Pyrexia of unknown origin

Pyrexia of unknown origin

1. Pyrexia of Unknown Origin PUO or FUO Dr.T.V.Rao MD 1/20/2013 Dr.T.V.Rao MD 1

2. What is the normal human body temperature? A. 37.5 ° C B. 98.6° F C . Each human being is a unique individual, and therefore, normal temperature cannot be defined. 1/20/2013 Dr.T.V.Rao MD 2

3. What is the normal human body temperature? A. 37.6 ° C B. 98.6° F C Each human being is a unique individual, and therefore, normal temperature cannot be defined. 1/20/2013 Dr.T.V.Rao MD 3

4. Normal Body Temperature For healthy individuals 18 to 40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F) Low levels occur at 6 A.M. and higher levels at 4 to 6 P.M. The maximum normal oral temperature is 37.2°C (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M. These values define the 99th percentile for healthy individuals. Mackowiak, et al., JAMA 1992;268:1578 1/20/2013 Dr.T.V.Rao MD 4

5. Definition Fever > 38.3 on several occasions Fever lasting more than 3 weeks No diagnosis despite 1 week of inpatient workup 1/20/2013 Dr.T.V.Rao MD 5

6. Terminology Old Definition : Fever higher than 38.3 o C on several occasions. Duration of fever – 3 weeks Uncertain diagnosis after one week of study in hospital New Definition : Eliminated the in-hospital evaluation requirements → 3 outpatient visits, or 3 days in hospital. … Ambulatory as well as in hospital 1/20/2013 Dr.T.V.Rao MD 6

7. Historical Causes of FUO Hippocrates: excess of yellow bile Middle Ages: demonic possession (encephalitis?) 18 th Century: Friction associated with the flow of blood through the vascular system and from fermentation and putrefaction occurring in the blood and intestines 1/20/2013 Dr.T.V.Rao MD 7

8. Definition Expansion Classical PUO Nosocomial PUO Neutropenia PUO HIV-Associated Transplant 1/20/2013 Dr.T.V.Rao MD 8

9. Categories of FUO Feature Nosocomial Neutropenic HIV-associated Classic Patient’s situation Hospitalized, acute care, no infection when admitted Neutrophil count either <500/ µL or expected to reach that level in 1-2 days Confirmed HIV-positive All others with fevers for ≥3 weeks Duration of illness while investigated 3 days b 3 days b 3 days b (or 4 weeks as outpatient) 3 days b or 3+ outpatient visits Examples Septic thrombophlebitis, sinusitis, C. difficile colitis, drug fever Perianal infection, aspergillosis, candidemia MAI c infection, TB, non-Hodgkin’s lymphoma, drug fever Infections, malignancy, inflammatory diseases, drug fever a All require temperatures of ≥38.3°C (101°F) on several occasions. b Includes at least 2 days’ incubation of microbiology cultures. c M. avium/M. intracellulare . Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds): Current Clinical Topics in Infectious Diseases . Cambridge, MA, Blackwell, 1991. 1/20/2013 Dr.T.V.Rao MD 9

10. Pattern of Fever 1/20/2013 Dr.T.V.Rao MD 10

11. Etiologies of PUO Infection: Three major causes Abscess .. especially occult .. Intracellular organisms. (salmonella mycobacterium, brucella) Intravascular … SBE 1/20/2013 Dr.T.V.Rao MD 11

12. “ True Fever” Occurs when IL-1, IL-6, TNF- ά or other cytokines are released from monocytes and macrophages in response to infection, tissue injury, drugs, and other inflammatory processes, increasing the body’s set point. The anterior hypothalamus maintains an inherent set point near 36 º C(98.6 º F). Normal circadian rhythm, which is highest(up to 2 º C, 3 º F) ~6pm and lowest at 6am. This accounts for increased volume of ER visits that peaks in the evening. Most true fevers follow this diurnal pattern.

