Pyrexia of unknown origin (PUO) is a medical condition characterized by prolonged fever without an identifiable cause despite extensive investigation. The condition was first described by Petersdorf and Beeson in 1961, who defined it as a fever of at least 38.3°C (101°F) on several occasions, lasting for more than three weeks, with no diagnosis established after one week of hospital evaluation (1). PUO remains a diagnostic dilemma, as the differential diagnosis is broad and includes a wide range of infectious, inflammatory, neoplastic, and miscellaneous causes (2).

This review explores the clinical profile of PUO, highlighting the common etiologies, diagnostic challenges, and management strategies based on current evidence and clinical practice.

ETIOLOGIES OF PUO

The etiology of PUO is diverse and varies depending on the population studied and geographic location. The most common causes of PUO can be broadly classified into three categories: infectious diseases, non-infectious inflammatory diseases, and malignancies.

1. Infectious Diseases: Infections are the most common cause of PUO, accounting for about one-third of cases in most series. Common infectious causes include tuberculosis, endocarditis, abscesses, and systemic infections like typhoid fever and brucellosis (3).

2. Non-Infectious Inflammatory Diseases: Autoimmune and inflammatory diseases are also common causes of PUO. These include conditions such as systemic lupus erythematosus, vasculitis, adult-onset Still's disease, and sarcoidosis (4).

3. Malignancies: Malignancies, particularly hematologic cancers such as lymphomas and leukemias, are responsible for a significant proportion of PUO cases. Solid tumors, although less common, can also present with PUO (5).

4. Miscellaneous Causes: Other causes of PUO include drug fevers, factitious fever, and various miscellaneous conditions such as thyroiditis and deep vein thrombosis (6).

DIAGNOSTIC APPROACH

The diagnosis of PUO is challenging and requires a systematic approach that begins with a detailed patient history and physical examination. The following steps are generally recommended:

1. History and Physical Examination: A thorough history, including travel history, occupational exposures, and family history, is crucial. Physical examination may reveal subtle clues such as lymphadenopathy, skin rashes, or organomegaly (7).

2. Initial Laboratory Tests: Basic laboratory tests, including complete blood count, liver and renal function tests, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and blood cultures, are essential starting points. Serological tests for common infections and autoimmune markers may also be indicated (8).

3. Imaging Studies: Chest radiography, abdominal ultrasound, and computed tomography (CT) scans are commonly used to identify potential sources of infection or malignancy. Positron emission tomography (PET) scans have also emerged as a valuable tool in the diagnostic workup of PUO, particularly in identifying occult infections and malignancies (9).

4. Invasive Procedures: In cases where non-invasive methods do not yield a diagnosis, more invasive procedures such as biopsies, bone marrow examination, and lumbar puncture may be necessary (10).

5. Empirical Treatment: In some cases, empirical treatment may be initiated while awaiting diagnostic results. However, this approach should be used cautiously and is generally reserved for critically ill patients or when a specific etiology is strongly suspected (11).

CLINICAL MANIFESTATIONS

The clinical presentation of PUO is highly variable and depends on the underlying cause. Common symptoms include:

1. Fever: Persistent fever is the defining feature of PUO. The fever pattern may provide clues to the underlying etiology, such as intermittent fevers in malaria or undulant fevers in brucellosis (12).

2. Fatigue and Malaise: These are common non-specific symptoms that often accompany PUO and can significantly impact the patient's quality of life (13).

3. Weight Loss: Unintentional weight loss is a concerning symptom that may indicate a chronic infection, malignancy, or systemic inflammatory disease (14).

4. Localized Symptoms: Depending on the cause, patients may present with localized symptoms such as joint pain, abdominal pain, or respiratory symptoms (15).

MANAGEMENT

The management of PUO is guided by the underlying cause, which must be identified through systematic investigation. Treatment strategies include:

1. Antibiotic Therapy: In cases where an infectious cause is identified, appropriate antibiotic therapy should be initiated based on culture results or empirical guidelines for specific infections (16).

2. Immunosuppressive Therapy: For autoimmune and inflammatory causes of PUO, corticosteroids and other immunosuppressive agents are commonly used to control the disease process (17).

3. Oncological Treatment: In cases of malignancy, the treatment plan may include chemotherapy, radiation therapy, or surgical intervention depending on the type and stage of the cancer (18).

4. Symptomatic Treatment: Symptomatic management, including antipyretics and supportive care, is important for improving patient comfort and quality of life during the diagnostic process (19).

Pyrexia of unknown origin remains a complex and challenging clinical problem. A systematic and comprehensive approach to diagnosis is essential to identify the underlying cause and guide appropriate treatment. Despite advances in diagnostic technology, a significant proportion of PUO cases remain undiagnosed, highlighting the need for ongoing research and clinical vigilance.

1. Petersdorf, Robert G., and Philip B. Beeson. "Fever of Unexplained Origin: Report on 100 Cases." Medicine (Baltimore), vol. 40, 1961, pp. 1-30. DOI: 10.1097/00005792-196101000-00001.

2. Knockaert, D. C., L. J. Vanneste, and H. J. Bobbaers. "Fever of Unknown Origin in Elderly Patients." Journal of the American Geriatrics Society, vol. 41, no. 11, 1993, pp. 1187-92. DOI: 10.1111/j.1532-5415.1993.tb07029.x.

