Chapter 019. Fever of Unknown Origin (Part 6) Nosocomial FUO (See also Chap. 125) The primary considerations in diagnosing nosocomial FUO are the underlying susceptibility of the patient coupled with the potential complications of hospitalization. The original surgical or procedural field is the place to begin a directed physical and laboratory examination for abscesses, hematomas, or infected foreign bodies. More than 50% of patients with nosocomial FUO are infected. Intravascular lines, septic phlebitis, and prostheses are all suspect. In this setting, the best approach is to focus on sites where occult infections may be sequestered, such as the sinuses of intubated patients or a prostatic abscess in a man with a urinary catheter. Clostridium difficile colitis may be associated with fever and leukocytosis before the onset of diarrhea. In ~25% of patients with nosocomial FUO, the fever has a noninfectious cause. Among these causes are acalculous cholecystitis, deep-vein thrombophlebitis, and pulmonary embolism. Drug fever, transfusion reactions, alcohol/drug withdrawal, adrenal insufficiency, thyroiditis, pancreatitis, gout, and pseudogout are among the many possible causes to consider. As in classic FUO, repeated meticulous physical examinations, coupled with focused diagnostic techniques, are imperative. Multiple blood, wound, and fluid cultures are mandatory. The pace of diagnostic tests is accelerated, and the threshold for procedures—CT scans, ultrasonography, 111 In WBC scans, noninvasive venous studies—is low. Even so, 20% of cases of nosocomial FUO may go undiagnosed. Like diagnostic measures, therapeutic maneuvers must be swift and decisive, as many patients are already critically ill. IV lines must be changed (and cultured), drugs stopped for 72 h, and empirical therapy started if bacteremia is a threat. In many hospital settings, empirical antibiotic coverage for nosocomial FUO now includes vancomycin for coverage of methicillin-resistant Staphylococcus aureus as well as broad-spectrum gram-negative coverage with piperacillin/tazobactam, ticarcillin/clavulanate, imipenem, or meropenem. Practice guidelines covering many of these issues have been published jointly by the Infectious Diseases Society of America (IDSA) and the Society for Critical Care Medicine and can be accessed on the IDSA website (www.journals.uchicago.edu/IDSA/guidelines). Neutropenic FUO (See also Chap. 82) Neutropenic patients are susceptible to focal bacterial and fungal infections, to bacteremic infections, to infections involving catheters (including septic thrombophlebitis), and to perianal infections. Candida and Aspergillus infections are common. Infections due to herpes simplex virus or CMV are sometimes causes of FUO in this group. While the duration of illness may be short in these patients, the consequences of untreated infection may be catastrophic; 50–60% of febrile neutropenic patients are infected, and 20% are bacteremic. The IDSA has published extensive practice guidelines covering these critically ill neutropenic patients; these guidelines appear on the website cited in the previous section. In these patients, severe mucositis, quinolone prophylaxis, colonization with methicillin-resistant S. aureus, obvious catheter-related infection, or hypotension dictates the use of vancomycin plus ceftazidime, cefepime, or a carbapenem with or without an aminoglycoside to provide empirical coverage for bacterial sepsis. HIV-Associated FUO HIV infection alone may be a cause of fever. Infection due to Mycobacterium avium or Mycobacterium intracellulare, tuberculosis, toxoplasmosis, CMV infection, Pneumocystis infection, salmonellosis, cryptococcosis, histoplasmosis, non-Hodgkin's lymphoma, and (of particular importance) drug fever are all possible causes of FUO. Mycobacterial infection can be diagnosed by blood cultures and by liver, bone marrow, and lymph node biopsies. Chest CT should be performed to identify enlarged mediastinal nodes. Serologic studies may reveal cryptococcal antigen, and 67 Ga scan may help identify Pneumocystis pulmonary infection. FUO has an infectious etiology in >80% of HIV-infected patients, but drug fever and lymphoma remain important considerations. Treatment of HIV-associated FUO depends on many factors and is discussed in Chap. 182. Fever of Unknown Origin: Treatment The focus here is on classic FUO. Other modifiers of FUO—neutropenia, HIV infection, a nosocomial setting—all vastly affect the risk equation and dictate therapy based on the probability of various causes of fever and on the calculated risks and benefits of a guided empirical approach. The age and physical state of the patient are factors as well: the frail elderly patient may merit a trial of empirical therapy earlier than the robust young adult. The emphasis in patients with classic FUO is on continued observation and examination, with the avoidance of "shotgun" empirical therapy. Antibiotic therapy (even that for tuberculosis) may irrevocably alter the ability to culture fastidious bacteria or mycobacteria and delineate ultimate cause. However, vital- sign instability or neutropenia is an indication for empirical therapy with a fluoroquinolone plus piperacillin or the regimen mentioned above (see "Nosocomial FUO"), for example. Cirrhosis, asplenia, intercurrent immunosuppressive drug use, or recent exotic travel may all tip the balance toward earlier empirical anti-infective therapy. If the PPD skin test is positive or if granulomatous hepatitis or other granulomatous disease is present with anergy (and sarcoid seems unlikely), then a therapeutic trial with isoniazid and rifampin (and possibly a third drug) should be undertaken, with treatment usually continued for up to 6 weeks. A failure of the fever to respond over this period suggests an alternative diagnosis. The response of rheumatic fever and Still's disease to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) may be dramatic. The effects of glucocorticoids on temporal arteritis, polymyalgia rheumatica, and granulomatous hepatitis are equally dramatic. Colchicine is highly effective in preventing attacks of familial Mediterranean fever but is of little use once an attack is well under way. The ability of glucocorticoids and NSAIDs to mask fever while permitting the spread of infection dictates that their use be avoided unless infection has been largely ruled out and unless inflammatory disease is both probable and debilitating or threatening. When no underlying source of FUO is identified after prolonged observation (>6 months), the prognosis is generally good, however vexing the fever may be to the patient. Under such circumstances, debilitating symptoms are treated with NSAIDs, and glucocorticoids are the last resort. The initiation of empirical therapy does not mark the end of the diagnostic workup; rather, it commits the physician to continued thoughtful reexamination and evaluation. Patience, compassion, equanimity, and intellectual flexibility are indispensable attributes for the clinician in dealing successfully with FUO. . Chapter 019. Fever of Unknown Origin (Part 6) Nosocomial FUO (See also Chap. 125) The primary considerations in diagnosing nosocomial FUO are the underlying susceptibility of the. >80% of HIV-infected patients, but drug fever and lymphoma remain important considerations. Treatment of HIV-associated FUO depends on many factors and is discussed in Chap. 182. Fever of Unknown. therapy based on the probability of various causes of fever and on the calculated risks and benefits of a guided empirical approach. The age and physical state of the patient are factors as well: