Pyrexia of unknown origin
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This document discusses fever and pyrexia of unknown origin (PUO). It begins by defining fever and explaining thermoregulation. Pyrogens that cause fever are discussed, including exogenous and endogenous pyrogens like cytokines. PUO is defined as an unexplained fever persisting over 3 weeks despite testing. Common causes of PUO are discussed, including infections, cancers, and collagen vascular diseases. The approach to evaluating a patient with PUO in stages is also summarized.
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Pyrexia of unknown origin
- 2. Introduction • Fever: Abnormal increase in body temperature, oral -more than 37.6 °C (100.4 °F) Rectal – more than 38 °C (101 °F) • Homeostatic mechanism : fluctuation of ±1 to 1.5 °C
- 3. Thermoregulation: • Continuom of neural structure to and from hypothalamus and limbic system • Preoptic area- temperature sensitive area • Thermal set point • Negative feed back control.
- 5. Pathophysiology of fever: Pyrogens : • Substances mediate the elevation of core body temperature. • Exogenous and endogenous pyrogens.
- 6. Exogenous pyrogens: • Derived from outside the host. • Microorganisms, toxins and microbial products. • Initiate fever by inducing host cells (macrophages)
- 7. Endogenous pyrogens: • Host cell derived • Monomeric molecules (17 kDa) • Undetectable at basal conditions • Short half life • Maximal response
- 8. Endogenous pyrogens: • Pyrogenic cytokines • IL-1( α and β ) • tumor necrosis factor (TNF α) • IL-6 • Ciliary neurotropic factor (CNF) • Interferon (IFN)
- 10. Endogenous molecules activating endogenous pyrogens: • Antigen antibody complex • Complement • Androgenic steroid metabolite • Lymphocyte derived molecules • Inflammatory bile acids
- 11. Pyrexia of Unknown Origin (PUO) Definition: by Petersdorf and Beeson in 1961 “Temperature higher than 38.3°C (101°F) on several occasions , persisting without diagnosis for at least 3 weeks, in spite of at least 1 week investigation in hospital”.
- 12. Durack and Street’s classification: • Classical • Nosocomial • Neutropenic • PUO associated with HIV infection
- 13. Classical PUO: Temperature ˃ 38.3°C, on several occasions, stipulating 3 OPD visits or 3 days in hospital with out elucidation of a cause or 1 week of intelligent and invasive investigation.
- 14. Nosocomial PUO: Temperature ˃ 38.3°C, on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission. 3 days of investigation include at least 2 days of cultures.
- 15. Neutropenic PUO: Temperature ˃ 38.3°C on several occasions in a patient whose neutrophil count is ˂ 500 / µL or is expected to fall to that level in 1 to 2 days. The specific cause of fever is not identified after 3days of investigation including at least 2 days of incubation of cultures.
- 16. HIV associated PUO: Temperature ˃ 38.3°C on several occasions over a period of ˃ 4 weeks for out patients or > 3 days for hospitalized patients with HIV, specific cause of fever is not identified after 3days of investigation including at least 2 days of incubation of cultures.
