PYREXIA OF UNKNOWN ORIGIN (PUO)

By : Zaid Al-Ghnaneem

Before talking about PUO , lets talk briefly about Fever (Pyrexia) ..

What is fever ?‘Fever’ implies an elevated core body temperature of more than 38.0°C, it is a response tocytokines and acute phase proteins.It occur in infectious and non infectious conditions.

The acute phase response refers to the production of a variety of proteins by the liver inresponse to inflammatory stimuli.

These proteins have a wide range of activities, for example :Circulating levels of C-reactive protein (CRP) and serum amyloid A may be increased 1000-fold,contributing to host defense and stimulating repair and regeneration.

What is PUO ?a temperature above 38.0°C on multiple occasions for more than 3 weeks, withoutdiagnosis, despite initial investigation in hospital for 1 week.

Also, it includes :Investigation over 3 days of inpatient care, or3 outpatient (Ambulatory) visit's, or1 week of intensive ambulatory investigation .

But without result in determining the cause.

The PUO has been divided to 3 subsets :Either : 1- HIV-1 related 2- immune-deficient 3- nosocomial

Does that mean every PUO will be diagnosed in one of these Subsets ?

CAUSES OF PUO ?

• There are so many causes of PUO and that means a lot of investigations to know theexact etiology, but we will categorize them as follow :

• 1- Infectious (30%)

• 2- Malignancy (20%)

• 3- Connective tissue disorders (15%)

• 4- Miscellaneous (20%)

• 5- Idiopathic (15%)

→ Infectious causes :• TB and other mycobacterial infection• Occult abscesses (e.g., hepatic, retroperitoneal)• UTI/complicated UTI• Endocarditis• Sinusitis• HIV• Infectious mononucleosis and other viruses• Malaria and other parasitic infections

→ Malignancy :• Lymphoma• Leukemia

→ Connective tissue disorders :• SLE• PAN• Temporal arteritis• Polymyalgia rheumatica• Adult-onset Still's disease (AOSD)• Polymyositis• Behcet Disease

→ Miscellaneous :- CVS ( Atrial myxoma, aortitis, aortic dissection )- RS ( Sarcoidosis, PE, allergic alveolitis )- GI ( IBD, Pancreatitis, Alcoholic liver disease )- Metabolic ( Thyrotoxicosis, thyroiditis, PC,

hypertriglyceridemia, any hypothalamic lesions )- Hematological ( Hemolytic anemia, PNH, TTP, GVHD )- Inherited ( FMF, Periodic fever symptoms )- Drug reactions ( Antibiotic fever, some drugs )- Factitious Fever

So as we see in the previous slide, there are so many causes, and the diagnosis of PUO ischallenging, because you have to do the Investigations for every one of possible causes toexclude it .

Please note that some causes we may find them in specific groups , for example :

1- Periodic fever syndromes should be considered in those with a family history.2- Children and younger adults are more likely to have infectious causes – in particular, viralinfections.3- Older adults are more likely to have certain infectious and non-infectious causes.4- In men, the prostate should be considered as a potential source of infection.

* In some cases of PUO, fevers may resolve spontaneously without ever being diagnosed.

Some of associated signs and symptoms that may occur with PUO :

- Sweating- Chills and shivering- Headache- Loss of appetite- Dehydration- Irritability- General weakness- Unusual skin rash, especially if the rash rapidly worsens- Persistent vomiting

One of the most important things is detailed history and examination should be repeated atregular intervals to detect emerging features such as rashes, vasculitis… etc.

Investigations :If initial investigation of fever is negative, further microbiological and non-microbiologicalinvestigations should be consideredAlso, we must take the priority to start with the most possible test depending on the potentialexposure to pathogens and suspected cause , the usual investigations are :1- sputum or other specimens for mycobacterial stains and culture .2- serological tests, including an HIV test, and ferritin estimation .3- imaging of the abdomen by ultrasonography or computed tomography (CT) .4- ECO

Lesions identified on imaging should usually be biopsied in order to seek evidence of relevantpathogens by culture, histopathology or nucleic acid detection.Particularly in patients who have received prior antimicrobials, 16S rRNA analysis, may aiddiagnosis if a microorganism is not cultured.The chance of a successful diagnosis is greatest if procedures for obtaining and transporting thecorrect samples in the appropriate media are carefully planned between the clinical team, theradiologist or surgeon performing the procedure, and the local microbiologist andhistopathologist.

• Is there anyway to aid diagnosis of vasculitis ? Or to help select the biopsy site ?Yes by Positron emission tomography (PET)

Temporal artery biopsy should be considered in patients over the age of 50 years, even in theabsence of physical signs or a raised ESR

‘Blind’ biopsy of other structures in the absence of localizing signs or laboratory or radiologyresults is unhelpful.

→Observation is sometimes necessary to make a diagnosis

→Laboratory tests :- CBC with differential- Urinalysis- Inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)- Cultures of blood, sputum, CSF, urine, and stool when indicated by clinical presentation- Analysis and culture of abnormal fluid collections (e.g., joint, pleural)- Complement assay- LFTs, ESR, ANA, rheumatoid factor, TSH- antibodies to HIV-1

Treatment :Rest, drinking plenty of fluids, stop taking any medications for unnecessary cases because thesedrugs maybe pyrogenic and increase fever, paying attention to nutrition and supplements,Cooling the skin.

Drug Therapies :- Acetaminophen “Paracetamol”- Aspirin and other nonsteroidal anti-inflammatory drugs- Antipyretics- In cases of infection, antibiotic, antifungal, or antiviral drug, depending on the cause of the

infection.

→ Further management is focused on the underlying cause.

Prognosis :No cause is found in approximately 10% of PUO cases, but as long as there is no significantweight loss or signs of another disease, the long-term mortality is low.

THANK YOU