Laboratory diagnosis of Pyrexia of Unknown Origin (PUO)

 

Introduction:

•        The normal body temperature is 36.5-37.5⁰C (97.7-99.5⁰F)

•        Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point

•        Fever of unknown origin (FUO) or Pyrexia of unknown origin (PUO) is a very common term used by clinicians to refer to any febrile illness without an initially obvious etiology.

•        Most febrile illnesses either resolve before a diagnosis can be made or eventually show typical clinical features or positive for specific investigations  that lead to arrive at a correct diagnosis. These group of febrile illness are not called as FUO.

•        The term FUO is reserved only for

–       prolonged febrile illnesses

–       without an established etiology

–       despite of intensive evaluation and diagnostic testing.

Learning objectives

•        Classification & definitions of FUO

•        Pathophysiology of fever

•        Etiology of FUO

•        Clinical manifestations of FUO

•        Laboratory diagnosis of FUO

Classification&definitions of FUO

Durack and Street definition of FUO

Classical FUO •        Temperature of >38.3° C (101°F) •        Duration of fever > 3 weeks •        Three out patient visits or •        3 days in the hospital without elucidation of a cause or •        1 week of intelligent and invasive ambulatory investigations

Nosocomial FUO •        Temperature of >38.3° C (101°F) develops in a hospitalized patient; in whom infection was not manifested or incubating on admission •        Three days of investigations including cultures  reveals no source

Neutropenic FUO •        Temperature of >38.3° C (101°F) •        Neutrophil count < 500/ µl •        Three days of investigation including  cultures  reveals no source

HIV associated FUO •        Temperature of >38.3° C (101°F) for > 4 weeks for outpatients or > 3 days for hospitalized patients •        HIV infection has been confirmed •        Three days of investigation including  cultures  reveals no source

 

Etiology of FUO

•        Infections (36%): accounts for majority of FUO cases

•        Neoplasms (19%): lymphoma, leukemia, myeloma, renal, colon and liver cancers, etc.

•        Non-infectious Inflammatory Diseases (19%): connective tissue disorders - rheumatoid arthritis, SLE, etc.

•        Miscellaneous Causes (19%):Granulomatous diseases, Inherited and metabolic diseases, Thermoregulatory disorders, Undiagnosed cases (7%)

Tabble:1- Infectious causes of Classical FUO

Bacterial causes		Viral infections	Parasitic infections	Fungal infections
Localized pyogenic infections	Systemic bacterial infection	Cytomegalovirus and EBV infection	Malaria	Aspergillosis
Appendicitis	Mycobacterial infections	Coxsackievirus group B infection	Amoebiasis	Mucormycosis
Cholangitis	Typhoid fever	Viral hepatitis	Leishmaniasis	Blastomycosis
Abscess	Rickettsial infections	HIV infection	Chagas’ disease	Histoplasmosis
Mesenteric lymphadenitis	Mycoplasma infections	Dengue / Chikunguniya	Toxoplasmosis	Coccidioidomycocis
Osteomyelitis	Chlamydial infections		Strongyloidiasis	Paracoccidioidomycosis
Pelvic inflammatory disease	Brucellosis			Candidiasis
Sinusitis	Meliodosis			Cryptococcosis
Suppurative thrombophlebitis	Listeriosis			Pneumocystis infection
Intravascular infections	Bartonellosis			Sporotrichosis
	Spirochete infections: •        Syphilis •        Lyme disease •        Relapsing fever •        Leptospirosis

 

Clinical manifestations of FUO:

•        In person with acute febrile illness (microbial infection), the symptoms are:

–       Chills followed by rapid rise of temperature

–       Flushing of tissue

–       Intense sweating

–       Malaise

–       Lethargy

–       Weakness

–       Shock

•        In person with neoplastic disease, the symptoms are:

–       Emaciation

–       Fever

–       Chills,  weight loss

–       Headache

–       Photophobia

–       General malaise

•        Systemic symptoms in fever are:

–       Pain in back

–       Generalized myalgias

–       Arthralgia without arthritis

–       Sometimes delirium and convulsions

Laboratory diagnosis of FUO:

The differential diagnosis for FUO is extensive, but it is important to remember that FUO is far more often caused by an atypical presentation of a rather common disease than by a very rare disease

First and foremost step is to establish that fever really exist (by strict temperature record) and, to verify the prolonged fever meets the fever-of unknown-origin definition

Because FUOs are caused by a wide variety of disorders, the diagnostic approach to the FUO patient is often extensive consisting of three stages:

Stage – 1:The most important initial step is the search for PDCs (potentially diagnostic clues) through complete and repeated history – taking, physical examination, and non-specific investigations. (Table: 2) After identification of all PDCs, determine the Category of FUO (infectious, neoplastic, inflammatory, or miscellaneous) to direct the diagnostic workup.

Table: 2 – Potentially diagnostic clues

History	Suspected Infectious Category of PUO
Previous surgical procedures	Abscesses, SBE
Recent insect exposure/bites,	Malaria, ehrlichiosis/anaplasmosis, Dengue, Chikunguniya
Blood transfusions	CMV, HIV
Travel	Typhoid, Legionnaire’s disease, brucellosis, HIV, malaria, Q fever
Animal contact	Brucellosis, typhoid/enteric fever, Q fever, CSD, rat bite fever
Physical Examination
Relative bradycardia	Typhoid/enteric fever, leptospirosis, brucellosis, malaria, Legionnaire’s disease, trichinosis)
Conjunctival suffusion	Relapsing fever
• Subconjunctival hemorrhage	SBE
• Regional adenopathy ()	Toxoplasmosis, CSD, HIV
Hepatomegaly	Relapsing fever, typhoid/enteric fever, Q fever
Splenomegaly	Miliary TB, SBE, brucellosis, EBV, CMV, relapsing fever, typhoid/enteric fever
• Hyperpigmentation	Visceral leishmaniasis (kala-azar), Whipple’s disease, histoplasmosis
Roth spots	SBE, malaria
Non-specific tests
Leukopenia	HIV, miliary TB, brucellosis, typhoid/enteric fever
Lymphocytosis	Miliary TB, EBV, CMV, toxoplasmosis
Thrombocytopenia	HIV, CMV, relapsing fever, malaria, babesiosis, ehrlichiosis/anaplasmosis, Dengue, Chikunguniya
Highly elevated ESR >100 mm/h	Abscess, osteomyelitis, SBE
Increased serum transaminases	EBV, CMV, Q fever, toxoplasmosis, relapsing fever, brucellosis)

 

Stage – 2 : A limited list of the specific non-invasive investigations should be aimed at confirming or excluding the suspected disease.

Stage – 3 : Invasive investigations should be considered in the workup of FUO if the non-invasive investigations are unrevealing and if fever is prolonged.

 

Microbiologic investigations:

As the most common cause of unexplained fever is infection, collection and careful examination of appropriate specimens are essential.

 The most important specimens include:

·        blood for culture

·        blood for examination of antibodies.- Serological tests are helpful, particularly in the diagnosis of cytomegalovirus (CMV) and Epstein–Barr virus (EBV)infection, toxoplasmosis, psittacosis and rickettsial infections.

·        direct examination of blood to diagnose malaria, trypanosomiasis and relapsing fever

·        Multiplex PCR are also helpful for detection of viral infections

 

Repeated sampling of blood, urine and other body fluids maybe required, and the laboratory should be alerted to search for unusual and fastidious organisms (e.g. nutritionally variant streptococci as a cause of endocarditis)

If possible, serial cultures should be collected before antimicrobial therapy is commenced

All biopsy specimens should be cultured for bacteria, mycobacteria, and fungi.