Clinicians commonly refer to a febrile episode without an initially obvious aetiology or without localising signs as pyrexia of unknown origin (PUO). PUO actually refers to a prolonged febrile illness without an established aetiology despite intensive diagnostic testing. In this article, Dr. Sudhir Mehta enumerates the key practice points for PUO below.

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Pyrexia of unknown origin (PUO)

The definition of PUO defined by Petersdorf and Beeson (1961) [1] has long been the clinical standard, characterised by:

• Fever >38.3ºC on several occasions
• Duration of fever for at least 3 weeks
• Uncertain diagnosis after one week of evaluation in the hospital

Nowadays, the in-hospital evaluation criterion has been abandoned. The degree and duration of fever are not the only criteria for defining PUO. Prior to concluding that a patient has PUO, the following evaluation should be performed, though not revealing the diagnosis:

• Meticulous history
• Thorough physical examination
• Complete blood count, peripheral smear examination
• Blood cultures
• Routine blood chemistries, including liver function tests (LFTs)
• If liver tests are abnormal, hepatitis viral serology
• Urine microscopic examination and culture
• Chest X-ray

If there are any signs or symptoms that point to a particular organ system, further testing, imaging, and/or biopsy should be performed to pinpoint the diagnosis.

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Causes

Three general categories of illness account for the majority of "classic" PUO cases:

• Infections
• Malignancies
• Systemic rheumatic disease (e.g. vasculitis, rheumatoid arthritis)

Among infections, tuberculosis and abscesses are the most common aetiologies presenting as PUO. Systemic juvenile idiopathic arthritis (formerly called Still's disease) in younger patients and giant cell arteritis in older individuals are the most common rheumatologic disorders presenting as PUO.

The most common malignancies to present with PUO are lymphoma, especially non-Hodgkin's, leukaemia, renal cell carcinoma, and hepatocellular carcinoma or other tumours metastatic to the liver. Drug fever due to a variety of drugs is also a common cause of PUO.

There are many factors that alter the pattern of PUO. For example, frequent use of empiric antimicrobials can delay the diagnosis of some occult abscesses and infections. Aggressive immunosuppressive regimens, lengthy intensive care unit admissions, and the increase in multiresistant organisms as resident hospital flora have all altered the types of PUO’s encountered.

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Epidemiology

True PUOs are uncommon in western countries. This was illustrated in a report from the Netherlands in which only 73 patients were identified between December 2003 and July 2005 at a 950-bed academic referral hospital and five community hospitals comprising 2800 hospital beds. [2]

However, in healthcare resource constraint countries, PUO is still a challenging problem for clinicians. Infectious causes of prolonged fever in resource-limited countries include tuberculosis, typhoid, amebic liver abscesses, and AIDS.

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Clinical approach

Assessment of a patient with PUO requires a detailed history and meticulous physical examination, which may be repeated at regular intervals, to detect any new signs that may appear later in the course of the disease. It is important to look for uncommon presentations of common diseases rather than looking for rare diseases.

The history and physical examination, like laboratory tests, have the potential to generate valuable diagnostic clues in patients with PUO. A thorough history should not miss the following information:

• Travel history
• Animal exposure (e.g., pets, occupational, living on a farm)
• Type of immunosuppression
• Drug and toxin history, including antimicrobials
• Localising symptoms

Subtle findings, many times, can be uncovered through careful history-taking. Revisiting the history several times may provide new clues in difficult to diagnose cases. In other words, serial/repeated history taking and physical examination are important techniques to establish a diagnosis of PUO.

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Investigations

The list of tests for evaluation of PUO is quite exhaustive and the extent to which a patient is investigated depends at what point diagnosis is clinched.  A battery of the following tests is pursued as part of the investigative protocol, in addition to those listed above:

• Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
• Serum lactate dehydrogenase
• HIV immunoassay and HIV viral load for patients at high risk
• Three routine blood cultures drawn from different sites over a period of at least several hours without administering antibiotics
• Immuno-17 profile
• Creatine phosphokinase
• Serum protein electrophoresis
• Computed tomography (CT) scan of the abdomen
• HRCT scan of the chest
• Markers of malignancies

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Acute-phase reactants

Almost all clinicians favour obtaining an ESR or CRP, despite their lack of specificity. One study [4] reviewed ESR elevations above 100 mm/h among 263 patients with PUO:

• 58% had malignancy, most commonly lymphoma, myeloma, or metastatic colon or breast cancer
• 25% had infections such as endocarditis or systemic rheumatic diseases like rheumatoid arthritis or giant cell arteritis

In a hospital-based observational cross-sectional study (unpublished data; personal communication), conducted in adults aged 18 years and above, out of 178 patients with extremely elevated ESR (>100 mm/hr), infection was the most common cause which included:

• Bacterial pneumonia (12.9%)
• Sepsis (11.9%)
• Pulmonary tuberculosis (7.2%)
• Bacterial abscess (4.9%)
• COVID-19 (4.9%)
• Scrub typhus (2.7%)
• HIV (2.2%)

Renal insufficiency which included acute kidney injury (10.1%) and chronic kidney disease (3.9%), malignancy (7.8%), chronic inflammatory conditions like HTN, DM, COPD and CVA were other causes. Extremely elevated ESR was not found in chronic liver disease and malaria. Drug hypersensitivity reactions, thrombophlebitis, and renal disease may be accompanied by a very high ESR in the absence of infection or malignancy.