13. Infectious Causes of FUO Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/20/2013 Dr.T.V.Rao MD 13

14. Infectious Causes of FUO Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, Cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/20/2013 Dr.T.V.Rao MD 14

15. Infectious Causes of FUO Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, Cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/20/2013 Dr.T.V.Rao MD 15

16. Bacterial Pyroge ns Lipopolysaccharide (LPS) endotoxin Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNF α . Staphylococcus aureus enterotoxins 1/20/2013 Dr.T.V.Rao MD 16

17. Infectious Causes of FUO Tuberculosis, Mycobacterium avium complex, syphilis, Q fever, Legionellosis Salmonellosis (including typhoid fever), Listeriosis, ehrlichiosis, Actinomycosis, nocardiosis, Whipple’s disease Fungal (candidaemia, cryptococcosis, sporotrichosis, Aspergillosis, Mucormycosis, Malassezia furfur) Malaria , Babesiosis, toxoplasmosis , schistosomiasis, fascioliasis, Toxocariasis, amoebiasis, infected hydatid cyst, trichinosis, trypanosomiasis Cytomegalovirus, HIV , Herpes simplex, Epstein-Barr virus , parvovirus B19 1/20/2013 Dr.T.V.Rao MD 17

18. Miscellaneous Causes of FUO Complex partial status epilepticus, cerebrovascular accident, brain tumor, encephalitis Drug fever , Sweet’s syndrome, familial Mediterranean fever Gout, pseudo gout Kawasaki’s syndrome, Kikuchi’s syndrome Crohn’s disease, ulcerative colitis, sarcoidosis, granulomatous hepatitis Deep vein thrombosis Atelectasis? 1/20/2013 Dr.T.V.Rao MD 18

19. Bacterial Pyrogens Staphylococcus aureus toxic shock syndrome toxin (TSST) Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNF α and TNF β , and interferon (IFN)-gamma in large amounts Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only TNF α but also IL1 and IL-6 1/20/2013 Dr.T.V.Rao MD 19

20. CAUSES CLASSIC PUO INFECTIVE 20-30% CANCER 10-20% AUTOIMMUNE 15-20% MISC 15-25% UNDIAGNOSED 5-10% 1/20/2013 Dr.T.V.Rao MD 20

21. Classic FUO Infection Malignancy Collagen vascular diseases 1/20/2013 Dr.T.V.Rao MD 21

22. Infectious Causes of FUO Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/20/2013 Dr.T.V.Rao MD 22

23. Infectious Causes of FUO Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/20/2013 Dr.T.V.Rao MD 23

24. Infectious Causes of FUO Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/20/2013 Dr.T.V.Rao MD 24

25. Geography Malaria Saudi (malaria area)/Africa/India Brucella Saudi/Gulf Area Kala-Azar Yemen/Jazan/Sudan/India Leprosy Yemen/Najran… Typhoid India/Pakistan/Egypt/Indonesia Histoplasmosis USA … (West Coast) N.B.: Ease of Travel → Infection → All parts of the world. Tuberculosis All over the world. Liver Abscess AIDS 1/20/2013 Dr.T.V.Rao MD 25

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27. Pathophysiology Meningitis and sepsis are serious etiologies of fever in infants and young children. Neonates' immature immune systems place them at greater risk of systemic infection. Hematogenous spread of infection is most common in this age group or in patients who are immunocompromised. For these same reasons, infants who have a focal bacterial infection have a greater risk of developing sepsis. 1/20/2013 Dr.T.V.Rao MD 27

28. Bacterial Pyrogens Lipopolysaccharide (LPS) endotoxin Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNF α . Staphylococcus aureus enterotoxins Staphylococcus aureus toxic shock syndrome toxin (TSST) Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNF α and TNF β , and interferon (IFN)-gamma in large amounts Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only TNF α but also IL1 and IL-6 1/20/2013 Dr.T.V.Rao MD 28

29. What are common Causes The following are among the most common bacterial etiologies of serious bacterial infection in this age group: Streptococcus pneumoniae Group B streptococci Neisseria meningitidis Haemophilus influenzae type b Listeria monocytogenes Escherichia coli 1/20/2013 Dr.T.V.Rao MD 29

30. Consequences of Fever can be confusing Approximately 2.5-3% of highly febrile children younger than 3 years develop occult bacteremia , which typically is caused by S pneumoniae. Viral infections are common in the young child as well; however, exclude serious bacterial infection prior to assuming a viral etiology for the fever. 1/20/2013 Dr.T.V.Rao MD 30

