Diagnostic Approach to Prolonged Chronic Fever

Initial Investigations

• The Centers for Disease Control and Prevention (CDC) recommends liver function tests, complete blood count (CBC) with differential, and serology testing for suspected chronic infections like Q fever, including testing phase I and II IgG and IgM antibodies, and considers paired samples (acute and convalescent) to demonstrate rising titers 1
• Nucleic acid detection, such as PCR testing of whole blood, is particularly valuable early in the course of infection before antibody response develops, as suggested by the CDC 1
• Immunohistochemistry to detect pathogens in tissues even after antibiotic therapy is recommended as part of invasive testing if noninvasive tests are unrevealing, as suggested by the CDC 1
• Serologic monitoring at intervals of 3, 6, 12, 18, and 24 months may be necessary for patients with persistent fever, especially for those at risk of developing chronic infections, as recommended by the CDC 1

Special Considerations

• Immunocompromised patients may require a more extensive workup, including specialized testing for opportunistic infections, as recommended by the American College of Physicians 1
• A focused diagnostic approach including blood cultures, complete blood count, basic metabolic panel, and chest radiography is recommended as the initial investigations for patients presenting with fever, as suggested by the American College of Critical Care Medicine 2
• Blood cultures should be collected from different anatomical sites, with at least two sets (ideally 60 mL of blood total) without time interval between them, as suggested by the Critical Care Medicine guidelines 2
• Complete blood count with differential should be performed to assess for leukocytosis, lymphopenia, thrombocytopenia, or eosinophilia, which may indicate specific infectious processes, according to the Journal of Infection guidelines 3
• C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) are particularly useful if bacterial infection probability is low to intermediate, as recommended by the Critical Care Medicine guidelines 2
• Procalcitonin (PCT) should be considered if bacterial infection probability is low to intermediate and no clear focus of infection is identified, as recommended by the Critical Care Medicine guidelines 2
• Serum sample for serology should be stored for potential later testing based on clinical evolution, according to the Journal of Infection guidelines 3
• Chest radiograph is recommended as a standard investigation for all patients with fever, as suggested by the Critical Care Medicine guidelines 2
• Abdominal ultrasound should be considered if abdominal symptoms or abnormal liver function tests are present, as recommended by the Critical Care Medicine guidelines 2
• CT scan should be considered for patients who have recently undergone thoracic, abdominal, or pelvic surgery and no etiology is readily identified, as suggested by the Critical Care Medicine guidelines 2

Diagnostic Testing for Specific Conditions

• For patients with recent travel to tropical regions, malaria testing (thick and thin blood films plus rapid diagnostic test) should be performed for any patient who has visited a tropical country within the past year, as recommended by the Journal of Infection guidelines 3
• Testing for viral pathogens, including SARS-CoV-2 PCR, should be considered based on community transmission levels and respiratory symptoms, as suggested by the Critical Care Medicine guidelines 2
• The CDC recommends serological testing for Rocky Mountain spotted fever (RMSF), Ehrlichia chaffeensis, and Anaplasma phagocytophilum, including IgM and IgG antibody titers, with paired early and late convalescent samples to confirm diagnosis and monitor resolution in patients with suspected recovery from tickborne illness who are still experiencing fatigue 4
• PCR for tickborne illnesses should be considered if suspicion exists, as recommended by the CDC 4
• Urinalysis and urine culture are crucial for evaluating urinary symptoms, with the presence of pyuria (>10 WBCs/high-power field) and bacteriuria indicating a urinary tract infection, as recommended by the Infectious Diseases Society of America 5

Imaging Studies

• Chest X-ray can be used to rule out pneumonia as a source of fever, which can be a complication of urinary tract infections, as recommended by the Critical Care Medicine guidelines 2, 6
• Abdominal ultrasound can be used to evaluate for abdominal pathology, which can be a cause of bloating and other symptoms, as recommended by the Critical Care Medicine guidelines 6
• CT abdomen/pelvis with IV contrast should be considered if abdominal symptoms are severe or focal, as recommended by the American College of Radiology 7
• MRI would be indicated if native vertebral osteomyelitis is suspected, as recommended by the Infectious Diseases Society of America 8

Clinical Evaluation and Referral

• Vital signs should be assessed and targeted physical examination should be performed, focusing on skin (rashes), neck stiffness, lymphadenopathy, and abdominal examination, to look for localizing signs of infection, as recommended by the Critical Care Medicine guidelines 2
• Repeating physical examinations is crucial as new findings may emerge over time, and delaying transfer to the emergency department when concerning features (altered mental status, hypotension) are present should be avoided, as recommended by the Critical Care Medicine guidelines 2
• If neck stiffness is present with fever, especially with headache or altered mental status, immediate referral to emergency department is warranted, according to the Infectious Diseases Society of America 9
• If signs of meningitis or severe sepsis are present, immediate referral to emergency department is recommended, and do not delay transfer for additional testing, as advised by the American College of Cardiology 10
• If pre-syncope is present, a 12-lead ECG is essential for evaluating cardiac conditions, as recommended by the American College of Cardiology 11

Potential Pitfalls

• Failing to consider tickborne illnesses in patients with fever and nonspecific symptoms is a potential pitfall, as warned by the CDC 4
• Relying on presence of rash to diagnose or exclude tickborne diseases is a potential pitfall, as warned by the CDC 4
• Delaying transfer to emergency department when concerning features are present is a potential pitfall, as warned by the American College of Cardiology 10
• Overlooking urinary tract infection as a common cause of symptoms can lead to delayed diagnosis and treatment, as warned by the American College of Physicians and the Infectious Diseases Society of America 6, 5
• Neglecting to consider non-infectious causes of symptoms can lead to delayed diagnosis and treatment, as warned by the American College of Physicians and the Infectious Diseases Society of America 6, 5, 2
• Missing cardiac causes of pre-syncope can lead to delayed diagnosis and treatment, as warned by the American College of Cardiology 11