PUO-pyrexia of unknown origin pyrexia of unknown origin
- 2. INTRODUCTION Body temperature is normally maintained within a range of 37 – 38°c , normal body temperature is generally considered to be 37°c . BODY TEMPERATURE
- 3. PHYSIOLOGY Normal body temperature is maintained by a complex regulatory system in the anterior hypothalamus, preoptic area, temperature sensitive area, thermal set point.
- 4. PATHOGENESIS Substances the mediate the elevation of core body temperature There are two types; exogenous and endogenous pyrogens. PYROGENS EXOGENOUS PYROGENS It is derived from outside of the host, such as microorganisms, toxins and microbial products They are generally large molecules – cannot pass blood brain barrier They induce the release of endogenous pyrogens from macrophages.
- 5. PATHOGENESIS ENDOGENOUS PYROGENS Endogenous pyrogens are derived from the macrophages. They are small molecules – can pass blood brain barrier Pyrogen cytokines trigger the hypothalamus to release PGE2, resulting in: 1. Resetting of thermostatic temperature 2. Activation of vasomotor center 3. Vasodilatation 4. Heat production
- 6. PYREXIA OF UNKNOWN ORIGIN ORIGINAL DEFINITION (Petersdotf anf Beeson, 1961) Temperature ≥ 38.3ºC (101ºF) on several occasions Fever ≥ 3 weeks Failure to reach a diagnosis despite 1 week of inpatient investigations or 3 outpatient visits NEW DEFINITION (Petersdotf anf Beeson, 1961) Temperature ≥ 38.3ºC (101ºF) lasting for more than 14 days without an obvious cause despite a complete history, physical examination and routine screening with laboratory evaluation
- 7. FACTORS FACTORS THAT MAY HAVE CONTRIBUTED TO THE DIFFICULTY IN FINDING THE CAUSE OF FEVER INCLUDE: A common illness that does not have the usual symptoms – may be asymptomatic Illness whose symptoms appear later Illnesses with possibly delayed positive test Person is unable to communicate about other symptoms Genetic condition that causes periodic fever.
- 8. COMMON CAUSES COMMON CAUSES OF PYREXIA OF UNKNOWN ORIGIN 40% 25% 15% 10% 10% Infection (40%) Malignancy (25%) Autoimmune Disease (15%) Others/ Miscellaneous (10%) Undiagnosed (10%)
- 9. CLASSIFICATION DURACK AND STREET’S CLASSIFICATION 1. Classical 2. Nosocomial 3. Neutropenic 4. Pyrexia of unknown origin with HIV infection
- 10. CLASSIFICATION
- 11. 1. CLASSICAL CLASSIC PYREXIA OF UNKNOWN ORIGIN Temperature >38.3°C (100.9°F) Duration of >3 weeks Evaluation of at least 3 outpatient visits or 3 days in hospital AETIOLOGIES 1. Infections 2. Malignancies 3. Collagen vascular disease 4. Others / miscellaneous which includes drug-induced fever
- 12. 1. CLASSICAL A. INFECTIONS Bacterial Abscesses, tuberculosis, uncomplicated UTI, endocarditis, osteomyelitis, sinusitis, prostatitis, cholecystitis, empyema, biliary tract infection, brucellosis, typhoid, etc. Viral Cytomegalovirus, infectious mononucleosis, HIV, etc. Parasites Malaria, toxoplasmosis, leishmaniasis, etc. Fungal Histoplasmosis, etc. As the duration of fever increases, infectious etiology decreases. Malignancy and factitious fevers are more common in patients with prolonged pyrexia of unknown origin
- 13. 1. CLASSICAL B. MALIGNANCIES HEMATOLOGICAL 1. Lymphoma 2. Chronic leukemia NON-HAEMATOLOGICAL 1. Renal cell cancer 2. Pancreatic cancer 3. Colon cancer 4. Hepatoma
- 14. 1. CLASSICAL C. COLLAGEN VASCULAR DISEASE / AUTOIMMUNE DISEASE Temporal arthritis Rheumatoid arthritis Rheumatoid fever Inflammatory bowel disease Reiter’s syndrome Systemic lupus erythematosus Polyarthritis nodosa Giant cell arthritis Kawasaki disease