31. History Taking Family History: Scrutinized for possible infectious or hereditary disorders Tuberculosis FMF Past Medical Condition: Lymphoma → may recur Rheumatic Fever → may recur Still’s Disease → may recur Behcet’s Disease → may recur Exposure to sexual partner … Acute HIV Illicit drug abuse (IV) … infective endocarditis, Hepatitis … HIV 1/20/2013 Dr.T.V.Rao MD 31

32. Physical Examination ….. Looking for the KEY physical sign … . Diagnostic yield 60% in children (50%repeated) Document the Fever: Significant and persistent for more than ONE occasion. Analyzing the Pattern: Neither specific Nor sensitive enough to be considered diagnostic … EXCEPT Tertian & Quarter Pattern → Malaria Pel-Ebstein Pattern → Lymphoma/ Tuberculosis Pulse-Temp Dissociation → Typhoid/ Brucellosis 1/20/2013 Dr.T.V.Rao MD 32

33. Infections Tuberculosis (especially extrapulmonary) Abdominal abscesses Pelvic abscesses Dental abscesses Endocarditis Osteomyelitis 1/20/2013 Dr.T.V.Rao MD 33

34. Infections Sinusitis Cytomegalovirus Epstein-Barr virus Human immunodeficiency virus Lyme disease Prostatitis Sinusitis 1/20/2013 Dr.T.V.Rao MD 34

35. Etiologies of PUO Infection Tuberculosis: .. Disseminated The single most common infection in most PUO series except in children and elderly. Usually extrapulmonary or military, or Occurs in the lungs and significant pre-existing lung disease. Pulmonary TB in AIDS is often subtle (normal chest x-rays → 15 – 30%). PPD is (+ve) < 50% of TB with PUO. Diagnosis often requires Bx of LN/Liver/Bone marrow. Sputum smear (+) only 25% 1/20/2013 Dr.T.V.Rao MD 35

36. Etiologies of PUO Abscess: Usually located in abdomen or pelvis. Secondary to appendicitis or diverticulitis. Pyogenic liver abscess usually follow biliary tract dis./abd. Suppuration. Amoebic liver abscess is similar to pyogenic → amoebic serology is positive > 95% of cases. Splenic abscess is usually secondary to hematogenous seeding. Perinephric or renal abscess is usually secondary to UTI. 1/20/2013 Dr.T.V.Rao MD 36

37. Etiologies of PUO Bacterial Endocarditis Culture remains negative in 5% of patient. Culture negative is likely with the following organisms: Coxiella burnetii → no growth. HACEK group → incubate blood 7 – 21 days Brucella } Special media/ Legionelle } long time Mycoplasm/Chlamydia } Fungal → usually sterile Peripheral signs may not be detected. Right-side Endocarditis → Lack murmurs → self antibiotics → growth (-ve). 1/20/2013 Dr.T.V.Rao MD 37

38. Etiologies of PUO Infection Tuberculosis: .. Disseminated The single most common infection in most PUO series except in children and elderly. Usually extra pulmonary or military, or Occurs in the lungs and significant pre-existing lung disease. Pulmonary TB in AIDS is often subtle (normal chest x-rays → 15 – 30%). PPD is (+ve) < 50% of TB with PUO. Diagnosis often requires Bx of LN/Liver/Bone marrow. Sputum smear (+) only 25% 1/20/2013 Dr.T.V.Rao MD 38

39. Geography Malaria Saudi (malaria area)/Africa/India Brucella Saudi/Gulf Area Kala-Azar Yemen/Jazan/Sudan/India Leprosy Yemen/Najran… Typhoid India/Pakistan/Egypt/Indonesia Histoplasmosis USA … (West Coast) N.B.: Ease of Travel → Infection → All parts of the world. Tuberculosis All over the world. Liver Abscess AIDS 1/20/2013 Dr.T.V.Rao MD 39

40. HIV associated PUO HIV alone TB,M avium/intracelulare Toxoplasmosis CMV ,PCP ,Salmonella Cryptococcus, Histoplasmosis Non Hodgkins Lymphoma Drug induced 1/20/2013 Dr.T.V.Rao MD 40

41. Malignancies Chronic leukemia Lymphoma Metastatic cancers Renal cell carcinoma Colon carcinoma Hepatoma Myelodysplastic syndromes Pancreatic carcinoma Sarcomas 1/20/2013 Dr.T.V.Rao MD 41

