Pyrexia of unknown origin essential points.pptx

Important points in Basic Medicine. the slide contains all the essential points for differential and management of fever of Unknown Origin.
Required for Final year MBBS exams

1. FEVER OF UNKNOWN ORIGIN Dr Dev jaisy Lecturer Internal Medicine

2. Fever versus Hyperthermia Fever : Increase in body temp above normal daily variation Change in set point of thermoregulatory center (anterior hypothalamus) Hyperthermia : an elevation in body temperature that occurs in the absence of resetting of the hypothalamic thermoregulatory center

3. 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.

4. Normal Body Temperature Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. Tympanic membrane (TM) values are 0.8°C (1.6°F) lower than rectal temperatures when thermometer is in the unadjusted-mode.

5. Hypothetical Model for the Febrile Response Interleukin-1 β and TNF-α play prominent roles in fever production by stimulating the release of cyclic AMP from the glial cells and activating neuronal endings from the thermoregulatory center that extend into the area.

6. Fever of Unknown Origin (Historical Definition) Fever of at least 3 weeks’ duration Temperature of 101° F (38.3° C) on several occasions No diagnosis after a 1 week evaluation in the hospital

7. The definition of FUO has been further modified by the exclusion of immunocompromised patients, whose workup requires an entirely different diagnostic and therapeutic approach.

8. FUO is now defined as follows: 1. Fever ≥38.3°C (≥101°F) on at least two occasions 2. Illness duration of ≥3 weeks 3. No known immunocompromised state 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: Determination of erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST) or interferon γ release assay (IGRA).

9. The commonest cause of PUO IS Common disease presenting ATYPICALLY

10. Classification Classic FUO Nosocomial FUO Neutropenic FUO and FUO associated with HIV infection.

11. Classical FUO Fever of at least 3 weeks’ duration Temperature of 101° F (38.3° C) on several occasions No diagnosis after a detailed work up.

12. Nosocomial FUO Fever > 38.3 Patient hospitalized > 24 hours, but no fever on admission Cause not found despite 3 days of OPD visits or 3 days of hospitalization

13. Neutropenic PUO Fever of at least 3 weeks duration Temperature of 101° F (38.3° C) on several occasions Neutrophils <500/ μ L or expected to fall to that level in 1or 2 dayss Cause not found despite 3 days of OPD visits or 3 days of hospitalization

14. HIV associated PUO Temperature of 101° F (38.3° C) on several occasions in HIV positive over period ≥4 weeks of OPD visits or ≥ 3 days for hospitalization Cause not found despite 3 days of OPD visits or 3 days of hospitalization

15. 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 .

16. 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

17. Infectious Causes of FUO Tuberculosis, Mycobacterium avium complex, syphilis, Q fever, legionellosis Salmonellosis (including typhoid fever), listeriosis Actinomycosis, nocardiosis, Whipple’s disease Fungal (candidaemia, cryptococcosis, sporotrichosis, aspergillosis) Malaria , toxoplasmosis , schistosomiasis, toxocariasis, amoebiasis, infected hydatid cyst, trichinosis, trypanosomiasis Cytomegalovirus, HIV , Herpes simplex, Epstein-Barr virus , parvovirus B19

18. Collagen Vascular Diseases Adult Still’s disease, SLE Giant cell arteritis/polymyalgia rheumatica, ankylosing spondylitis Wegener’s granulomatosis Rheumatic fever Polymyositis, rheumatoid arthritis Felty’s syndrome

19. Malignancies Lymphoma Renal cell carcinoma Hepatocellular carcinoma

20. Miscellaneous Causes of FUO Complex partial status epilepticus, cerebrovascular accident, brain tumour, encephalitis Drug fever , familial Mediterranean fever Gout, pseudogout Kawasaki’s syndrome Crohn’s disease, ulcerative colitis, sarcoidosis, granulomatous hepatitis Deep vein thrombosis

21. 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 Chest radiography Hepatitis serology (if abnormal LFTs)

22. History Verify the presence of fever Duration of Fever: The longer the duration → the less likely to have infection and malignancy.

