Pyrexia of unknown orgin (PUO) Mosul Medical College Presented by: Dr. Salam Fareed

contents Objectives Definition Classification and causes Approach to patient with PUO Golden point Case scenario

Objectives To be able to define PUO, and its tyups. To be able to have a plan to approach a patient with Fever when the basic clinical and laboratory tests did not reveal much as to the cause of fever

Fever of unknown origin (FUO) :- is a sustained, unexplained fever despite a comprehensive diagnostic evaluation. Patients with undiagnosed FUO generally have a benign long-term course, especially when the fever is not accompanied by substantial weight loss or other signs of a serious underlying disease.

Classification of PUO Health care associated HIV Neutropinc Classic

Classic Temperature >38.3 °C (100.9 °F) for at least 3 weeks with at least 1 week of in-hospital investigation

Causes 1- Infections (30%):- Abscess at any site; Cholecystitis/cholangitis Urinary tract infection: prostatitis Dental and sinus infections Bone and joint infections Imported infections, e.g. malaria, dengue, brucellosis Enteric fevers Infective endocarditis Tuberculosis (particularly extra pulmonary) Viral infections (cytomegalovirus-CMV, Epstein-Barr virus-EBV, human immunodeficiency virus-HIV) and toxoplasmosis

2-Malignancy (20%):- Lymphoma and myeloma Leukemia Solid tumors (renal, liver, colon, stomach, pancreas)

3-connective tissue disorders(15%):- Vasculitic disorders (including polyarteritis nodosa and rheumatoid disease with vasculitis) Temporal arteritis/polymyalgia rheumatica Systemic lupus erythematosus (SLE) Still's disease Polymyositis

4-Miscellaneous (20%):- Inflammatory bowel disease Liver disease: cirrhosis and granulomatous hepatitis Sarcoidosis Drug reactions Atrial myxoma Thyrotoxicosis Hypothalamic lesions Familial Mediterranean fever 5-Factitious 6-No diagnosis (15%)  

Health care associated Temperature >38.3 °C (100.9 °F) in patients hospitalized ≥72 hours but no fever or evidence of potential infection at the time of admission, and negative evaluation of at least 3 days.

Causes Drug fever thrombophlebitis pulmonary embolism sinusitis, postoperative complications (occult abscesses) Clostridium difficile enterocolitis device- or procedure-related endocarditis

Neutropenic (immune deficient) Temperature >38.3 °C (100.9 °F) and neutrophil count <500/µL for >3 days and negative evaluation after 48 hours.

Causes Occult bacterial and opportunistic fungal infections (aspergillosis, candidiasis) drug fever pulmonary emboli underlying malignancy cause not documented in 40%-60% of cases

HIV associated Temperature >38.3 °C (100.9 °F) for >3 weeks (outpatients) or >3 days (inpatients) in patients with confirmed HIV infection.

Approach to patient with PUO History Physical examination Targeted investigations

History Inquire about symptoms involving all major organ systems and get a detailed history of general symptoms (eg, fever, weight loss, night sweats, headaches, rashes). The history can provide important clues to FUO due to surgery, zoonoses, malignancies, and inflammatory/immune disorders. Record all symptoms, even those that disappeared before the examination. Previous illnesses (including psychiatric illnesses) and surgeries are important.

Make a detailed evaluation that includes the following: Family history Immunization status Occupational history Travel history Nutrition (including consumption of dairy products) Drug history (over-the-counter medications, prescription medications, illicit substances) Sexual history Recreational habits Animal contacts (including possible exposure to ticks and other vectors)

Physical Examination Definitive documentation of fever and exclusion of factitious fever are essential early steps in the physical examination. On physical examination, pay special attention to the eyes, skin, lymph nodes, spleen, heart, abdomen, and genitalia. Pulse-temperature relationships (ie, relative bradycardia) are useful in evaluating for typhoid fever, Q fever, psittacosis, lymphomas, and drug fevers.

Repeat a regular physical examination daily while the patient is hospitalized. Pay special attention to rashes, new or changing cardiac murmurs, signs of arthritis, abdominal tenderness or rigidity, lymph node enlargement, funduscopic changes, and neurologic deficits.

Investigations PUO should be investigated in a stepwise fashion in order of increasing complexity and invasiveness, starting with blood tests and moving to imaging techniques and, finally, more invasive procedures such as 'blind' biopsies

FBC with differential , (ESR) and C-reactive protein (CRP) Urea, creatinine and electrolytes Liver function tests (LFTs) and γ-glutamyl transferase Blood glucose Urinalysis, Midstream urine (MSU) for microscopy and culture Creatine phosphokinase Malaria blood films

Faeces culture Sputum for routine microscopy and culture and microscopy and culture for mycobacteria Blood cultures ×3 Chest X-ray Ultrasound examination of abdomen Electrocardiogram (ECG) Echocardiogram

Viral (CMV, Infectious mononucleosis, HIV, Hepatitis A, B and C) Bacterial (chlamydial infection, Q fever, brucellosis , mycoplasma infection, syphilis, leptospirosis, Lyme disease, Yersinia infection, streptococcal infection) Fungal(Cryptococcus antigen, histoplasmosis, coccidioidomycosis) Protozoal and parasitic (toxoplasmosis, amoebiasis, schistosomiasis, leishmaniasis, trypanosomiasis)

PCR e.g for tuberculosis, herpes simplex virus (HSV), CMV, HIV, erythrovirus, dengue, Toxoplasma, Whipple's disease Immunology like Autoantibody screen, including anti-double-stranded DNA, anti-neutrophil cytoplasmic antibody (ANCA), Immunoglobulins, Complement (C3 and C4) levels &Cryoglobulins Imaging like CT/MRI chest and abdomen, skeletal survey , isotope bone scan, labelled white cell scan Biopsy: Bone marrow biopsy, Temporal artery biopsy

Factitious fever It is most commonly encountered among young adults with health care experience or knowledge. Evidence of psychiatric problems or a history of multiple hospitalizations at different institutions is common in patients with factitious fever. Rapid changes of body temperature without associated shivering or sweating, large differences between rectal and oral temperature, and discrepancies between fever, pulse rate, or general appearance are typically observed in patients who manipulate or exchange their thermometers.

Golden Point The longer a fever persists without a diagnosis, the less likely it is to have an infectious origin.  

1-The most probable cause of immune deficient PUO is :- Streptococcal pneumonia Thrombophlebitis Drug fever Unknown  

2-A 45 years old male known to have chronic renal failure, admitted to the hospital to start hemodialysis at that time he was afebrile, 3 days later he developed fever of (39°C) persist for 3 days. CBC showed Hb=9 g/dl, WBC=13*109 cells/l, platelets count=170*109 this type of fever is most probably:- Immune deficient PUO Health care associated PUO Classic PUO None of above  

3) All the followings are criteria for immune deficient (neutropenic) PUO except :- Temperature >38.3°C Duration > 3 weeks Neutrophile count 400 No valuabie diagnosis despite initial 48 hours of assessment

4-A patient can be considered to have classic PUO in which of the followings scenario :- 69 years old female with fever ranging (38.4°C - 38.8°C) for 40 days without finding a source of infection despite 10 days of inpatient investigations. 33 years old diabetic female present with fever of (39.5°C) for 3 days associated with rigor and loin pain. 18 years old female presented with fever ranging (38.5°C -39.7°C) for 1 month duration, with previous history of multiple hospital admissions and history of psychiatric problem. 23 years old female presented with fever of (38.9°C) and backache for 14 days duration, initial assessment showed high titer of Brucella agglutination test.