- 17. Classic PUO • Chronic or sub acute course • Median duration of 40 days • Etiology:- infection - neoplasm -connective tissue disorders -miscellaneous -undiagnosed
- 18. Infections: Localized pyogenic infections: • Appendicitis • Cholangitis • Cholecystitis • Dental abscess • Diverticulitis/abscess • Lesser sac abscess • Liver abscess • Mesenteric lymphadenitis • Osteomyelitis • Pancreatic abscess • Pelvic inflammatory disease • Perinephric/intrarenal abcess • Prostatic abscess • Renal malacoplakia • Sinusitis • Subphrenic abscess • Tubo-ovarian abscess
- 19. Intra-vascular infections: •Bacterial endocarditis •Bacterial aortitis •Vascular catheter infection
- 20. Systemic bacterial infections: • Bartonellosis • Brucellosis • Campylobacter infection • Cat-scratch disease/bacillary angiomatosis (B. henselae) • Gonococcemia • Legionnaires' disease • Leptospirosis • Listeriosis • Lyme disease • Melioidosis • Meningococcemia • Rat-bite fever • Relapsing fever • Salmonellosis • Syphilis • Tularemia • Typhoid fever • Vibriosis • Yersinia infection
- 21. Mycobacterial infections • M. avium/M. intracellulare infections • Other atypical mycobacterial infections • Tuberculosis Mycoplasmal infections Chlamydial infections • Lymphogranuloma venereum • Psittacosis
- 22. Other bacterial infections • Actinomycosis • Bacillary angiomatosis • Nocardiosis • Whipple's disease Rickettsial infections • Anaplasmosis • Ehrlichiosis • Murine typhus • Q fever • Rickettsial pox • Rocky Mountain spotted fever • Scrub typhus
- 23. Viral infections: • Chikungunya fever • Colorado tick fever • Coxsackie virus group B infection • Cytomegalovirus infection • Dengue • Epstein-Barr virus infection • Hepatitis A, B, C, D, and E • HIV infection • Human herpes virus 6 infection • Lymphocytic choriomeningitis • Parvovirus B19 infection • Picornavirus infection
- 24. Fungal infections: • Aspergillosis • Blastomycosis • Candidiasis • Coccidioidomycosis • Cryptococcosis • Histoplasmosis • Mucor mycosis • Paracoccidioidomycosis • Pneumocystis infection • Sporotrichosis
- 25. Parasitic infections: • Amebiasis • Babesiosis • Chagas' disease • Leishmaniasis • Malaria • Strongyloidiasis • Toxocariasis • Toxoplasmosis • Trichinellosis
- 26. Presumed infection : • Kawasaki’s disease • Kikuchi’s necrotizing lymphadenitis.
- 27. NEOPLASMS: Malignant: • Colon cancer • Gall bladder carcinoma • Hepatoma • Hodgkin's lymphoma • Leukemia • Renal cell carcinoma • Sarcoma • Immunoblastic T-cell lymphoma • Lymphomatoid granulomatosis • Malignant histiocytosis • Non-Hodgkin's lymphoma • Pancreatic cancer
- 28. Benign: • Atrial myxoma • Castleman's disease • Renal angiomyolipoma
- 29. Collagen vascular disease and hypersensitivity disorders: • Adult Still's disease • Behcet's disease • Erythema multiformae • Erythema nodosum • Giant-cell arteritis (polymyalgia rheumatica) • Hypersensitivity pneumonitis • Hypersensitivity vasculitis • Mixed connective-tissue disease • Polyarteritis nodosa • Relapsing polychondritis • Rheumatic fever • Rheumatoid arthritis • Schnitzler's syndrome • Systemic lupus erythematosus • Takayasu's aortitis • Weber-Christian disease • Granulomatosis with polyangitis
- 30. Granulomatous diseases: • Crohn's disease • Granulomatous hepatitis • Midline granuloma • Sarcoidosis
- 31. Miscellaneous conditions: • Aortic dissection • Drug fever • Gout • Hematomas • Hemoglobinopathies • Laennec's cirrhosis • PFPA syndrome: periodic fever, adenitis, pharyngitis, aphthae • Postmyocardial infarction syndrome • Recurrent pulmonary emboli • Subacute thyroiditis (de Quervain's) • Tissue infarction/necrosis
- 32. Inherited and metabolic disorders • Adrenal insufficiency • Cyclic neutropenia • Deafness, urticaria, and amyloidosis • Fabry’s disease • Familial cold urticaria • Familial Mediterranean fever • Hyperimmunoglobulinemia D and periodic fever • Muckle-Wells syndrome • Tumor necrosis factor receptor– associated periodic syndrome (familial Hibernian fever) • Type V hypertriglyceridemia
- 33. Thermoregulatory disorders: Central • Brain tumor • Cerebrovascular accident • Encephalitis • Hypothalamic dysfunction Peripheral • Hyperthyroidism • Pheochromocytoma Factitious Fevers "Afebrile" FUO [<38.3°C (100.94°F)]
- 34. • Relative frequencies depends on age, geographic region etc. • Overall infection is leading cause (25 to 50 %) • In age > 65 yrs infection has become 2nd or 3rd , in a study by Knockart and associates.
