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Pyrexia of unknown origin

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fever of unknown origin, classification, etiology, approach to a patient with FUO, management, prognosis

fever of unknown origin, classification, etiology, approach to a patient with FUO, management, prognosis

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  • 1. 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
  • 2. Thermoregulation: • Continuom of neural structure to and from hypothalamus and limbic system • Preoptic area- temperature sensitive area • Thermal set point • Negative feed back control.
  • 3. Pathophysiology of fever: Pyrogens : • Substances mediate the elevation of core body temperature. • Exogenous and endogenous pyrogens.
  • 4. Exogenous pyrogens: • Derived from outside the host. • Microorganisms, toxins and microbial products. • Initiate fever by inducing host cells (macrophages)
  • 5. Endogenous pyrogens: • Host cell derived • Monomeric molecules (17 kDa) • Undetectable at basal conditions • Short half life • Maximal response
  • 6. Endogenous pyrogens: • Pyrogenic cytokines • IL-1( α and β ) • tumor necrosis factor (TNF α) • IL-6 • Ciliary neurotropic factor (CNF) • Interferon (IFN)
  • 7. Endogenous molecules activating endogenous pyrogens: • Antigen antibody complex • Complement • Androgenic steroid metabolite • Lymphocyte derived molecules • Inflammatory bile acids
  • 8. 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”.
  • 9. Durack and Street’s classification: • Classical • Nosocomial • Neutropenic • PUO associated with HIV infection
  • 10. 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.
  • 11. 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.
  • 12. 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.
  • 13. 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.
  • 14. Classic PUO • Chronic or sub acute course • Median duration of 40 days • Etiology:- infection - neoplasm -connective tissue disorders -miscellaneous -undiagnosed
  • 15. 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
  • 16. Intra-vascular infections: •Bacterial endocarditis •Bacterial aortitis •Vascular catheter infection
  • 17. 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
  • 18. Mycobacterial infections • M. avium/M. intracellulare infections • Other atypical mycobacterial infections • Tuberculosis Mycoplasmal infections Chlamydial infections • Lymphogranuloma venereum • Psittacosis
  • 19. 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
  • 20. 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
  • 21. Fungal infections: • Aspergillosis • Blastomycosis • Candidiasis • Coccidioidomycosis • Cryptococcosis • Histoplasmosis • Mucor mycosis • Paracoccidioidomycosis • Pneumocystis infection • Sporotrichosis
  • 22. Parasitic infections: • Amebiasis • Babesiosis • Chagas' disease • Leishmaniasis • Malaria • Strongyloidiasis • Toxocariasis • Toxoplasmosis • Trichinellosis
  • 23. Presumed infection : • Kawasaki’s disease • Kikuchi’s necrotizing lymphadenitis.
  • 24. 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
  • 25. Benign: • Atrial myxoma • Castleman's disease • Renal angiomyolipoma
  • 26. 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
  • 27. Granulomatous diseases: • Crohn's disease • Granulomatous hepatitis • Midline granuloma • Sarcoidosis
  • 28. 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
  • 29. 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
  • 30. Thermoregulatory disorders: Central • Brain tumor • Cerebrovascular accident • Encephalitis • Hypothalamic dysfunction Peripheral • Hyperthyroidism • Pheochromocytoma Factitious Fevers "Afebrile" FUO [<38.3°C (100.94°F)]
  • 31. • 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.
  • 32. 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
  • 33. NOSOCOMIAL PUO • After 3 days of hospitalization • Risk factors encountered in hospital -surgical procedure -urinary& respiratory instrumentation -I V devices -drug therapy - immobilisation
  • 34. 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
  • 35. • Acalculous Cholecystitis • DVT/ pulmonary embolism • Drug fever • Transfusion reactions • Alcohol/ drug withdrawl • Adrenal insufficiency Non infectious causes:
  • 36. • Thyroiditis • Pancreatitis • Gout/ pseudogout • Intracranial mass effects in stroke patients • Persistent post operative fever
  • 37. 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.
  • 38. 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
  • 39. 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
  • 40. HIV RELATED PUO • Initial phase-Mononucleosis like illness • Later phase- opportunistic infections • Distorted presentation
  • 41. Etiology : Infections • Disseminated mycobacterium avium complex. • Pneumocystis jiroveci • Cytomegalovirus • Histoplasmosis • Toxoplasmosis and disseminated cryptosporidiosis • Disseminated Cryptococcosis and pulmonary Aspergillosis
  • 42. • Other virus: – Hepatitis C & B, – adenovirus pneumonia, – herpes simplex esophagitis, – varicella-zoster encephalitis
  • 43. Neoplasia: • Lymphoma • Kaposi’s sarcoma Miscellaneous: • Drug fever • Castleman’s disease
  • 44. 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
  • 45. Stage 1 History taking: • Occupation • Personal history • Exposure to animals • Travel history • Past medical history • Family history
  • 46. Fever patterns: • Continuous • Remittent • Intermittent • Tertian ( 48 hrs) • Quotidian (24 hrs) • Quartan (72 hrs) • Saddle back • Picket fence
  • 47. 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:
  • 48. 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
  • 49. Laboratory investigations: • Complete blood count • Differential leukocyte count • ESR/ CRP • Electrolytes • Microscopic urine analysis • Cultures of blood & urine • Chest X ray • Abdominal & pelvic ultrasonography
  • 50. 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.
  • 51. • 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.
  • 52. Microscopy: • Direct examination of blood smears: malaria, trypanosomiasis ,babesia, leishmania, relapsing fever rat bite fever, ehrlichiosis. • Intra cellular organisms, bacteria, inclusion bodies, protozoal amastigotes.
  • 53. 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.
  • 54. 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)
  • 55. 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
  • 56. Imaging studies: • GI contrast study • High resolution spiral CT • Arteriography • Echocardiography • Duplex imaging
  • 57. Radionucleotide scanning: • Technetium (Tc) 99 M sulfur colloid • Gallium (Ga) 67 citrate • Indium ( In) 111 • Flurodeoxy – PET scanning
  • 58. 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
  • 59. Stage 4 Therapeutic trials: • Empirical treatment with corticosteroids or NSAIDS or antimicrobials • Antimycobacterial agents in AIDS & neutropenic • Blind therapy- delay in correct diagnosis
  • 60. 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,
  • 61. 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
  • 62. 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.
  • 63. References • Harrison’s principles of internal medicine 18th edition. • Mandell, Bennet & Dolin’s, principle of infectious disease 6th edition. • Mims’ Medical microbiology 4th edition.