PUO (Pyrexia of Unknown Origin) – Causes & Workup

puo fuo fever

PUO or Pyrexia of unknown or FUO (Fever of unknown origin) origin refers to a febrile state of a prolonged duration without any obvious cause.

It is important to note that PUO is not a diagnosis, it is a failure on the part of the physician to reach a diagnosis.

Quite often, the physician is misguided by the investigations. This happens with those physicians, especially who are focusing just on investigations.

But, investigations when advised without a clinical clue and unintelligently, the diagnosis can become very difficult to make.

An example of unintelligent investigations:

A young female aged 24 years visited a physician for a one-day history of high-grade fever with rigors and chills associated with a dry cough and mild headache.

She was advised a lot of investigations including:

Her investigations were all normal except the sputum cultures grew pseudomonas and she was started on intravenous piperacillin-tazobactam and cefepime.

After one day, her fever settled and she was asked to continue the antibiotics at home.

The next day at home, she again spiked a fever of 103 F at which time she was brought to our OPD.

The attendants were requested to consult their primary physician but they did not agree. After a detailed history and examination, she was started on paracetamol (acetaminophen) on as needed basis and all the other medicines including the antibiotics were stopped.

She spiked a temperature of 105 F on the third day

She was alright and was fever free for two days. On the third day, she spiked a temperature of 105 F and she was started on antimalarials after sending the thick and thin smear and ICT-MP.

The patient responded very well to the treatment and was discharged. She wasted Rs. 24000 during these three days on the medications and investigations only (excluding the hospital charges).

So, What went wrong here?

Obviously, the sputum report was not required in the first instance. The patient had a dry cough with a normal chest X-Ray and Blood CBC.

Even though the sputum test was sent, it was contamination. How can we justify a drug-resistant pseudomonas growing on the sputum (or saliva) of a healthy patient?

Let’s come back to the main topic – PUO:

The above example is of a patient with fever of one day and not a PUO. The definition of PUO is given as follows:

PUO was previously defined as:

    • Fever higher than 38.3ºC on several occasions
    • Duration of fever for at least three weeks
    • Uncertain diagnosis after one week of study in the hospital.

This definition has been used for decades, until recently.

The current definition of PUO has been divided into four different subcategories:

  1. Classic FUO
  2. Nosocomial FUO
  3. Neutropenic FUO
  4. FUO associated with HIV infection.

Classic PUO:

Classic FUO is more or less the same as previously defined with just slight modifications. These include three outpatient visits or three days in the hospital without a known cause or one week of intelligent and invasive ambulatory investigation.

Nosocomial PUO:

It is defined as a temperature of 38.3°C (101°F) on several occasions in a hospitalized patient who has been investigated for three days including at least 2 days’ incubation of cultures.

Neutropenic PUO:

It is defined as a temperature of 38.3°C (101°F) in a patient whose absolute neutrophil count is less than 500/uL and a specific cause is not identified after three days of investigation, including at least 2 days’ incubation of cultures.

HIV-associated PUO:

It is defined by a temperature of 38.3°C (101°F) over a period of 4 weeks or more for outpatients or more than 3 days for hospitalized patients with HIV infection if appropriate investigation over three days, including 2 days’ incubation of cultures, reveals no source.

Causes of PUO (pyrexia of unknown origin):

There is a long list of causes ranging from infections, autoimmune diseases, malignancies, drugs, and endocrine causes.


Infections are still among the most common causes of PUO, especially in developing countries. The common infections that may present as PUO are:

  1. Tuberculosis
  2. Typhoid fever
  3. Fungal infections
  4. Hidden bacterial infections and abscesses like infective endocarditis, perinephric, liver, and splenic abscesses.

Autoimmune causes:

Autoimmune causes may also present with a febrile state. Most autoimmune rheumatic or collagen vascular diseases have associated systemic symptoms including arthralgias, arthritis, myalgias, and a rash

These include

  1. Systemic lupus erythematosus
  2. Rheumatoid arthritis
  3. Stills disease
  4. Myositis
  5. Vasculitides like Wegener’s granulomatosis, polyarteritis nodosa, and others
  6. Polymyalgia rheumatica

Other immune-mediated causes of PUO include:

  • Extrinsic allergic alveolitis
  • Eosinophilic pneumonia
  • Granulomatous hepatitis
  • Inflammatory Bowel diseases
  • Hypersensitivity pneumonitis


Malignancies may sometimes present with fever and PUO. Apart from fever, most malignancies have associated weight loss, anorexia, and symptoms related to the specific system.