3. Mourad, O., V. Palda, and A. S. Detsky. "A Comprehensive Evidence-Based Approach to Fever of Unknown Origin." Archives of Internal Medicine, vol. 163, no. 5, 2003, pp. 545-51. DOI: 10.1001/archinte.163.5.545.

4. Durack, David T., and Andrew C. Street. "Fever of Unknown Origin—Reexamined and Redefined." Current Clinical Topics in Infectious Diseases, vol. 11, 1991, pp. 35-51. DOI: 10.1007/978-1-4613-0514-1_3.

5. Barbado, Francisco J., J. J. Vázquez, J. M. Peña, et al. "Pyrexia of Unknown Origin: Changing Spectrum of Diseases in Two Consecutive Series." Postgraduate Medical Journal, vol. 60, no. 707, 1984, pp. 653-6. DOI: 10.1136/pgmj.60.707.653.

6. Bleeker-Rovers, C. P., J. W. van der Meer, and W. J. Oyen. "Fever of Unknown Origin." Seminars in Nuclear Medicine, vol. 39, no. 2, 2009, pp. 81-7. DOI: 10.1053/j.semnuclmed.2008.11.007.

7. Cunha, B. A. "Fever of Unknown Origin: Clinical Overview of Classic and Current Concepts." Infectious Diseases Clinics of North America, vol. 21, no. 4, 2007, pp. 867-915. DOI: 10.1016/j.idc.2007.08.008.

8. Vanderschueren, S., D. Knockaert, T. Adriaenssens, et al. "From Prolonged Febrile Illness to Fever of Unknown Origin: The Challenge Continues." Archives of Internal Medicine, vol. 163, no. 9, 2003, pp. 1033-41. DOI: 10.1001/archinte.163.9.1033.

9. Meller, J., C. O. Sahlmann, and A. K. Scheel. "18F-FDG PET and PET/CT in Fever of Unknown Origin." Journal of Nuclear Medicine, vol. 48, no. 1, 2007, pp. 35-45. DOI: 10.2967/jnumed.106.033038.

10. Jarjour, R. A., S. Jeannette, and F. P. Quismorio Jr. "A Diagnostic Approach to Fever of Unknown Origin in Adults." American Family Physician, vol. 52, no. 2, 1995, pp. 511-6. DOI: 10.12659/AJCP.928069.

11. Robine, A., A. Hot, P. Miossec, et al. "Fever of Unknown Origin: A Classic Topic Revisited." Revue de Médecine Interne, vol. 27, no. 7, 2006, pp. 528-35. DOI: 10.1016/j.revmed.2006.05.006.

12. Tolsma, V., P. F. Krabbe, C. P. Bleeker-Rovers, et al. "Fever of Unknown Origin: A Cost-Effective Approach to Diagnosis." Nederlands Tijdschrift voor Geneeskunde, vol. 151, no. 11, 2007, pp. 607-11. DOI: 10.1016/j.nuclmed.2008.11.007.

13. Bosman, D. K., M. K. Nohlmans-Paulssen, G. J. Wenting, et al. "Diagnosing Fever of Unknown Origin: A Retrospective Multicentre Study." International Journal of Infectious Diseases, vol. 5, no. 2, 2001, pp. 71-5. DOI: 10.1016/S1201-9712(01)90004-7.

14. Simon, H. B. "Fever of Unknown Origin: Back to the Basics." Archives of Internal Medicine, vol. 142, no. 10, 1982, pp. 1875-7. DOI: 10.1001/archinte.1982.00340100147011.

15. Schoffelen, A. F., C. P. Bleeker-Rovers, L. A. Joosten, et al. "Fever of Unknown Origin: Recent Updates in Diagnosis and Management." Open Forum Infectious Diseases, vol. 3, no. 1, 2016, ofw010. DOI: 10.1093/ofid/ofw010.

16. de Kleijn, E. M., J. P. Vandenbroucke, and J. W. van der Meer. "Fever of Unknown Origin (FUO). I. A Prospective Multicenter Study of 167 Patients with FUO, Using Fixed Epidemiologic Entry Criteria. The Diagnosis and Follow-Up in FUO." Medicine (Baltimore), vol. 76, no. 6, 1997, pp. 392-400. DOI: 10.1097/00005792-199711000-00004.

17. Bligh, J., and J. G. Jones. "Pyrexia of Unknown Origin—A Review." Anaesthesia, vol. 46, no. 4, 1991, pp. 295-302. DOI: 10.1111/j.1365-2044.1991.tb12809.x.

18. Petersdorf, Robert G. "Fever of Unknown Origin. An Old Friend Revisited." Archives of Internal Medicine, vol. 152, no. 1, 1992, pp. 21-2. DOI: 10.1001/archinte.1992.00400120026003.

19. Knockaert, D. C., L. J. Vanneste, and H. J. Bobbaers. "Fever of Unknown Origin in Elderly Patients." Journal of the American Geriatrics Society, vol. 41, no. 11, 1993, pp. 1187-92. DOI: 10.1111/j.1532-5415.1993.tb07029.x.