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feverofunkownorigin-190121090327.pdf ram
- 1. Fever of UnknownOrigin
- 2. Objective Terminology Epidemiology and Etiology DiagnosticApproach Therapeutic Trials Outcome
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- 8. Classification 1. Classical FUO 2.Nosocomial FUO 3. Neutropenic FUO 4. HIV-Associated New addition Transplant FUO
- 9. Epidemiology and Etiology Infections30 - 60 % Collagen Vascular Disease 20 – 35 % Malignancies 10 – 20 % Miscellaneous 15 – 20 % Undiagnosed 10 – 15 % Categories of PUO in India Handa et al Handa et al (1996) D Kejarwal et al (2001) Di panjan Bhandyopadha yay et al (2011) Infections 43.8% 53% 53.8% Collagen Vascular Disease 15.7% 11% 11% Neoplasm 8.3% 17% 22%
- 10. Etiologies of FUO Infection:Three major causes Intracellular organisms. (Salmonella Mycobacterium, Brucella) Intravascular … SBE Abscess .. especially occult ..
- 11. Etiologies of FUO Infection-Tuberculosis: .. Disseminated Single most common infection in most PUO series Usually extrapulmonary or miliary, or Occurs in the lungs and significant pre-existing lung disease. Pulmonary TB in HIV is often subtle (normal chest x- rays 15 – 30%). → PPD is (+ve) < 50% of TB with FUO. Diagnosis often requires Bx of LN/Liver/Bone marrow. Sputum smear (+) only15- 25%
- 12. Etiologies of FUO BacterialEndocarditis: Culture remains negative in 5-30% 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 Mycoplasma/Chlamydia } Fungal usually sterile → Peripheral signs may not be detected. Right-side Endocarditis Lack murmurs self antibiotics → → → growth (-ve).
- 13. Etiologies of FUO Abscess: Usually located in abdomen or pelvis. Secondary to appendicitis or diverticulitis. Pyogenic liver abscess usually follow biliary tract dis./abd. Suppuration. Splenic abscess is usually secondary to hematogenous seeding. Perinephric or renal abscess is usually secondary to UTI. Subphrenic Abscess Retroperitoneal Abscess Paravertebral Abscess
- 14. Etiologies of FUO Collagen-Vascular-Disease Youneed to recognize the syndrome otherwise no diagnosis SLE Still’s disease (young or adult)—23-50% Giant cell arteritis } 15% of PUO → Polymyalgia Rheumatica } Behcet’s Disease Relapsing polychondritis
- 15. Etiologies of FUO Malignancy Lymphoma … Fever is a presenting feature Leukemia … M. Myeloma Renal cell carcinoma … HCC or secondary metastasis to the liver Benign Neoplasm
- 16. Etiologies of FUO MiscellaneousCauses: (Non-Infectious) Vascular Causes: Pulmonary Emboli 50% are febrile Fever is < 39o C Patient typically has predisposing factors cancer or recent → immobility. Hematoma in closed space When it cause PUO usually arise from hemorrhage in the → retroperitoneal space or within the wall of an aneurysm or dissection of the thoracic or abdominal aorta.
- 17. Etiologies of FUO Hyperthyroidism Occasionally cause PUO most frequently diagnosed clinically. → Often accompanied by weight loss. Familial Mediterranean Fever Recurrent fever Arthritis pain out of proportional to signs Polyserositis (peritonitis … may be pleuritis) Leukocytosis Not always hereditary
- 18. Etiologies of PUO FactitiousFever Febrile PUO In one study … 9% of cases of PUO False fever: thermometer manipulation using external heat or substitute thermometer. H/O Psychiatric illness Increasing somewhat in elderly … Generally young women with connection to health care … often NURSES.