- 15. 1. CLASSICAL C. MISCELLANEOUS Hyperthyroidism Alcoholic hepatitis Inflammatory bowel disease Deep venous thrombosis DRUGS Allopurinol Captopril Cimetidine Clofibrate Erythromycin Heparin Hydralazine Hydrochlorothiazide Isoniazid Meperidine Methydopa Nifedipine Nitrofurantoin Penicillin Phenytoin Procainamide Quinidine
- 16. 1. CLASSICAL C. MISCELLANEOUS FACTITIOUS FEVER Central 1. Brain tumor 2. Hypothalamic dysfunction Peripheral 3. Hyperthyroidism 4. Pheochromocytoma Munchausen syndrome Munchausen by proxy THERMOREGULATORY DISORDER
- 17. FEVER PATTERN • Intermittent Fever Any fever characterized by intervals of normal temperature Malaria, pyaemia, septicemia • Continuous Fever Temperature remains above normal throughout the day and does not fluctuate more than 1C in 24 hours Lobar pneumonia, Typhoid, Meningitis, UTI, Brucellosis • Remittent Fever A fever pattern in which temperature varies during each 24 hour period but never reaches normal. Enteric Fever, Bacterial Endocarditis, Viral Pneumonia
- 18. FEVER PATTERN • Relapsing Fever An acute infection with recurrent episodes of fever caused by spirochetes of the genus Borrelia which are borne by ticks or lice. • Undulant Fever An infectious disease due to the bacteria Brucella. It is called undulant because the fever is typically undulant, rising and falling like a wave. It is also called brucellosis after its bacterial cause
- 19. FEVER PATTERN • Relapsing Fever An acute infection with recurrent episodes of fever caused by spirochetes of the genus Borrelia which are borne by ticks or lice. • Undulant Fever An infectious disease due to the bacteria Brucella. It is called undulant because the fever is typically undulant, rising and falling like a wave. It is also called brucellosis after its bacterial cause
- 20. FEVER PATTERN
- 21. 2. NOSOCOMIAL NOSOCOMIAL PYREXIA OF UNKNOWN ORIGIN Temperature > 38.3°C Patient hospitalized ≥ 24 hours but no fever or incubating on admission Evaluation of at least 3 days More than 50% of patients with nosocomial PUO are due to infection Focus on sites where occult infections may be sequested, such as: - Sinusitis of patients with NG or Oro-tracheal tubes - Prostatic abscess in a man with urinary catheter 25% of non-infectious cause includes: - Acalculous colecystitis - Deep vein thrombophlebitis - Pulmonary embolism
- 22. 3. NEUTROPENIC IMMUNE DEFICIENT / NEUTROPENIC PUO Temperature >38.3°C Neutrophil count ≤ 500 per mm3 Evaluation of at least 3 days Patients on chemotherapy or immune deficiencies are susceptible to: - Opportunistic bacterial infection - Fungal infections such as candidiasis - Infections involving catheters - Perianal infections Examples of etiological agent: - Aspergillus - Candida - CMV - Herpes simplex
- 23. 4. HIV-ASSOCIATED IMMUNE DEFICIENT / NEUTROPENIC PUO Temperature > 38.3°C Duration of > 4 weeks for outpatients, > 3 days for inpatients HIV infection confirmed HIV infection alone may be a cause of fever Common secondary causes include: - Tuberculosis - CMV infection - Non-hodgkin lymphoma - Drug-induced fever
- 24. CLINICAL APPROACH PYREXIA OF UNKNOWN ORIGIN : A CLINICAL APPROACH 1. Onset a. Acute b. Gradual 2. Character 3. Antecedents a. Dental extraction b. Urinary catheterization HISTORY OF PRESENTING ILLNESS
- 25. CLINICAL APPROACH PYREXIA OF UNKNOWN ORIGIN : A CLINICAL APPROACH 4. Associated symptoms Chills and rigors Night sweats Loss of weight Cough and dyspnea Headache Joint pain Abdominal pain Bone pain Sore throat Dysuria and rectal pain Altered bowel habit Skin rash
- 26. CLINICAL APPROACH PYREXIA OF UNKNOWN ORIGIN : A CLINICAL APPROACH PAST MEDICAL HISTORY PAST SURGICAL HISTORY DRUG HISTORY FAMILY HISTORY
