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 ?

Dr Mohammad Abdul Matin MRCP(Ire) MRCP(UK), FACP, FRCP(Edin) Consultant, Internal Medicine Pyrexia of Unknown Origin(PUO)/ Fever of Unknown origin(FUO)

Agenda: 50 minutes Introduction Definition and classification Causes of classic PUO Ten leading causes of classic PUO Evaluation Diagnostic workup/Investigations Therapeutic management of PUO Conclusion

Why we have fever ? Complex cytokine mediated (TNF-alfa, IL-1, Il-6) response of the body TNF LPS 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 PUO Nosocomial PUO Neutropenic PUO PUO 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 FeatureNosocomialNeutropenicHIV- 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 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 abscess Tuberculosis Infective Endocarditis Toxoplasmosis Viral Infections : EBV infection, Cytomegalovirus infection Brucellosis Lyme Disease

Malignant Diseases (10-30%): Lymphoma Leukaemia Renal cell carcinoma HCC Post Transplant Lymphoproliferative disorder Liver Metastasis Colon Cancer Atrial myxoma

Vasculities(15-20%): Adult Still’s Disease RA SLE Wegener’s Granulomatosis Giant Cell Arterities Polymyalgia 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 Lymphoma16 Collagen vascular disease Abscess Undiagnosed cause9 Solid tumor8 Thrombosis or hematoma7 Granulomatous disease, nonmycobacterial5 Endocarditis5 Mycobacterial Disease5 Viral disease5 Remaining causes11 100

Evaluation: Comprehensive history and Physical exam is necessary. H/O presenting illness: The onset and duration of the illness Fever characteristic, temporal pattern of the febrile episodes Documented 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 far Detailed systemic enquiry Risk factor for IE History 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 malignancies Previous 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, CRP Urine analysis LFTs, CPK, U &E Ca, Fe, Transferrin, Ferritin, TIBC, Vitamin B12, TFT Protein electrophoresis VDRL, HIV, CMV, EBV, C. Burnetii (Q fever), Brucella Serology and culture, ANA, RF, PPD, Culture: Blood, Urine, Stool, Sputum, fluids as appropriate Chest X-ray Lumbar 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 PUO Fever >38.3*C for 3 weeks, 1 week of ‘intelligent and invasive investigation Physical ExamRepeat history Laboratory Testing CBC, 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 appropriate CxR Potentially diagnostic clueNo potentially diagnostic clue Directed ExamCT CAP with contrast, Colonoscopy Gallium scan, WBC scan -+ Needle biopsy, invasive testing -+

Approach to the patient with classic PUO………cont… Directed Exam CT CAP with contrast, Colonoscopy Gallium scan, WBC scan -+ Needle biopsy, invasive testing -+ No diagnosis Empiric therapyWatchful ewaiting Anti TB, Anti mocrobial therapy Colchicine, NSAIDs Steroids Diagnosis Specific therapy

Therapeutic Management: Identify cause and treat accordingly Therapeutic 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 examination Daily review the patient, look for any new symptoms/signs Careful analysis of the results of investigations

Thanks