- 19. Miscellaneous Causes ofFUO Cerebrovascular accident, brain tumour, encephalitis Sweet’s syndrome Gout, Pseudogout Kawasaki’s syndrome, Kikuchi’s syndrome Crohn’s disease, ulcerative colitis Sarcoidosis, Granulomatous hepatitis,Alcoholic Hepatitis Drug fever Deep vein thrombosis
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- 21. Drug Fever Nocharacteristic fever pattern was observed. Maximum temperatures ranged from 38°C to 43°C The mean lag time between initiation of a drug and the onset of fever was 21 days, but lag times varied considerably. Alpha methyldopa and quinidine were the two drugs most commonly implicated, but antimicrobials (as a group) were responsible for the largest number of episodes. Episodes Episodes in Dallas in Dallas (n=51) (n=51) Episodes Episodes in Lit. in Lit. (n=97) (n=97) Total Total Episodes Episodes (n=148) (n=148) n n n n % % Gender (male/female) Gender (male/female) 27/18 27/18 53/44 53/44 56/44 56/44 Hx of atopic disease Hx of atopic disease 0 0 3 3 2 2 Previous hx of drug allergy Previous hx of drug allergy 4 4 12 12 11 11 Fever patterns reported Fever patterns reported Continuous Continuous Remittent Remittent Intermittent Intermittent Hectic Hectic 51 51 0 0 19 19 6 6 26 26 41 41 9 9 7 7 13 13 12 12 62 62 10 10 28 28 21 21 41 41 Rigors Rigors 26 26 52 52 53 53 Relative bradycardia Relative bradycardia 5 5 4 4 11 11 Hypotension Hypotension 6 6 21 21 18 18 Rash Rash Pruritus Pruritus 20 20 11 11 6 6 0 0 18 18 7 7 Leukocytosis (>10K) Leukocytosis (>10K) 11 11 0 0 7 7 Eosinophilia (>300/mm Eosinophilia (>300/mm3 3 ) ) 21 21 12 12 22 22 Hematologic Hematologic 1 1 12 12 9 9 Deaths Deaths 2 2 4 4 4 4 Mackowiak and LeMaistre Ann Intern Med 1997;106:728
- 22. Diagnostic Approach Careful History PhysicalExamination (repeated) Diagnostic Testing
- 23. History Verify the presenceof fever: Duration & Pattern of Fever Tertian & Quartian Pattern→ Malaria Pel-Ebstein Pattern → Lymphoma Pulse-Temp Dissociation → Typhoid/Brucellosis
- 24. History Family History: Scrutinizedfor possible infectious or hereditary disorders Tuberculosis FMF Past Medical Condition: Lymphoma,Rheumatic Fever,Still’s Disease,Behcet’s Disease may recur → Travel History Work Environment Exposure to sexual partner … HIV, Syphilis Illicit drug abuse (IV) … Infective endocarditis, Hepatitis … HIV
- 25. Historical clues Headche: Malaria ,Mycoplasma, Leptospirosis, Qfever Temporal arteritis ,Ch .Meningitis,, Abd.Complaints: Liver & intra abdominal abscess,lymphoma & Carcinoma,IBD, PAN Backpain: Abscess,Myeloma,Metastasis, Osteomyelitis, Potts spine Animal Contact: Brucellosis, Lepto,Psittacosis, Cat Scratch Fever
- 26. Physical Examination Examine forLymphadenopathy Thyroid examination Temporal Artery examination Sinus tenderness
- 27. Physical Examination Examine theSkin: Rash: SLE ….. All types of rashes is described Still’s Disease Evanescent erythematous rash over the trunk Infective Endocarditis (Janeway’s lesion) Typhoid Fever … rose spots over abdomen Osler’s Nodes: Painful nodule on the pads of toes & fingers → Infective Endocarditis
- 28. Physical Examination Examine forOral 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. →
- 29. Physical Examination Examine : Liver & Spleen: Legs Teeth PR
- 30. Diagnostic Testing-Initial Workup CompleteBlood Count Anemia if present Suggest a serious underlying → disease Leukocytosis with bands Occult bacterial infection → Leucopenia and Lymphopenia Advanced HIV → Leukoerythroblastic Anemia Disseminated TB → Thrombocytopenia Malaria/Leukemia → Peripheral Blood Malaria →
- 31. Diagnostic Testing ESR If elevated significant inflammatory process → Greatest use in establishing a serious underlying disease, esp. if v. high ESR > 100 mm/h … → Tuberculosis,Myeloma,Temporal arteritis CRP-closely associated with inflammatory process • ESR & CRP is elevated in: • 1.Bacterial Infection 2. Neoplasm 3.Immunological-mediated inflammatory states 4.Tissue infarction
- 32. Diagnostic Testing Smear studies Urinalysis LFT Sputumexamination PPD Skin Test Chest X ray USG Culture –Blood , , Sputum, Urine
- 33. Diagnostic Testing- SecondEvaluation Blood Testing Anti-nuclear Antibodies Rheumatoid Factor CMV & EBV Antibody … IgM Brucellosis AB titre Thyroid Function Test HIV Screening
- 34. Diagnostic Testing- SecondEvaluation 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 ECHO Bone Marrow Aspiration & Culture Colonoscopy & Biopsy Radionucletide scans PET scan
- 35. Therapeutic Trials Limitations andrisk 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.
- 36. Therapeutic Trials Antimicrobial Trials: Expected to suppress, but not cure, an infectious process such as abscess may have false feeling of response. → Failure to have quick response does not mean wrong → diagnosis: Endocarditis Pelvic inflam. Disease Typhoid Fever Start early in certain conditions- Cirrhosis , Asplenia , Biologic Therapy, on Immuno Suppressive,Travel Exposure
- 37. Therapeutic Trials Empirical Drug: Suspected Tuberculosis Culture-negative Endocarditis Vasculitis Temporal Arteritis Neutropenia HIV
- 38. Therapeutic Trials Empiric drugtrial for suspected T.B: Presence of granuloma on Bx before culture result. Elderly or immunocompromised patient with (+ve) TB skin test and deteriorating clinical condition. No drug for stable patient without any suggestive features laboratory result.
- 39. Therapeutic Trials Empiric drugtrial for suspected culture: (-ve) Endocarditis: Patient with new or changing murmur or peripheral signs of endocarditis.
