Chapter 019. Fever of Unknown Origin (Part 4) Specialized Diagnostic Studies Classic FUO A stepwise flow chart depicting the diagnostic workup and therapeutic management of FUO is provided in Fig. 19-1. In this flow chart, reference is made to "potentially diagnostic clues," as outlined by de Kleijn and colleagues; these clues may be key findings in the history (e.g., travel), localizing signs, or key symptoms. Certain specific diagnostic maneuvers become critical in dealing with prolonged fevers. If factitious fever is suspected, electronic thermometers should be used, temperature-taking should be supervised, and simultaneous urine and body temperatures should be measured. Thick blood smears should be examined for Plasmodium; thin blood smears, prepared with proper technique and quality stains and subjected to expert microscopy, should be used to speciate Plasmodium and to identify Babesia, Trypanosoma, Leishmania, Rickettsia, and Borrelia. Any tissue removed during prior relevant surgery should be reexamined; slides should be requested, and, if need be, paraffin blocks of fixed pathologic material should be reexamined and additional special studies performed. Relevant x-rays should be reexamined; reviewing of prior radiologic reports may be insufficient. Serum should be set aside in the laboratory as soon as possible and retained for future examination for rising antibody titers. Figure 19-1 Approach to the patient with classic FUO. a "Potentially diagnostic clues," as outlined by de Kleijn and colleagues (1997, Part II), may be key findings in the history, localizing signs, or key symptoms. ANA, antinuclear antibody; CBC, complete blood count; CMV, cytomegalovirus; CRP, C-reactive protein; CT, computed tomography; Diff, differential; EBV, Epstein-Barr virus; ESR, erythrocyte sedimentation rate; FDG, fluorodeoxyglucose F18; NSAIDs, nonsteroidal anti-inflammatory drugs; PET, positron emission tomography; PMN, polymorphonuclear leukocyte; PPD, purified protein derivative; RF, rheumatoid factor; SPEP, serum protein electrophoresis; TB, tuberculosis; TIBC, total iron- binding capacity; VDRL, Venereal Disease Research Laboratory test. b Needle biopsy of liver as well as any other tissue indicated by "potentially diagnostic clues." c Invasive testing could involve laparoscopy. d Empirical therapy is a last resort, given the good prognosis of most patients with FUO persisting without a diagnosis. Febrile agglutinins is a vague term that in most laboratories refers to serologic studies for salmonellosis, brucellosis, and rickettsial diseases. These studies are seldom useful, having low sensitivity and variable specificity. Multiple blood samples (no fewer than three and rarely more than six, including samples for anaerobic culture) should be cultured in the laboratory for at least 2 weeks to ensure that any HACEK group organisms that may be present have ample time to grow (Chap. 140). Lysis-centrifugation blood culture techniques should be employed in cases where prior antimicrobial therapy or fungal or atypical mycobacterial infection is suspected. Blood culture media should be supplemented with L-cysteine or pyridoxal to assist in the isolation of nutritionally variant streptococci. It should be noted that sequential cultures positive for multiple organisms may reflect self-injection of contaminated substances. Urine cultures, including cultures for mycobacteria, fungi, and CMV, are indicated. In the setting of recurrent fevers with lymphocytic meningitis (Mollaret's meningitis), cerebrospinal fluid can be tested for herpesvirus, with use of the polymerase chain reaction (PCR) to amplify and detect viral nucleic acid (Chap. 172). A recent report described a highly multiplexed oligonucleotide microarray using PCR amplification and containing probes for all recognized vertebrate virus species and for 135 bacterial, 73 fungal, and 63 parasitic genera and species. The eventual clinical validation of such microarrays will further diminish rates of undiagnosed FUO of infectious etiology. . Chapter 019. Fever of Unknown Origin (Part 4) Specialized Diagnostic Studies Classic FUO A stepwise flow chart depicting the diagnostic workup and therapeutic management of FUO. indicated. In the setting of recurrent fevers with lymphocytic meningitis (Mollaret's meningitis), cerebrospinal fluid can be tested for herpesvirus, with use of the polymerase chain reaction. parasitic genera and species. The eventual clinical validation of such microarrays will further diminish rates of undiagnosed FUO of infectious etiology.