- 35. Causes of Fever in the Returned Traveler * Diagnosis MacLean et al[118] (n = 587) Doherty et al[119] (n = 195) Malaria 32 42 Hepatitis 6 3 Respiratory infection 11 2.6 Urinary tract infection/pyelonephritis 4 2.6 Dysentery 4.5 5.1 Dengue fever 2 6.2 Enteric fever 2 1.5 Tuberculosis 1 2 Rickettsial infection 1 0.5 Acute HIV infection 0.3 1.0 Amebic liver abscess 1 0 Other miscellaneous infections 4.3 9.2 Miscellaneous noninfectious causes 6 1 Undiagnosed 25 24.6
- 36. NOSOCOMIAL PUO • After 3 days of hospitalization • Risk factors encountered in hospital -surgical procedure -urinary& respiratory instrumentation -I V devices -drug therapy - immobilisation
- 37. Infectious causes: • Infected intravascular line • Septic phlebitis • Abcess/ hematoma/infected foreign bodies in post operative patients • Prostatic abscess in men • Infected urinary catheters • Clostridium difficile colitis •Sinuses of intubated patients
- 38. • Acalculous Cholecystitis • DVT/ pulmonary embolism • Drug fever • Transfusion reactions • Alcohol/ drug withdrawl • Adrenal insufficiency Non infectious causes:
- 39. • Thyroiditis • Pancreatitis • Gout/ pseudogout • Intracranial mass effects in stroke patients • Persistent post operative fever
- 40. NEUTROPENIC PUO • Strong predisposition infections. • Atypical clinical manifestations • Absence of radiological abnormalities. • 50 – 60 % are infective, 20 % are bacteremic. • Only 35 % of patients respond to broad spectrum antibiotics.
- 41. Causative organisms: Infection Causative agent Vascular line related Staphylococci Oral infection Candida, HSV Pneumonia Gram negative rods, Candida, Aspergillus, CMV Soft tissues, e.g.. perianal Mixed aerobes & anaerobes
- 42. Probable cause of fever in neutropenic patients not responding to broad spectrum antibiotic therapy: • Fungal infections • Bacterial infections with resistant organism or cryptic foci • Toxoplasma gondii, mycobacteria, or fastidious pathogens (legionella, mycoplasma, Chlamydophila pneumoniae, bartonella) • Viral infections • Graft vs. host disease • undefined
- 43. HIV RELATED PUO • Initial phase-Mononucleosis like illness • Later phase- opportunistic infections • Distorted presentation
- 44. Etiology : Infections • Disseminated mycobacterium avium complex. • Pneumocystis jiroveci • Cytomegalovirus • Histoplasmosis • Toxoplasmosis and disseminated cryptosporidiosis • Disseminated Cryptococcosis and pulmonary Aspergillosis
- 45. • Other virus: – Hepatitis C & B, – adenovirus pneumonia, – herpes simplex esophagitis, – varicella-zoster encephalitis
- 46. Neoplasia: • Lymphoma • Kaposi’s sarcoma Miscellaneous: • Drug fever • Castleman’s disease
- 47. Approach to patient with PUO • Stage 1: Careful history taking, physical examination and screening tests • Stage 2: Review the history, repeating physical examination, specific diagnostic tests & non invasive investigations • Stage 3: Invasive tests • Stage 4: Therapeutic trials
- 48. Stage 1 History taking: • Occupation • Personal history • Exposure to animals • Travel history • Past medical history • Family history
- 49. Fever patterns: • Continuous • Remittent • Intermittent • Tertian ( 48 hrs) • Quotidian (24 hrs) • Quartan (72 hrs) • Saddle back • Picket fence
- 51. Body site Physical finding diagnosis Head Sinus tenderness sinusitis Temporal artery nodules & reduced pulsation Temporal arteritis oropharynx ulceration Disseminated Histoplasmosis Tender tooth Periapical abscess Fundi / conjunctiva Choroid tubercle Disseminated granulomatosis Petechiae, Roth’s spots Infective endocarditis Thyroid thyroid enlargement Thyroididtis Physical examination:
- 52. Heart murmur myxomas, endocarditis Abdomen Enlarged iliac crest lymph nodes , spleenomegaly lymphomas., disseminated granulomatosis Rectum Perirectal fluctuance and tenderness Abcess Prostatic tenderness Abcess Lower limbs deep vein tenderness DVT & thrombophlebitis Skin & nail Petechiae, splinter hemorrhages, subcutaneous nodules, clubbing Vasculitis, endocarditis
- 53. Laboratory investigations: • Complete blood count • Differential leukocyte count • ESR/ CRP • Electrolytes • Microscopic urine analysis • Cultures of blood & urine • Chest X ray • Abdominal & pelvic ultrasonography
- 54. Stage 2 • Review history & repeat physical examination • Specific investigations • Repeat sampling of blood & other body fluids. • Skin tests • Blood for antibodies – HIV antibodies, CMV antibodies, EBV antibodies.