- 40. Therapeutic Trials Empiric drugtrials for suspected Vasculitis: Elderly with weight loss and any symptoms suggestive (headache, visual disturbance, jaw claudication) and ESR > ↑ 50 mm/hr → Patient above 50 yrs who is c/o muscle pain and stiffness around hip and shoulder with ESR ↑ → Ongoing vasculitis Dramatic response is enough to establish the DX. NSAIDS & Colchichine
- 41. 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
- 42. Outcome If the causeof fever remains elusive repeat history → and examination. 5 – 15% of cases The diagnosis remain obscure. → However, most of these patients defervesce without treatment no disease later. →
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- 45. Maculopapular Erythematous Enterovirus EBV, CMV,Toxoplasma gondii HIV Colorado tick fever Salmonella thyphi Leptospira interrogans Measles virus Rubella virus Hepatitis B virus Treponema pallidum Parvovirus B19 Human herpesvirus 6 Infections producing Infections producing Fever and Rush Fever and Rush 1. 1.
- 46. Vesicular Varicella-zooster Herpes simplex virus CoxackieA virus Vibrio vulnificus Cutaneous petechiae Neisseria gonorrhoea N. meningitidis Rickettsia rickettsii (RMSF) Ehrlichia chaffeensis Echoviruses Viridans-streptococci (endocarditis) Infections producing Infections producing Fever and R Fever and Ra ash sh 2. 2.
- 47. Diffuse erythroderma Group Astreptococci (scarlet fever, toxic shock syndr.) Staphylococcus aureus (toxic shock syndr.) Distinctive rash Ecthymia gangrenosum – Pseudomonas aeruginosa Erythema chronicum migrans – Lyme disease Mucous membrane lesions Vesicular pharyngitis – Coxackie A virus Palatal petechiae – rubella, EBV, Scarlet fever Erythema – toxic shock syndr. Oral ulceronodular lesion – Histoplasma capsulatum Infections producing Infections producing Fever and R Fever and Ra ash sh
- 48. Viral Measles Rubella Hepatitis B BacterialScarlet fever Brucellosis Leptospirosis Tuberculosis Syphilis Lyme disease Infections with Infections with Fever and Lymphadenomegaly Fever and Lymphadenomegaly (generalized) (generalized)
- 49. MISCELLANEOUS CAUSES - drug-inducedfever - sarcoidosis LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw- Hill, 2005
- 50. MISCELLANEOUS CAUSES - drug-inducedfever - sarcoidosis - Whipple's disease LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw- Hill, 2005
- 51. MISCELLANEOUS CAUSES - drug-inducedfever - sarcoidosis - Whipple's disease - familial Mediterranean fever LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw- Hill, 2005
- 52. MISCELLANEOUS CAUSES - drug-inducedfever - sarcoidosis - Whipple's disease - familial Mediterranean fever - recurrent pulmonary emboli LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw- Hill, 2005
- 53. MISCELLANEOUS CAUSES - drug-inducedfever - sarcoidosis - Whipple's disease - familial Mediterranean fever - recurrent pulmonary emboli - alcoholic hepatitis LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw- Hill, 2005
- 54. MISCELLANEOUS CAUSES - drug-inducedfever - sarcoidosis - Whipple's disease - familial Mediterranean fever - recurrent pulmonary emboli - alcoholic hepatitis - Thyroiditis LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw- Hill, 2005
- 55. MISCELLANEOUS CAUSES - drug-inducedfever - sarcoidosis - Whipple's disease - familial Mediterranean fever - recurrent pulmonary emboli - alcoholic hepatitis - Thyroiditis - Castleman disease LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw- Hill, 2005
- 56. MISCELLANEOUS CAUSES - drug-inducedfever - sarcoidosis - Whipple's disease - familial Mediterranean fever - recurrent pulmonary emboli - alcoholic hepatitis - Thyroiditis - Castleman disease - factitious fever LM. Tierney (ed). Current Medical Diagnosis & Treatment. McGraw- Hill, 2005
- 57. Etiologies of PUO AlcoholicHepatitis Often unsuspected pt. deny → Fever is usually low grade < 38.5o C May have jaundice and hepatomegaly. AST > ALT 2:1 AST < 500 ↑ Leukocytosis is often there. If you do not think about it in the right time and with the right patient … then you will be troubled and will work a lot in order to get the etiology.
- 58. Diagnostic Testing ↑High ESR lacks specificity: → Drug Reaction } Thrombophlebitis } may cause very high ESR Nephrotic Syndrome } Normal ESR significant inflammatory process is → absent with exception.
- 59. Diagnostic Testing Laparoscopy Tovisualize 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
- 60. Diagnostic Testing- Biopsy 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 →
- 61. 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
- 62. Diagnostic Testing Imaging Studies:… Chest x-ray: Miliary 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 → USG
- 63. Management of FUO Withholdtherapy until the cause is found Exceptions: Neutropenic Fever Unstable hospitalized patient Corticosteroids in suspected Temporal Arteritis HIV Patients