- 27. CLINICAL APPROACH PYREXIA OF UNKNOWN ORIGIN : A CLINICAL APPROACH Travel Residential area Occupation Contact with domestic / wild animals / birds Diet history Sexual orientation Close contact with TB patients
- 28. PHYSICAL EXAMINATION Pattern of fever – continuous, intermittent, relapsing Ill or not ill Weight loss – chronic illness Skin rash GENERAL HANDS Stigmata of infective endocarditis Vasculitis changes Clubbing Presence of arthropathy Raynaud’s phenomenon
- 29. Drug injection sites (IV drug usage) Epithrochlear and axillary nodes (lymphoma, sarcoidosis, focal infection) Skin ARMS HEAD AND NECK Feel temporal arteries (tender and thicken) Eyes – iritis / conjunctivitis Jaundice (ascending cholangitis) Fundus – choroidal tubercle (miliary TB), Roth’s spot (infective endocarditis) and retinal hemorrhage (leukemia) Lymphadenopathy PHYSICAL EXAMINATION
- 30. Butterfly rash Mucous membranes Seborrhoic dermatitis (HIV) Mouth ulcers (SLE) Buccal candidiasis Teeth and tonsil infections (abscess) Parotid enlargement Ears – otitis media FACE AND MOUTH CHEST Bony tenderness Cardiovascular – murmurs Respiratory – signs of pneumonia, tuberculosis, empyema and lung cancer PHYSICAL EXAMINATION
- 31. Rose colored spot – typhoid fever Hepatomegaly Splenomegaly – haemopoietic malignancy, IE, malaria Renal enlargement – renal cell carcinoma Testicular enlargement – seminoma Penis & scrotum – discharge/rash Inguinal ligament Per-rectal exam Mass / tenderness in rectum/pelvis (abscess, carcinoma, prostatitis) Vaginal examination Collection of pelvic pus/ pelvic inflammatory disease PHYSICAL EXAMINATION ABDOMEN
- 32. Signs of meningism (chronic TB meningitis) Focal neurological signs (brain abscess, mononeuritis multiplex in plyarthritis nodosa) PHYSICAL EXAMINATION CENTRAL NERVOUS SYSTEM
- 33. a. Full blood count b. ESR and CRP c. BUSE d. LFTs e. Blood culture f. Serum virology g. Urinalysis and culture h. Sputum culture and sensitivity i. Stool FEME and occult blood j. Chest x-ray k. Mantoux test INVESTIGATION STAGE 1 – SCREENING TESTS
- 34. a. Repeat history and examination b. Protein electrophoresis c. CT (chest, abdomen, pelvis) d. Autoantibody screen e. Electrocardiogram (ECG) f. Bone marrow examination g. Lumbar puncture h. Temporal artery biopsy i. HIV test counselling j. Ultrasonography INVESTIGATION STAGE 2
- 35. INVESTIGATION STAGE 3 • Tuberculosis, malignancy, Pneumocystis carinii pneumonia Chest radiograph • Abscess, malignancy CT of abdomen or pelvis with contrast agent • Infection, malignancy Gallium 67 scan • Occult septicemia Indium-labeled leukocytes • Acute infection and inflammation of bones and soft tissue Technetium Tc 99m • Malignancy, autoimmune conditions MRI of brain • Malignancy, inflammation PET scan • Bacterial endocarditis Transthoracic or transesophageal echocardiography • Venous thrombosis Venous Doppler study
- 36. a. Treat TB b. Endocarditis c. Vasculitis d. Trial of aspirin / steroids INVESTIGATION STAGE 4
- 38. DIAGNOSIS More invasive testing, such as LP or biopsy of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation.
- 39. THERAPEUTIC TRIALS WHAT IS THE BEST THERAPEUTIC TRERAPY FOR PUO PATIENTS? Therapeutic trials consist of combination of broad spectrum antibiotics and are given in :- 1. Patient who is very sick to wait. 2. All tests have failed to uncover the etiology.
- 40. SUMMARY WHAT IS THE BEST THERAPEUTIC TRERAPY FOR PUO PATIENTS? PUO is often a diagnostic dilemma, quandary. Infections comprise ~30% of cases Bone marrow biopsies are of low diagnostic yield Diagnostic approach should occur in a step-wise fashion based on the H&P Patient’s that remain undiagnosed generally have a good prognosis