- 55. • Serological tests for toxoplasmosis, psittacosis and rickettsial infections, syphillis. • Serology for rheumatologic disorders like antinuclear and antineutrophilic cytoplasmic antibodies, rheumatoid factor • Quatiferon TB Gold in tube and T spot TB – detects ϒ interferon release.
- 56. Microscopy: • Direct examination of blood smears: malaria, trypanosomiasis ,babesia, leishmania, relapsing fever rat bite fever, ehrlichiosis. • Intra cellular organisms, bacteria, inclusion bodies, protozoal amastigotes.
- 58. Blood for culture: • Detect fastidious organism e.g. nutritionally variant streptococci, HACEK group. • Media containing pyridoxal and L-cystein. • 3 to 6 samples • Incubated with and without CO2.
- 59. Infective endocarditis: Patient group Etiological agent Native valve •Oral streptococci & enterococci •Staph aureus •CONS •Enteric rods •Fungi (candida) Intravenous drug users •Staph aureus •Oral streptococci & enterococci •Enteric rods •Fungi (candida) Prosthetic valve (early) •CONS •Staph aureus •Oral streptococci & enterococci •Enteric rods •Fungi (candida)
- 60. Prosthetic valve late •Oral streptococci & enterococci •Staph aureus •CONS •Enteric rods •Fungi (candida) Rare causes •Haemophilus spp •Actinobacillus actinomycetemcomitans, Cardiobacterium spp •Eikenella spp •Kingella spp. •Brucella, •Francisella
- 61. Imaging studies: • GI contrast study • High resolution spiral CT • Arteriography • Echocardiography • Duplex imaging
- 62. Radionucleotide scanning: • Technetium (Tc) 99 M sulfur colloid • Gallium (Ga) 67 citrate • Indium ( In) 111 • Flurodeoxy – PET scanning
- 63. Stage 3 • Biopsy of liver and bone marrow • Lymph node biopsy • Blind biopsy of 1 or both temporal artery in patient > 50 yrs • Exploratory laparotomy
- 64. Stage 4 Therapeutic trials: • Empirical treatment with corticosteroids or NSAIDS or antimicrobials • Antimycobacterial agents in AIDS & neutropenic • Blind therapy- delay in correct diagnosis
- 66. MANAGEMENT • Therapy withheld until cause is found • Empirical corticosteroids or anti inflammatories in temporal arteritis. • Vital sign instability & neutropenia – Fluoroquinolones + piperacillin, vancomycin + ceftazidime/cefepime/ carbapenem with or without aminoglycoside,
- 67. Management of Nosocomial PUO: • Change of IV lines, catheters • Empirical treatment: Vancomycin for MRSA Broad spectrum Gram negative coverage Piperacillin + tazobactum Ticarcillin + clavulinic acid Meropenem
- 68. PROGNOSIS • Poorest prognosis - elderly & malignant • Delay in diagnosis affects prognosis of intraabdominal infections, miliary tuberculosis, disseminated fungal infections & recurrent pulmonary emboli • Undiagnosed PUO for prolonged duration – good prognosis.
- 69. References • Harrison’s principles of internal medicine 18th edition. • Mandell, Bennet & Dolin’s, principle of infectious disease 6th edition. • Mims’ Medical microbiology 4th edition.