Decoding the Unexpected: How Cell-Free DNA Sequencing Unveiled an Elusive Tularemia Case

Typhoidal tularemia is a rare form of <i>Francisella tularensis</i> infection with nonspecific systemic symptoms that pose diagnostic challenges. Microbial cell-free DNA (mcfDNA) sequencing offers promise for detecting difficult-to-diagnose pathogens, including tularemia. An 80-year-old woman presented with fever and acute encephalopathy, with in-hospital evaluation unrevealing of an identifiable source or pathogen. She was discharged with clinical improvement on empiric levofloxacin. Following her hospitalization, mcfDNA sequencing results detected <i>Francisella tularensis</i>, leading to diagnosis of typhoidal tularemia. This case demonstrated mcfDNA's utility for diagnosing rare zoonotic infections that would likely remain undiagnosed using conventional methods. The authors propose molecular testing should be considered for updated tularemia case definitions for public health surveillance. Clinicians should maintain suspicion for zoonotic diseases in patients with undifferentiated fever in California.