Pyrexia of unknown origin and Fever in returning traveller Dr Richard Drew Research Fellow Dept Clinical Microbiology

What is PUO Originally defined in 1961 by Petersdorf and Beeson Originally defined in 1961 by Petersdorf and Beeson Fever >38.3C on 3 or more occasions Fever >38.3C on 3 or more occasions Fever for more then three weeks Fever for more then three weeks Uncertain diagnosis after one week in hospital Uncertain diagnosis after one week in hospital Very rare nowadays in hospital Very rare nowadays in hospital

How to solve the problem History History Physical examination Physical examination Blood tests Blood tests Imaging Imaging Endoscopy and tumour markers Endoscopy and tumour markers

Aetiology 1. Infections 2. Malignancies 3. Connective tissue disorders

History Fever: Pattern, periodicity, how was it measured Fever: Pattern, periodicity, how was it measured Associated symptoms such as sweating, vomiting, headaches etc. Associated symptoms such as sweating, vomiting, headaches etc. Target specific organ systems if patient has problems in that system Target specific organ systems if patient has problems in that system Past med and surg hx. NB prostheses in situ Past med and surg hx. NB prostheses in situ Medications/ vaccines Medications/ vaccines Family hx of hereditary diseases, connective tissue disorders or recent illnesses (TB/ AIDS) Family hx of hereditary diseases, connective tissue disorders or recent illnesses (TB/ AIDS) Sexual history Sexual history Occupation, pets, travel Occupation, pets, travel

Examination Full physical examination is needed. Should be very detailed and review all systems. Full physical examination is needed. Should be very detailed and review all systems. For exams make sure to examine: For exams make sure to examine: Hands for stigmata of infective endocarditis Hands for stigmata of infective endocarditis Retinal exam for candidiasis or toxoplasmosis Retinal exam for candidiasis or toxoplasmosis Teeth (infective endo or abscess) Teeth (infective endo or abscess) Lymphadenopathy (AIDS or chronic infections) Lymphadenopathy (AIDS or chronic infections) Hepatosplenomegaly (Lymphoma/leukaemia) Hepatosplenomegaly (Lymphoma/leukaemia) Breast/testicular exams Breast/testicular exams Any sore joints Any sore joints

Infections Tuberculosis Tuberculosis HIV/AIDS HIV/AIDS Abscess Abscess Osteomyelitis Osteomyelitis Infective Endocarditis Infective Endocarditis

tuberculosis Classical prevention is fever, haemoptysis, cough, weight loss and night sweats Classical prevention is fever, haemoptysis, cough, weight loss and night sweats Risk Factors: Alcoholic, homeless, drug abuser, immigrant Risk Factors: Alcoholic, homeless, drug abuser, immigrant On exam can have pleural rub, pleural effusion and lymphadenopathy. Check if BCG vaccinated On exam can have pleural rub, pleural effusion and lymphadenopathy. Check if BCG vaccinated Do Mantoux test, CXR and sputum for AFB and TB culture. Do Mantoux test, CXR and sputum for AFB and TB culture. Treatment is 4 drug regimen (RIPE) and inform public health Treatment is 4 drug regimen (RIPE) and inform public health Isolate patient for 2 weeks in negative pressure room and wear FFP3 masks Isolate patient for 2 weeks in negative pressure room and wear FFP3 masks Always consider in differential of patient with cough and PUO Always consider in differential of patient with cough and PUO

HIV/ AIDS No classical presentation. Can present with fever, weight loss, sweats, lymphadenopathy or with opportunistic infection No classical presentation. Can present with fever, weight loss, sweats, lymphadenopathy or with opportunistic infection Hx: Sexual contacts, Birthplace, Maternal hx if child, Exposure events, occupation Hx: Sexual contacts, Birthplace, Maternal hx if child, Exposure events, occupation O/E Full exam. Lymph nodes and spleen O/E Full exam. Lymph nodes and spleen Ix: HIV antibody test and HIV viral load, CD4 count Ix: HIV antibody test and HIV viral load, CD4 count Mx: Refer to ID team. HAART Mx: Refer to ID team. HAART

Osteomyelitis Infection of the bone Infection of the bone Spontaneous osteomyelitis is rare apart from in Sickle cell disease patients Spontaneous osteomyelitis is rare apart from in Sickle cell disease patients Consider if prosthesis is in situ or if there is a history of preceeding compound fractures Consider if prosthesis is in situ or if there is a history of preceeding compound fractures FBC, ESR, Imaging of joint, bone biopsy FBC, ESR, Imaging of joint, bone biopsy Mx: Targeted antimicrobial therapy and prosthesis removal Mx: Targeted antimicrobial therapy and prosthesis removal

Non-infectious causes Malignancies Malignancies Lymphoma Lymphoma Leukaemia Leukaemia Solid organ tumours Solid organ tumours Connective tissue disorders Connective tissue disorders Still’s disease Still’s disease Giant cell arteritis Giant cell arteritis

