You are referred a 49 year-old teacher with persistent fever. Symptoms started 6 weeks earlier, no cause has been found despite investigation by the GP.

HOW TO APPROACH FOR THAT ?

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Dr Mohammad Abdul MatinMRCP(Ire) MRCP(UK), FACP, FRCP(Edin)

Consultant, Internal Medicine

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Pyrexia of Unknown Origin(PUO)/ Fever of Unknown origin(FUO)

Agenda: 50 minutes

IntroductionDefinition and classificationCauses of classic PUOTen leading causes of classic PUOEvaluationDiagnostic workup/InvestigationsTherapeutic management of PUOConclusion

Why we have fever ?

Complex cytokine mediated (TNF-alfa, IL-1, Il-6) response of the body

TNFLPS IL-6 PGE2 Fever IL-1

Infectious and non-infectious origin Source of fever can be diagnosed in most cases by history, physical

exam or basic lab investigations Subgroup of patients: cause of fever can not be established, then it is

called PUO/FOU.

Definition of PUO/FUO

Pyrexia of Unknown Origin(PUO) or Fever of unknown Origin (FUO) was classically defined by Petersdorf and Beeson in 1961 as:

Temperature of > 38.3 *C(101.0*F) on several occasions,

duration of fever of > 3 weeks,failure to reach a diagnosis despite 1 week of inpatient

investigation.

This definition has stood for more than 30 years, latter on Durack and Street proposed a new system for classification.

New system for Classification of PUO/FUO:

Classic PUONosocomial PUONeutropenic PUOPUO associated with HIV infection

Classic PUO:

Resembles closely to the earlier definition of PUO.

Only difference is the prior requirement for one week inpatient investigation.

New definition includes: 3 outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of ‘intelligent and invasive” ambulatory investigation.

Nosocomial PUO:

Temperature of =/> 38.3*C (101*F) develops on several occasions in a hospitalized patient receiving acute care

Infections was not manifest or incubating on admission

3 days of investigation, including at least 2 days’ incubation culture, is the minimum requirement for this diagnosis

Neutropenic PUO:

Temperature of =/> 38.3*C (101*F) develops on several occasions in a patient whose neutrophil count is <500/micro L

3 days of investigation, including at least 2 days’ incubation culture, reveals no specific cause.

HIV-associated PUO:

Temperature of =/> 38.3*C (101*F) develops on several occasions over a period of >4 weeks for outpatients or >3 days for hospitalized patients with HIV infection

3 days of investigation, including at least 2 days’ incubation culture, reveals no source.

Categories of PUO

Feature Nosocomial Neutropenic

HIV-Associated

Classic PUO

Patient’s situation

Hospitalized, acute care, no infection when admitted

Neutrophil count < 500/mm3

Confirmed HIV postive

All otherts with fever for >3 weeks

Duration of Illness while under investigation

3 days 3 days 3 days or 4 weeks as outpatient

3 days or 2 outpatient visits

Example of cause

Septic thrombophlebitis, Clostridium dificile colitis, drug fever

Perianal infection, aspergillosis, candidiasis

MAI infection, TB, non-Hodgkins Lymphoma, drug fever

Infections, Malignancy, Inflammatory diseases, drug fever

Causes of PUO/FUO:

Causes of PUO:

Infection (20-30%)Pyogenic abscessTuberculosisInfective EndocarditisToxoplasmosisViral Infections : EBV infection, Cytomegalovirus

infectionBrucellosisLyme Disease

Malignant Diseases (10-30%):LymphomaLeukaemiaRenal cell carcinomaHCCPost Transplant Lymphoproliferative disorderLiver MetastasisColon CancerAtrial myxoma

Vasculities(15-20%):Adult Still’s DiseaseRASLEWegener’s GranulomatosisGiant Cell ArteritiesPolymyalgia Rheumatica

Miscellaneous(10-25%): Drug fever- phenytoin, Rifampicin, azathioprine Thyrotoxicosis IBD Sarcoidosis Granulomatous Hepatitis Non-mycobacterial diseases Factitious fever FMF Thromboembolic Diseases

Undiagnosed (5-25%) some says upto 50% undiagnosed

10 leading causes of classic PUO: (In a USA hospital)

Cause % of Total

Lymphoma 16

Collagen vascular diseaseAbscess

1613

Undiagnosed cause 9

Solid tumor 8

Thrombosis or hematoma 7

Granulomatous disease, nonmycobacterial 5

Endocarditis 5

Mycobacterial Disease 5

Viral disease 5

Remaining causes 11

100

Evaluation:Comprehensive history and Physical exam is necessary.