A normal ESR or CRP also suggests that a significant inflammatory process is unlikely. However, there are exceptions. For example, some patients with giant cell arteritis can have a normal ESR. Procalcitonin, a serum biomarker that is elevated with certain bacterial infections has no clear role as part of the PUO evaluation; however, it is often used by clinicians to detect occult bacterial infection.

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CT scan

For similar reasons, CT scanning of the chest is invaluable in the identification of small nodules (indicative of fungal, mycobacterial, or nocardial infection or malignancy). The identification of hilar or mediastinal adenopathy may prompt biopsy by mediastinoscopy, providing a diagnosis of lymphoma, histoplasmosis, or sarcoidosis.

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Nuclear medicine testing

Nuclear medicine testing is a more controversial area in the diagnosis of PUO. It is usually ordered when the initial evaluation (including abdominal and chest CT) remains negative and a screening look at the entire body is desired. Both gallium-67- and indium-111-labelled leukocyte scanning are highly sensitive by virtue of including the whole body. Neither study, however, can pinpoint a diagnosis. They are nonspecific tests to localise a site for more specific evaluation such as with CT. When studied, the overall yield of gallium-67– or indium-111–labelled leukocyte scanning may be higher than with CT or ultrasound.

F-fluorodeoxyglucose positron emission tomography (FDG-PET) appears to be very sensitive in identifying anatomic sites of inflammation and malignancy. This modality may find a valuable place in the evaluation of PUO, [5] but additional data is needed to determine its added value beyond repeated clinical evaluation over time and routine CT.

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Specific tests

When the history, examination, or imaging suggests a possible source, specific testing should be performed. Examples include:

1. Subtle central nervous system symptoms or signs should prompt a lumbar puncture and imaging of the head and/or spine.
2. A history of trauma, adjacent infection or intravenous drug use may suggest thrombophlebitis of the legs, arms, or pelvic vessels. Venous duplex imaging can be diagnostic. Fever usually responds to anticoagulation within several days.
3. A biopsy is a critical modality in the diagnosis of PUO. For example,
   1. Liver biopsy for possible miliary tuberculosis, granulomatous hepatitis, or other granulomatous diseases such as sarcoidosis
   2. Lymph node biopsy for possible malignancy, especially lymphoma, tuberculosis
   3. Biopsy of affected tissue to diagnose a vasculitic process such as polyarteritis nodosa
   4. Pleural or pericardial biopsy for the evaluation of extrapulmonary tuberculosis
   5. Bone marrow biopsy is useful in the diagnosis of haematological malignancy, disseminated tuberculosis, fungal infections, kala-azar etc

Two retrospective reviews of bone marrow biopsies to evaluate PUO demonstrated high diagnostic yields and a high prevalence of haematologic malignancies. [6,7] Lymphomas constituted >40% of diagnoses, whereas infections were detected in <15% of patients.

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Concept of ‘therapeutic trial’ in PUO

Therapeutic trials of antibiotics or steroids, in an attempt to 'do something' rarely help in making a diagnosis. In addition, the diagnostic yield of blood cultures and cultures of biopsy material will be affected following empirical antibiotics.

Antibiotics can have an effect on other infections than the ones towards which therapy is directed. Rifampin, for example, used in a therapeutic trial for tuberculosis may suppress staphylococcal osteomyelitis or diminish the ability to detect difficult-to-isolate organisms causing endocarditis.

A therapeutic trial of steroids for an inflammatory disease should not replace relevant biopsies for steroid-responsive diseases such as sarcoidosis, other granulomatous diseases, or vasculitis. A careful evaluation for infection should precede such a trial.

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Outcome of PUO

The outcome of patients with PUO depends upon the underlying aetiology and associated co-morbid diseases. Most adults who remain undiagnosed after an extensive evaluation also have a good prognosis. This was illustrated in a study of 199 patients with PUO, 61 of whom (30%) were discharged from the hospital without a diagnosis. [8]

Similar findings were noted in the Netherlands series of 73 patients cited above. Among the 37 patients with no diagnosis who were followed for at least six months, 16 spontaneously recovered, 5 recovered with nonsteroidal anti-inflammatory drugs or glucocorticoids, 15 had persistent fever, and 1 died.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Sudhir Mehta is a Haematology expert.