42. Autoimmune Conditions with Fever Adult Still's disease Polymyalgia rheumatic Temporal arteritis Rheumatoid arthritis Rheumatoid fever Inflammatory bowel disease Reiter's syndrome Systemic lupus erythematous Vasculitides 1/20/2013 Dr.T.V.Rao MD 42

43. Miscellaneous Drug-induced fever Complications from cirrhosis Factitious fever Hepatitis (alcoholic, granulomatous, or lupoid) Deep venous thrombosis Sarcoidosis 1/20/2013 Dr.T.V.Rao MD 43

44. Diagnosis A cost-effective individualized approach is essential in the evaluation of these patients to prevent performing inappropriate tests. 1/20/2013 Dr.T.V.Rao MD 44

45. Minimal Initial Diagnostic Workup For FUO Comprehensive history Physical examination CBC + differential Blood film reviewed by hematopathologist Routine blood chemistry UA and microscopy Blood (x 3) and urine cultures Antinuclear antibodies, rheumatoid factor HIV antibody CMV IgM antibodies; heterophile antibody test (if c/w mono-like syndrome) Q-fever serology (if risk factors) Chest radiography Hepatitis serology (if abnormal LFTs) Mourad, et al. Arch Intern Med .  2003;163:545 1/20/2013 Dr.T.V.Rao MD 45

46. Diagnostic Testing Blind application leads to excessive false tests … Complete Blood Count Anemia if present → suggest a serious underlying disease Leukocytosis with bands → occult bacterial infection Lymphocytosis & atypical Lymphocyte → Infectious mononucleosis Leucopenia and Lymphopenia → advanced HIV Leukoerythroblastic Anemia → Disseminated TB Thrombocytopenia → Malaria/Leukemia Peripheral Blood → Malaria 1/20/2013 Dr.T.V.Rao MD 46

47. Diagnostic Testing Urinalysis, Urine Culture, U/E, LFT ESR If elevated → significant inflammatory process Greatest use in establishing a serious underlying disease, esp. if v. high → ESR > 100 mm/h … Tuberculosis … m myeloma … temporal arteritis 1/20/2013 Dr.T.V.Rao MD 47

48. Diagnostic Testing 58% → malignancy → Lymphoma/myeloma 25% Infection – Endocarditis Giant cell arteritis ↑ High ESR → lacks specificity: Drug Reaction } Thrombophlebitis } may cause very high ESR Nephrotic Syndrome } Normal ESR → significant inflammatory process is absent with exception. 1/20/2013 Dr.T.V.Rao MD 48

49. Diagnostic Testing CRP-closely associated with inflammatory process Not invariable components of the febrile response. Usually does not go up with viral infection. * ESR & CRP is elevated in: Bacterial Infection Neoplasm Immunological-mediated inflammatory states Tissue infarction 1/20/2013 Dr.T.V.Rao MD 49

50. Diagnostic Testing Acute Phase Proteins Proteins Increased Proteins Decreased Fibrinogen Albumin Ferritin Transferrin Plasminogen Alpha- Fetoprotein Protein S Cerruloplasmin New England J Med. 1999, 340.448-454 1/20/2013 Dr.T.V.Rao MD 50

51. Diagnostic Testing Blood Testing Anti-nuclear Antibodies Rheumatoid Factor CMV Antibody … IgM Heterophile Antibody Test in children and young adult Tuberculin Skin Test … 5 unit ID Thyroid Function Test HIV Screening 1/20/2013 Dr.T.V.Rao MD 51

52. Diagnostic Testing Imaging Studies: … to localize abnormalities for definite tests or treatment Chest x-ray: Military shadows → disseminated tuberculosis Atelectasis } 1. Liver ↑ Hemi diaphragm } Abscess 2. Spleen Pleural Effusion } 3. Pancreatic 4. Subphrenic Mediastinal mass → Lymphoma/Tuberculosis/ Sarcoid If CXR is (N) → Repeat on weekly basis 1/20/2013 Dr.T.V.Rao MD 52

