DIAGNOSTIC DILEMMA: INFECTIOUS DISEASE Charles M. Wiener, MD, Section Editor Iron-clad Diagnosis Paul E. Bunce, MD, a Sharmistha Mishra, MD, FRCPC, a Wayne L. Gold, MD, FRCPC a,b a Department of Medicine and b Division of Infectious Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada. PRESENTATION Negative serology results do not necessarily prove that a patient is free of infection. A 23-year-old man had endured right lower-quadrant abdominal pain for 1 month, but a 4-day bout of fever and non-bloody diarrhea finally led him to seek treatment. His medical history was significant for beta thalassemia major, for which he had received multiple blood transfusions. As commonly occurs, this treatment resulted in iron overload and its associated metabolic com- plications, including insulin-dependent diabetes mellitus, hypogonadism, and osteoporosis. He was receiving defer- oxamine as iron chelation therapy. His last blood transfu- sion occurred 1 month prior to presentation. The patient had no history of tuberculosis, recent travel, ill contacts, or ingestion of undercooked meat or fish. He did, however, work as a food handler at several fast food restaurants. He had no family history of inflammatory bowel disease. ASSESSMENT On examination, the patient appeared unwell and had a blood pressure of 120/60 mmHg, a heart rate of 110 beats per minute, and a temperature of 101.8° F (38.8° C). An abdominal examination showed localized rebound tender- ness in the right lower quadrant, but no palpable hepato- splenomegaly or masses. He had a leukocyte count of 20.4  10 3 cells/mm 3 and a neutrophil count of 18.7  10 3 cells/ mm 3 (normal: 4.0-11  10 3 cells/mm 3 and 2.0-7.5  10 3 cells/mm 3 , respectively). A contrast-enhanced computed to- mography (CT) scan of the abdomen showed circumferen- tial thickening of a 10-cm segment of terminal ileum. The cecum was spared, and the appendix was normal. Mesen- teric lymph node enlargement with necrosis was seen, as well (Figures 1 and 2). DIAGNOSIS Initially, both infectious and noninfectious etiologies were considered for the patient’s fever and right lower- quadrant pain (Table 1). However, in light of his history of beta thalassemia and iron overload, an infectious eti- ology was deemed most likely, and empiric antimicrobial treatment was initiated with intravenous ceftriaxone and metronidazole. Blood and stool cultures obtained on admission were negative for bacterial pathogens. However, a strong clinical suspicion that terminal ileitis and mesenteric adenitis were caused by Yersinia species led us to request serology for this organism. The initial serology was negative, but over a 6-week period, the antibody titer, as determined by micro- agglutination assay, rose more than 64-fold, confirming infection with Y. enterocolitica serotype O:3. Beta thalassemia major is a genetic disorder marked by impaired production of beta hemoglobin chains and the development of microcytic hemolytic anemia. Complica- tions of beta thalassemia result directly from anemia and from iron overload caused by frequent transfusions of red blood cells. Iron overload can lead to cirrhosis; congestive heart failure secondary to cardiomyopathy; endocrinopa- thies, such as insulin-dependent diabetes mellitus; and an increased risk for infection. It also predisposes patients to infections caused by organisms that have enhanced growth and increased virulence in the presence of excess iron, for example, Yersinia species, Klebsiella species, Escherichia coli, Streptococcus pneumoniae, Pseudomonas aeruginosa, Listeria monocytogenes, and fungal pathogens. 1 Other causes of iron overload, such as hemochromatosis, also boost the likelihood of infection. 2 Multiple immune defects related to the iron overload state have been characterized, and these enhance the risk for infection (Table 2). Y. enterocolitica is a Gram-negative bacillus that can cause foodborne illness and less frequently, transfusion- related sepsis. Along with Y. pseudotuberculosis, it is Funding: There was no funding source for this project. Conflict of interest: None of the authors have any conflicts of interest to declare. Authorship: All authors had access to the data and contributed to the preparation of this manuscript. Requests for reprints should be addressed to Paul E. Bunce, MD, 200 Elizabeth Street 13EN-213, Toronto, Ontario, Canada, M5G 2C4. E-mail address: p.bunce@utoronto.ca 0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.08.010