H/O presenting illness:The onset and duration of the illnessFever characteristic, temporal pattern of the febrile

episodesDocumented or not ? How long ?Other associated symptoms that may give some clues to

the likely aetiology of the fever – weight loss, cough, rashes, night sweats

Any treatment received so farDetailed systemic enquiryRisk factor for IEHistory to determine the immune status ( transplant

recipient, cancer therapy, AIDS infection, Neutropenic)Immunization

Medication History: looking for drugs that cause fever

Past history:Immunocompromised ? Focused history on infectious conditions, connective

tissue diseases, vasculitic conditions and malignanciesPrevious surgery, Illness ??

Family history :Any similar illness in the family(FMF)

Social history: Hobbies Alcohol intake and recreational drug use Recent travel : -where ? Malaria if travelled to endemic area -When ? To know incubation period - What exposed to ? Unpateurized milk- Brucellosis, Fresh water exposure-

Leishmaniasis Sexual activity Contact with animals Pets ? Cat- Toxoplasmosis. Parrot-psittacosis Contact with sick people or with TB patients

Physical Examination:

Thorough physical examination Temperature Look in the skin for areas of infection or inflammation Rash- evanescent macular rash of Still’s diseases Throat and sinuses to look for any infections Lungs for evidence of infections Cardiac murmurs and any evidence of Infective endocarditis Pelvic and Rectal exam Temporal artery evaluation Lymphadenopathy Cardiac murmurs Hepatosplenomegaly, Joint pain and swelling Any lump and bump anywhere in the body Genitourinary exam Fundoscopy : retinitis, ophtalmitis, roth’s spot

Diagnostic workup/Investigations:

CBC, Differential, smear . Look for malarial parasite(MP)ESR, CRPUrine analysis LFTs, CPK, U &E Ca, Fe, Transferrin, Ferritin, TIBC,

Vitamin B12, TFTProtein electrophoresisVDRL, HIV, CMV, EBV, C. Burnetii (Q fever), Brucella

Serology and culture, ANA, RF, PPD,Culture: Blood, Urine, Stool, Sputum, fluids as

appropriateChest X-rayLumbar puncture if neurological features are present

Further investigations: (If above investigations are non-diagnostic)

US CT CAP: looking for abscesses and unsuspected lymphnode

enlargement TEE : looking for valvular vegetations, to exclude sub-acute

infective endocarditis Gallium scan, looking for areas of active inflammation or

lymphoma Indium labelled white cell scan, looking for foci of sepsis Three phase bone scan looking for osteomyelitis or other bony

lesion(inflammation or metastatic deposits) Swab as clinically indicated (e.g. canula site) Temporal artery biopsy if clinically indicated Liver biopsy Bone marrow biopsy if anemia and thrombocytopenia Bronchoscopy and bronchoalveolar lavage

Approach to the patient with classic PUOFever >38.3*C for 3 weeks, 1 week of ‘intelligent and invasive

investigation

Physical Exam Repeat history

Laboratory TestingCBC, Differential, smear, ESR, CRP, Urine analysis, LFTs, CPK,

VDRL,HIV,CMV,Ebv,ANA,RF,SPEP,PPD,U &E, Ca, Fe, Transferrin, TIBC, Vitamin B12, acute or convalescent serum set aside

Culture: Blood, Urine, Sputum, fluids as appropriateCxR

Potentially diagnostic clue No potentially diagnostic clue

Directed ExamCT CAP with contrast,

Colonoscopy

- +67 Gallium scan, WBC

scan

- +

Needle biopsy, invasive testing

- +

Approach to the patient with classic PUO………cont…

Directed ExamCT CAP with contrast,

Colonoscopy

- +67 Gallium scan, WBC

scan

- +

Needle biopsy, invasive testing

- +

No diagnosis

Empiric therapy

Watchful ewaiting

Anti TB, Anti mocrobial therapy

Colchicine,

NSAIDs

Steroids

Diagnosis

Specific therapy

Therapeutic Management:

Identify cause and treat accordinglyTherapeutic trial should be avoided unless all other

approaches have failed.

“ The temptation to commence the patient with PUO on empiric antibiotic therapy should be resisted unless they are severely ill. However once a reasonably secure clinical diagnosis has been established, there may be a place for judicious trials of appropriate therapy.”

A significant proportion of cases remain undiagnosed.Fully review the case again.If patient is stable, best to stop investigation and carefully

follow the progress.

Real case Scenario:

A 39 years old saudi lady, high school teacher has fever for 4 weeks with some sorethroat. She was seen in the family medicine clinic thrice and received 2 courses of antibiotics and still febrile and currently feeling extreme fatigue and unable to take classes and took off sick for the last one week. She has done some blood test and she attended to your clinic with those results. How you will approach her ???

Conclusion:

Confirm that the patient really has a fever.A thorough review of the history is essential-

occupation, travel history, pets, contacts (e.g. TB), medication, recreational drug use, past history and family history

Detailed clinical examinationDaily review the patient, look for any new

symptoms/signsCareful analysis of the results of

investigations

Thanks