Solving mystery infections: Genetic testing reveals hidden pathogens

Mystery infections—persistent and unexplained illnesses—are a rising global health challenge, often delaying critical treatment as patients and clinicians search for answers.

Today, advanced genetic testing technologies are transforming the landscape, rapidly identifying hidden pathogens and unlocking new pathways for accurate diagnosis and effective intervention.

The Global Burden and Diagnostic Challenges

These undiagnosed infections, clinically termed fever of unknown origin (FUO), affect millions globally. Defined by persistent symptoms such as fever above 38.3°C for at least three weeks without an identifiable cause, they account for 25–50% of undiagnosed cases in high-income nations and even more in resource-limited regions (The Journal of Infectious Diseases).

In sub-Saharan Africa, doctors often assume patients have malaria. But studies show a different picture: during Guinea’s 2014 Ebola outbreak, 20% of patients tested negative for Ebola but actually had bacterial infections such as Salmonella and Klebsiella (DZIF Study).

Human herpesviruses like Cytomegalovirus and Epstein-Barr virus cause 15–20% of fevers of unknown origin. In certain regions, tuberculosis and abscesses are the main causes. When several types of infections happen together, it makes diagnosis much harder.

The recent Democratic Republic of Congo flu-like disease outbreak, which killed 79 people, exemplifies the urgency of advanced diagnostics. Initial tests ruled out Ebola and Marburg, but WHO teams deployed mNGS to identify the culprit—a process still underway

The Congo outbreak underscores the urgency of rapid genomic surveillance. While the pathogen remains unidentified, advanced diagnostics have already excluded viral hemorrhagic fevers, guiding containment efforts.

Fever identification chat – Courtesy of thebmj.

Similarly, during India’s 2024 Kachchh outbreak, metagenomic next-generation sequencing (mNGS) revealed bacterial co-infections complicating viral illnesses—a finding missed by initial tests (The Indian Express).

“These cases aren’t anomalies. Up to 40% of ‘mystery’ infections involve multiple pathogens. mNGS shows the full picture”, notes Dr. Charles Chiu from University of California San Francisco.

Genomics Cuts Through the Fog

Traditional methods like cultures or PCR require clinicians to guess the culprit pathogen upfront—a fatal flaw when facing novel or complex infections. Metagenomic next-generation sequencing (mNGS) eliminates this bottleneck by analyzing all genetic material in a sample—bacterial, viral, fungal, or parasitic—without bias. A landmark study in Nature Medicine demonstrated mNGS’s superiority: it identified pathogens in 86% of neurological infections versus 67% via conventional methods.

Advanced sequencing technologies like BGI Genomics PMseq™ can detect pathogens at very low concentrations, sometimes as few as 500 copies per milliliter. These methods draw on large microbial genome databases that include thousands of species, even those resistant to drugs. Artificial intelligence further improves accuracy by reducing false positives and helps deliver results within about two days.

This approach proved transformative for a UK doctor whose chronic eye inflammation eluded diagnosis for five years. mNGS identified Leptospira, a rare bacteria, enabling targeted antibiotic therapy and vision recovery .

What makes PMseq® a game-changer for mystery infections diagnoses? Watch full video on BGI Genomics Instagram

Timely Intervention with mNGS

The integration of mNGS into routine care marks a paradigm shift. Automated platforms now process samples in less than six hours, which is crucial for ICU settings. Drug resistance profiling—detecting genes like CTX-M and MecA—guides antibiotic stewardship and helps curb the rise of antimicrobial resistance.

Recent research using mNGS is uncovering links between chronic infections and long-term health risks, such as the association between pathogenic bacterium and cardiovascular diseases. As Prof. Carlos Pavesio of Moorfields Eye Hospital observes, “This isn’t just about solving mysteries—it’s about redefining how we protect global health.”

Early detection, improved diagnosis, and personalized treatment through genetic testing are not only transforming individual patient outcomes but are also reshaping public health strategies worldwide. With the continued advancement of genomic technologies, the enigma of mystery infections may soon become a relic of the past.

About BGI Genomics PMseq™

PMseq™ uses mNGS to extract nucleic acids from clinical infection samples after performing pre-processing, followed by sequencing on a high-throughput platform. By comparing the results against the specialized clinical database PMDB and utilizing advanced bioinformatic algorithms, PMseq™ can efficiently identify potential pathogens. This method enables unbiased detection of bacteria, fungi, viruses, parasites, and other pathogens, as well as the assessment of drug resistance and virulence genes. As a result, it significantly enhances the accuracy of pathogen diagnosis and helps guide the targeted use of antibiotics, making infection diagnosis and treatment more precise.

About BGI Genomics

BGI Genomics, headquartered in Shenzhen, China, is the world's leading integrated solutions provider of precision medicine. Our services cover more than 100 countries and regions, involving more than 2,300 medical institutions. In July 2017, as a subsidiary of BGI Group, BGI Genomics (300676.SZ) was officially listed on the Shenzhen Stock Exchange.