23. History Travel: Travel to an area known to be endemic for certain disease: Name of the area, duration of stay Onset of illness … (incubation period) 1 – 10 Days 10 – 21 Days Weeks - Months Malaria Malaria Kala Azar Plague Typhoid Amoebiasis Dengue Brucella HIV Salmonella Hepatitis A Hepatitis

24. History Drug and Toxin History: Drug-induced fever … almost all drug can cause drug fever … Antihistamine/betalactam/heparin/coumarin/anti-TB … Salicylates and other NSAID … Alcohol Intake (regular use)

25. History Localizing Symptoms: May Indicate the source of fever: Back Pain TB Spondylitis Bone Metastasis Headache Chronic Meningitis RUQ Pain Liver Abscess LUQ Pain Splenic Abscess Oral & Genital Ulcer Behcet’s Disease Jaw Claudication Temporal Arteritis Subtle changes in behavior Granulomatous Meningitis

26. History 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

27. Physical Examination Document the Fever: Significant and persistent for more than ONE occasion. Analyzing the Pattern: Tertian & Quarter Pattern → Malaria Pel-Ebstein Pattern → Lymphoma/ Tuberculosis Pulse-Temp Dissociation → Typhoid/ Brucellosis

28. Physical Examination Examine for Lymphadenopathy Site → Cervical Area 1. Lymphoma (Localized) 2. Tuberculosis 3. Infectious Mononucleosis 4. Lymphadenitis (bacterial) Supraclavicular lymphadenopathy: Highest risk of malignancy: Patient > 40 yr → 90% Patient < 40 yr → 25%

29. Physical Examination Examine the Skin: Rash: SLE ….. Still’s Disease Evanescent erythematous rash over the trunk Infectious Mononucleosis … macular rash Infective Endocarditis (Janeway’s lesion) Typhoid Fever … rose spots over abdomen Osler’s Nodes: Painful nodule on the pads of toes & fingers → Infective Endocarditis

30. Embolic Skin Lesions … Janeway Lesion Conjunctival petechiae in a patient with bacterial endocarditis

31. Physical Examination Examine for Oral Ulcer SLE Behcet’s Syndrome Examine for Arthritis Examine the Fundus Roth’s spots (white-centered haemorrhage) → Infective Endocarditis Yellowish-white choroidal lesion → Tuberculosis Choriodoretinitis → Active Toxo or CMV in HIV patient.

32. Diagnostic Testing 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

33. Diagnostic Testing Urinalysis, Urine Culture, U/E, LFT ESR If elevated → significant inflammatory process Tuberculosis … m myeloma … temporal arteritis

34. Diagnostic Testing CRP-closely associated with inflammatory process Usually does not go up with viral infection. * ESR & CRP is elevated in: Bacterial Infection Neoplasm Immunological-mediated inflammatory states Tissue infarction

35. Diagnostic Testing Blood Testing Anti-nuclear Antibodies Rheumatoid Factor CMV Antibody … IgM Heterophile Antibody Test in children and young adult Tuberculin Skin Test … Thyroid Function Test HIV Screening

36. Diagnostic Testing Cultures Blood Obtain more than 3 blood cultures from separate venipunctures over 24 hr period if you are suspecting inf. Endocarditis prior antimicrobial use. Incubate the blood for 4 weeks, to detect the presence of SBE & Brucellosis Sputum: For Tuberculosis Any normal sterile: CSF/urine/pleural or peritoneal fluid Bone marrow aspirate → Tuberculosis/Brucellosis Lymph node Bx → TB

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

38. 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 haematoma MRI: spleen, lymph node and the brain

39. Diagnostic Testing Serology Test Brucella Titer CMV & EBV antibody test HIV testing (Elisa screening) ANF Radionuclear Scanning Bone TC-scan → osteomyelitis (skeletal) Gallium scan → occult inflammation Indium labeled WBC-scan → occult abscesses

40. Diagnostic Testing Radionuclear Scanning Overall Assessment: Non-specific tests to localize a site for more specific evaluation (such as CT-scan) Impressive no. of false (+) and false (-) results True positive scan only indicates an area of increased uptake → no anatomic detail

41. Gallium Scan Will be hot if there is: Increased blood flow Uptake by bacteria (lactoferrin) Update by WBC Sensitive but not specific Not good for abdomen or pelvis .. False +ve Effective in: Chronic Infection Lymphoma

42. Diagnostic Testing Laparoscopy To visualize and biopsy the pathology in the abdomen suggestive of: e.g. Tuberculous peritonitis Peritoneal carcinomatosis Biopsy Enlarged lymph node Granulomatous disease (Tuberculosis) Metastatic carcinoma Others

43. 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

44. Therapeutic Treatment of underlying cause detected after investigations Empiric Drug: Tuberculosis Culture-negative Endocarditis Vasculitis … Temporal Arteritis Pulmonary Emboli

45. Prognosis It depends on: Cause of fever Nature of the underlying disease(s) BUT .. Generally poor in: Elderly Neoplasm Diagnostic delay has adverse effect in: Intra Abdominal Infection Miliary Tuberculosis Recurrent Pulmonary Emboli Disseminated Fungal Infection Temporal Arteritis

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