53. Diagnostic Testing CT-Scan → CT scan chest Mediastinal mass → Tuberculosis/Lymphoma/ Sarcoidosis Dorsal Spine → Spondylitis and disc space disease CT-Scan Abdomen → very effective to visualize All types of abscesses Retroperitoneal tumor, lymph node or hematoma MRI: spleen, lymph node and the brain 1/20/2013 Dr.T.V.Rao MD 53

54. Diagnostic Testing Serology Test Brucella Titer CMV & EBV antibody test HIV testing (Elisa screening) ANF Radio nuclear Scanning Bone TC-scan → osteomyelitis (skeletal) Gallium scan → occult inflammation Indium labeled WBC-scan → occult abscesses 1/20/2013 Dr.T.V.Rao MD 54

55. Diagnostic Testing Hepatomegaly or Abnormal LFT Hepatic Granuloma Non-caseating: Tuberculosis/Sarcoidosis & Brucellosis Caseating: Tuberculosis Bone Marrow Granuloma ± Tubercle Bacilli → Tuberculosis Aplastic Cells → Leukemia Leishmania Bodies → Kala-Azar Atypical Cells → Lymphoma Atypical Plasma Cells → M. myeloma Temporal Artery → Giant Cell Arteritis Pleural or Pericardial → Extrapulmonary Tuberculosis 1/20/2013 Dr.T.V.Rao MD 55

56. Investigation Blood culture before the antibiotics Culturing of Urine Sputum culture Stool examination for Bacterial and Parasitic infectio n. 1/20/2013 Dr.T.V.Rao MD 56

57. Etiologies of PUO Abscess: Usually located in abdomen or pelvis. Secondary to appendicitis or diverticulitis. Pyogenic liver abscess usually follow biliary tract dis./abd. Suppuration. Amoebic liver abscess is similar to pyogenic → amoebic serology is positive > 95% of cases. Splenic abscess is usually secondary to haematogenous seeding. Perinephric or renal abscess is usually secondary to UTI. 1/20/2013 Dr.T.V.Rao MD 57

58. Tuberculosis Sputum examination for AFB Culturing for AFB Monteux test Tuberculin test X ray of the chest 1/20/2013 Dr.T.V.Rao MD 58

59. 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. When the definitive diagnosis remains elusive and the complexity of the case increases, an infectious disease, rheumatology, or oncology consultation may be helpful. 1/20/2013 Dr.T.V.Rao MD 59

60. Etiologies of PUO Factitious Fever Febrile PUO In one study … 9% of cases of PUO False fever: thermometer manipulation using external heat or substitute thermometer. Men use this way … physician are rare for this disorder. Increasing somewhat in elderly … 115 … 116 … Genuine fever (self induced) Administration of pyrogenic substances (bacterial suspensions) Generally young women with connection to health care … often NURSES. 1/20/2013 Dr.T.V.Rao MD 60

61. Pyrexia of Unknown Origin The majority of disease remaining after an initial NEGATIVE work-up are: Neoplasm Seronegative Collagen Vascular Disease Increasing Tuberculosis Increasing Drug Addition Elderly with Endocarditis HIV with or without infection or malignancy Implanted prosthetic devices Travel … New Exposure 1/20/2013 Dr.T.V.Rao MD 61

62. Therapeutic Trials Limitation and risk of empirical therapeutic trials: Rarely specific Underlying disease may remit spontaneously false impression of success. Disease may respond partially and this may lead to delay in specific diagnosis. Side effect of the drugs can be misleading. 1/20/2013 Dr.T.V.Rao MD 62

63. Therapeutic Trials What is the best therapy for PUO patient? To hold therapeutic trials in the early stage… except in: Patient who is very sick to wait. All tests have failed to uncover the etiology. 1/20/2013 Dr.T.V.Rao MD 63

64. Prognosis Prognosis is determined primarily by the underlying disease. Outcome is worst for neoplasms. FUO patients who remain undiagnosed after extensive evaluation generally have a favorable outcome and the fever usually resolves after 4-5 weeks. Larson et al. Medicine 1982;61:269 1/20/2013 Dr.T.V.Rao MD 64

65. Summary FUO is often a diagnostic dilemma 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 undiagno sed generally have a good prognosis 1/20/2013 Dr.T.V.Rao MD 65

66. Programme Created By Dr.T.V.Rao MD for Medical Students in the Developing World Email [email protected] 1/20/2013 Dr.T.V.Rao MD 66