Malignancies Leukaemia/Lymphoma Leukaemia/Lymphoma Hx: fever, sweats, weight loss, fatigue Hx: fever, sweats, weight loss, fatigue O/E, Lymph nodes, hepatosplenomegaly O/E, Lymph nodes, hepatosplenomegaly Ix: Bone Marrow aspirate, blood smear, FBC Ix: Bone Marrow aspirate, blood smear, FBC Mx: Chemotherapy+/- Bone Marrow transplant Mx: Chemotherapy+/- Bone Marrow transplant Solid Organ tumours Solid Organ tumours Target the particular organ you feel is involved. Target the particular organ you feel is involved. Connective tissue disorders Connective tissue disorders Hx: Fatigue, unexplained rashes, arthralgia, myalgia Hx: Fatigue, unexplained rashes, arthralgia, myalgia O/E arthralgia, uveitis, Raynaud’s phenomenon O/E arthralgia, uveitis, Raynaud’s phenomenon Ix: ESR Ix: ESR Mx: Steroids, NSAIDs Mx: Steroids, NSAIDs

Investigations Basic tests Basic tests FBC: WCC, blood smear, FBC: WCC, blood smear, bone marrow aspirate bone marrow aspirate ESR, CRP: Non-specific markers of inflammation ESR, CRP: Non-specific markers of inflammation CXR, Mammogram, Pap smear if relevant, Mantoux, CXR, Mammogram, Pap smear if relevant, Mantoux, Micro: Blood cultures (3 sets) Micro: Blood cultures (3 sets) Other tests to consider Other tests to consider The clue is in the history as to what tests are needed The clue is in the history as to what tests are needed HIV test, viral and bacterial serology HIV test, viral and bacterial serology CT thorax/ abdomen CT thorax/ abdomen Tumour markers Tumour markers Echocardiogram Echocardiogram

Management Determine if critically ill. If not can hold off on antibiotics Determine if critically ill. If not can hold off on antibiotics Don’t feel need to just treat a temperature Don’t feel need to just treat a temperature Clue is in the history and the exam and then order relevant tests. Do not send random serological tests off. Often these will cause more trouble then you want!!! Clue is in the history and the exam and then order relevant tests. Do not send random serological tests off. Often these will cause more trouble then you want!!!

Returning Traveller Very common problem Very common problem Geosentinel data review (Clin Infect Dis. 2007) of 25,000 ill returning travellers Geosentinel data review (Clin Infect Dis. 2007) of 25,000 ill returning travellers 28% had fever and 26% of these needed admission 28% had fever and 26% of these needed admission Malaria was the most common diagnosis Malaria was the most common diagnosis Considerable geographical variation Considerable geographical variation 17% had vaccine preventable diseases 17% had vaccine preventable diseases Will discuss methods of diagnosing the condition and not each disease in detail Will discuss methods of diagnosing the condition and not each disease in detail

History Crucial. Will help to narrow down possible list of diseases. Crucial. Will help to narrow down possible list of diseases. Don’t always get distracted by history of recent travel. May be more common diagnosis Don’t always get distracted by history of recent travel. May be more common diagnosis Exposure: Duration, exact location, urban/rural, type of accomadation Exposure: Duration, exact location, urban/rural, type of accomadation Timing: Consider incubation period and onset of symtoms. 66% of dengue presents within one week of return. 34% of hepA presents within 6 weeks Timing: Consider incubation period and onset of symtoms. 66% of dengue presents within one week of return. 34% of hepA presents within 6 weeks Food history is important Food history is important Sexual history is important Sexual history is important Vaccine history Vaccine history

Examination Full examination as per previous PUO talk Full examination as per previous PUO talk Need to consider the risk of a transmissible organism Need to consider the risk of a transmissible organism Consider isolating patient until diagnosis is known Consider isolating patient until diagnosis is known Critical if considering a viral haemorrhagic fever Critical if considering a viral haemorrhagic fever Signs that should trigger full resuscitation and precautions Signs that should trigger full resuscitation and precautions Bleeding symptoms, respiratory symptoms Bleeding symptoms, respiratory symptoms Hypotension Hypotension Signs of meningitis or raised intracranial pressure Signs of meningitis or raised intracranial pressure

Evaluation Thick and Thin smears for malaria Thick and Thin smears for malaria FBC: Look for raised white cells FBC: Look for raised white cells Renal profile: Dehydration, renal failure Renal profile: Dehydration, renal failure Liver profile: hepatitis Liver profile: hepatitis Coagulation screen Coagulation screen CXR if respiratory symptoms CXR if respiratory symptoms

Top 5 diagnoses (Geosentinel) 1. Malaria 2. Dengue Fever 3. EBV/CMV mononucleosis 4. Rickettsia 5. Typhoid

Clinical Case 1 26yr IVDA from Dublin 26yr IVDA from Dublin Self discharged twice before from hospital having been admitted with fever Self discharged twice before from hospital having been admitted with fever Reports to have had fever and night sweats for about 4 weeks. Reports to have had fever and night sweats for about 4 weeks. Has lost 2 stone in 3 months Has lost 2 stone in 3 months Some visible skin sores and needle marks Some visible skin sores and needle marks Pulse 110bpm, Temp 36C, BP 100/60 Pulse 110bpm, Temp 36C, BP 100/60 Differential diagnosis History Examination Lab tests at 3am Lab tests the following day Infection Control Management Public Health

Clinical Case 2 Returning GOAL worker. 28 yr male. Returning GOAL worker. 28 yr male. Worked for 12 months in rural clinic in Rwanda Worked for 12 months in rural clinic in Rwanda 2 episodes of infectious diarrhoea while there 2 episodes of infectious diarrhoea while there Presented to ED three days after coming home Presented to ED three days after coming home Looks very unwell. Non blanching skin rash Looks very unwell. Non blanching skin rash Differential diagnosis History Examination Lab tests at 3am Lab tests the following day Infection Control Management Public Health