Common malignancies presenting as PUO include:

  1. Lymphoma (Hodgkins and Non-Hodgkins lymphoma)
  2. Leukemias
  3. Lung cancer
  4. Colorectal cancer
  5. Breast cancer

Most of the solid tumors and metastatic tumors can cause fever. PUO is commonly associated with breast, colon, hepatocellular, lung, pancreatic, and renal cell carcinomas.

Benign tumors may include atrial myxoma, angiomyolipoma, and craniopharyngioma.

Endocrine Causes of PUO:

Endocrine causes of fever are among the most common causes of PUO. These patients have subtle multisystemic symptoms including weight changes, changes in blood sugars, mood swings, tingling and numbness of the body parts especially limbs, anorexia or increased appetite, changes in bowel habits, etc.

Common endocrine causes of PUO include:

  1. Hyperthyroidism
  2. Thyroiditis
  3. Adrenal insufficiency
  4. Pheochromocytoma

Other miscellaneous causes of fever include:

  • Familial Mediterranean fever
  • Factitious fever
  • Psychogenic fever

How to investigate a patient with PUO?

How to investigate PUO? You have already had a lot of investigations before you are labeled as a case of PUO. So, as mentioned earlier, you don’t need to advise a lot of investigations to reach a diagnosis.

You need to have intelligent investigations or investigations to be read intelligently. I am discussing here a few important investigations that are commonly prescribed.

Blood CBC – Neutrophilic leukocytosis:

Although neutrophilic leukocytosis is commonly seen in bacterial infections, it is not synonymous with an infective cause. Causes of neutrophilic leukocytosis other than infections include:

  1. Inflammatory diseases like inflammatory bowel diseases, rheumatoid arthritis, vasculitis, and Adult-Onset Stills disease.
  2. Drugs like corticosteroids, lithium, heparin, seizure medications (carbamazepine, phenobarbital, and phenytoin), antibiotics like minocycline, and DRESS syndrome.
  3. Malignancies including lymphomas, acute and chronic leukemias like chronic myelocytic leukemia (CML),  and solid organ malignancies like lung cancer and paraneoplastic syndromes.
  4. Stressful conditions like myocardial infarction and hypoxemia.

CRP or C-reactive protein:

CRP is a marker of inflammation. It is elevated in inflammatory conditions like autoimmune rheumatic diseases like SLE and Rheumatoid arthritis, apart from infections.

It is not a marker of infections!

Elevated CRP has also been associated with poor prognosis in cardiovascular and coronary artery disease, fibrosis, cancers, obstructive sleep apnea, and inflammatory bowel diseases.

ESR (erythrocyte sedimentation rate):

ESR is the rate at which the red cells settle in a standard tube. It is mainly dependent on plasma proteins especially fibrinogen.

ESR is typically elevated in the following conditions:

  • Anemia
  • Pregnancy
  • Inflammation and infections like tuberculosis
  • Autoimmune diseases like Rheumatoid arthritis
  • Cancers like multiple myeloma and leukemia
  • Temporal arteritis and Polymyalgia rheumatica
  • Thyroiditis


Lastly, Procalcitonin is commonly advised nowadays. Like CRP, this is not synonymous with an infection!

  • It is used as a marker of severe bacterial sepsis
  • It can guide the physician regarding the initiation, switching from intravenous to oral, and the discontinuation of antibiotics in patients with pneumonia
  • It can guide the physician to step-up or step-down therapy in asthmatics and patients with chronic obstructive pulmonary diseases.
  • Procalcitonin has recently been incorporated in the management algorithm of heart failure by the European Society of Cardiology.
  • Other uses include the confirmation of bacterial meningitis, for monitoring of recurrence in patients with medullary thyroid cancer, and excluding septic arthritis.
  • It is especially helpful as a marker to guide antibiotic stewardship.

puo get well soon

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