.”

In 2014, Dr. DeRisi was among a team of researchers and clinicians at UCSF who reported on one of the first patients to be successfully treated based on metagenomics sequencing—a 14-year-old boy whose treatable, but potentially fatal Leptospirosis bacterial brain infection went undiagnosed for several months until the test was performed.

The case convinced Dr. DeRisi and his colleagues that a metagenomics test should be deployed as a clinical tool for diagnosing brain infections and eventually led UCSF to offer the tests to other hospitals. Innovation in semiconductor technology is helping make the service possible, Dr. DeRisi said. “If we dial back 10 or 12 years ago, we couldn’t do this,” he said. “If we didn’t have increases in computer storage, memory and speed, we’d be sunk.”

The UCSF service focuses for now on brain infections, but researchers there and elsewhere say sepsis and respiratory infections such as pneumonia—two leading killers of hospital patients—are among other prime candidates for metagenomic testing. Both have multiple potential causes and usually can’t be treated effectively until the right one is identified, a process that with conventional lab cultures can take several days. In the interim, doctors often throw an expensive array of antibiotics at the bug in a hit-or-miss effort to save a dying patient. 

“What you’d like to do is know the bug straight away so you don’t give unnecessary antibiotics,” Dr. Topol says. 

Metagenomics has limitations. The test can pick up dormant or otherwise clinically irrelevant microbes, making it difficult to interpret results. It can miss pathogens that are detected by conventional means. UCSF’s brain infection test costs about $2,000, far less than the cost of a day in the ICU, but still a potential impediment to regular use. Insurance reimbursement is spotty. Turnaround time can be as long as six or seven days, Dr. DeRisi said.

Meantime, UCSF’s testing service is at full capacity, routinely analyzing as many as 50 cerebrospinal fluid samples a week, Dr. DeRisi said. Both costs and turnaround times are poised to come down, he said: “We need this to be actionable in 24 hours” or less. That’s possible in an emergency now, he said, but further advances are required to do it routinely. 

In the case of the Balamuthia patient, metagenomics found no evidence of the amoeba in the cerebrospinal fluid. The initial diagnosis came in a different type of test ordered after a sharp-eyed pathologist spotted what he thought resembled amoebas when he took a second look at tissue under a microscope. 

Under a research protocol, the UCSF scientists, including Dr. DeRisi, decided to run a metagenomics test of tissue from a brain biopsy, a test that isn’t yet validated for a clinical diagnosis. It identified the amoeba, confirming Balamuthia as the culprit.

Treating it posed a new challenge. The death rate for Balamuthia infections is greater than 90%, according to the U.S. Centers for Disease Control and Prevention, which recommends a six-drug regimen based on what known survivors were given. After initially improving, Dr. Spottiswoode’s patient developed severe side effects. Some drugs had to be stopped, and his prognosis turned dire. 

As it happened, UCSF had a previous Balamuthia case in 2015—a 74-year-old woman who died before she was diagnosed. Doctors decided to run a postmortem metagenomics test on her cerebrospinal fluid. “It was 99.99% human,” Dr. DeRisi recalls. “When we looked to see what the .01% was, it all mapped to” Balamuthia.

The researchers wondered whether a drug was available that might have helped had they been able to diagnose her sooner. Once again, Dr. DeRisi took an unbiased approach, although it didn’t involve metagenomics. The lab tested a broad array of more than 2,000 drugs against the amoeba. “Instead of picking 10 drugs I thought might work, I just did them all,” he said.

He got one promising hit: nitroxoline, a half-century-old antibiotic used in Europe for urinary tract infections. It proved potent against Balamuthia-infected brain tissue in further tests. They published a paper on the result, anticipating that a doctor encountering a future case of Balamuthia might find it helpful. 

Dr. Spottiswoode was that doctor. She was able to obtain the drug for her patient. Seven weeks later, brain imaging showed significant improvement. A report on the case was published in January in the journal Emerging Infectious Diseases. It will take more good patient outcomes before it is known whether nitroxoline is truly effective against Balamuthia, but 18 months after his initial admission the patient remains on the drug and is living independently. 

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