Case Presentation: A 19-year-old female presented to a children’s hospital with a two week history of daily fever, diffuse abdominal tenderness, vomiting, diarrhea, and body aches, starting three weeks after her immigration from Kenya. Laboratory studies revealed pancytopenia, coagulopathy, low fibrinogen, pancreatitis, hepatitis, and elevations in D-dimer and inflammatory markers. Abdominal x-ray showed air-fluid levels. Stool and blood cultures were negative. Upon hospitalization, she developed worsened cytopenia. Ferritin and soluble IL-2 receptor levels were elevated. Tuberculosis testing was indeterminate and a Candida antigen control was negative, raising concern for immunologic dysfunction. A stool molecular screen was positive for Salmonella typhi so ciprofloxacin was started. The organism did not grow in cultures to verify sensitivity, however, and the patient did not improve. The differential remained broad, including infections such as typhoid fever and tuberculosis, inflammatory conditions including macrophage activation syndrome (MAS), and malignancy. A bone marrow aspirate showed hypocellularity, rare hemophagocytosis, and no evidence of infection or malignancy. Given concern for antibiotic resistance, ceftriaxone was added, after which her symptoms improved. The patient’s brother then presented with fever and grew S. typhi from his stool and blood, which was sensitive to ceftriaxone and azithromycin but only intermediately sensitive to ciprofloxacin. The patient was discharged on azithromycin.
Discussion: The diagnosis of typhoid fever typically requires culture from a sterile site, as 61% will have a positive blood culture and 96% will have a positive bone marrow culture. Our suspicion was high, but distinguishing between the potential infectious, immunologic, and oncologic diagnoses was critical to guiding management. Steroid administration was considered for possible MAS, which has a high mortality rate; however, steroids confer a risk of harm for considered infectious and oncologic diagnoses. Typhoid fever masquerading as MAS has been described, but, unlike our case, this was in a patient who had increased hemophagocytic macrophages in the bone marrow and a positive blood culture for S. typhi. Our diagnosis was significantly delayed by negative cultures and unresponsiveness to treatment, which initially raised concern that the S. typhi molecular screen represented colonization. Resistance is growing to fluoroquinolones, the preferred drug for multidrug-resistant S. typhi, but ceftriaxone and azithromycin have been used successfully in areas with high resistance.
Conclusions: Multisystem disease processes often lead to significant diagnostic and therapeutic challenges, particularly when the appropriate management for one diagnosis may be contraindicated in another. Combined with unexpected laboratory challenges and diagnoses rarely encountered by pediatric hospitalists in the U.S., these scenarios can lead to significant delays in initiating appropriate therapy. Knowledge of the defining characteristics, rare complications, and evolving resistance patterns of typhoid fever is critical to appropriate diagnosis and management.