Fever Of Undetermined Origin

SUBJECT: Medicine 2 DATE: July 02, 2008 TOPIC: Fever of Undetermined Origin LECTURER: Mr. Alberto Gabriel TRANSGROUP:SMV DEFINITION

Classic definition by Petersdorf &Beeson, 1961 An illness that is characterized by a temperature of 38.3°C or greater on multiple occasions that lasts three weeks or longer, and that remains undiagnosed after one week of in-hospital evaluation. • Durack & Street, 1991 Proposed a new system of classification of FUO * (-) for any laboratory results

COMMON CAUSES OF CLASSIC FUO Table 2. Causes of FUO in Adults Petersd orf & Beeson (1961) 100 cases 36

Category

Table 1. Modifications of FUO definition by Durack & Street, 1991 IMMUNODEFICIENT NEUTROPEN IC

HIV – ASSOCIAT ED

NOSOCOMIA L

Patients not in other categories fever ≥ 3 weeks

Has < 500 neutrophils

Confirmed HIV positive

Hospitalized , Acute case, No infection when admitted

3 days or 3 OPD visits

3 days

CLASSIC

Patient type Duration of illness while under investigati on

Example of etiology

Infections, malignanci es, inflammato ry disease

Perianal infection, aspergillosis , candidemia

3 days or 4 weeks as OPD

3 days

MAI, TB, nonHodgkin’s lymphoma

Septic thrombophlebitis, sinusitis, C. difficile colitis

Infections

Larson, Featherslone & Petersdorf (1982) 105 cases

Knockaert Vanneste & Babbaers (1992) 187 cases

Klejin (1997) 167 cases

31

23

26

Malignancy Collagenvascular disease

19

31

7

12.5

15

9

22

24

Others

23

7

23

8

Undiagnosed

7

12

25

30

*Naproxen – treatment for rheumatic fever - test after 3 days = (-) fever → not infectious (+) fever → infectious Table 3. Causes of FUO in Children

CATEGORIES Diagnostic Categories of FUO • Infections – most common cause classical FUO  Systemic  Localized • Neoplasms • Collagen-vascular disease  Inflammatory diseases  CTD, autoimmune diseases • Miscellaneous causes  Drug fever  Pulmonary embolism  Factitious fever • Undiagnosed

of

Category

Pizzo, et al. (1972) 100 cases

Lohr & Hendley (1974) 84 cases

Mc Chung (1980) 99 cases

Infections

82

33

29

Malignancy

20

18

11

Collagen-vascular disease

6

13

8

Miscellaneous

10

15

19

Undiagnosed

12

19

32

Table 4. Local Experience (PGH, 1975-1990), unpublished

Infections Malignancy Collagen-vascular (autoimmune) Hypersensitivity Unknown Total

Number (%) 34 (46.6) 20 (27.4) 10 (13.7) 2 (2.7) 7 (9.6) 73 (100)

Source: M.F. Mendoza MD, 29th PSMID Conv Table 5. Diagnostic Categories of 72 Patients with FUO at the Santo Tomas University Hospital

Infections Neoplasms Connective tissue disease Miscellaneous Unknown INFECTIONS 1. TB 2. Abdominal abscess 3. Cryptic abscess 4. Typhoid fever

Number (%) 44 (61) 9 (13) 4 (6) 3 (4) 12 (17)

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SUBJECT: Medicine 2 DATE: July 02, 2008 TOPIC: Fever of Undetermined Origin LECTURER: Mr. Alberto Gabriel TRANSGROUP:SMV

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Chronic active hepatitis Infective endocarditis Leptospirosis Pyelonephritis Malaria Chronis sinusitis Toxoplasmosis Osteomyelitis

Predominant cause in developing countries High in infants and children Vary according to place (country) Ex. Visceral Leishmaniasis – Middle East Melioidosis – South East Asia & Australia K Fujimoto Disease – Japan - Cervical lymphadenopathy - Malaise - Fever

PARASITIC INFECTIONS AS CAUSE OF FUO - may occur with other concomitant cause • Schistosoma • Leishmaniasis • Toxoplasmosis • Others – Fasciola, Amoeba MALIGNANCIES & FUO • Hematologic and solid tumors:  Lymphoma  Acute leukemia (children)  Hypernephroma (Renal cell CA)  Bone sarcoma  Atrial myxoma  GI – gastric CA, liver, colon MALIGNANCY (Neoplasms) • Frequency decreasing • Higher in elderly • More in developed country • Infection is secondary COLLAGEN-VASCULAR DISEASE (Autoimmune)

• • • • • •

Systemic Lupus Erythematosus Rheumatoid arthritis Systemic vasculitis Mixed connective tissue disease Rheumatic fever (most common due to presence of Streptococcus pneumoniae/viridans → heart valves, kidney) Others e.g. Still’s disease

CONNECTIVE TISSUE DISEASE • Young adults –SLE • Still’s disease (JRA) • Elderly – Temporal arteritis and Polymyalgia rheumatica • More in developed countries

MISCELLANEOUS CAUSES • Pulmonary embolism • Chronic hepatitis • Other granulomatous diseases • CNS causes • Cyclic neutropenia • Factitious fever • GHVD HYPERSENSITIVITY DISEASES • Drug fever

• • • • • •

Erythema multiforme – skin infection Allergic vasculitis Serum sickness Milk allergy Halothane sensitization Post-pericardiotomy syndrome

AGENTS COMMONLY ASSOCIATED WITH DRUGINDUCED FEVER • Allopurinol (Zyloprim) • Captopril (Capoten) • Cimetidine (Tagamet) • Clofibrate (Atromid-S) • Erythromycin • Heparin • Hydralazine (Apresoline) • Hydrochlorothiazide (Esidrix) • Isoniazid • Meperidine (Demerol) • Methyldopa (Aldomet) • Nifedipine (Procardia) • Nitrofurantoin (Furadantin) • Penicillin • Phenytoin (Dilantin) • Procainamide (Pronestyl) • Quinidine HIV-RELATED FUO • Opportunistic infections  Atypical manifestations  Prior antibiotic prophylaxis • Mycobacterial infection – most common in the Philippines • Collagen-vascular – uncommon • Pneumonia – other countries NOSOCOMIAL FUO • > 48 hours in hospital or at least 3 days before the start of fever • Risk factors  Urinary & respiratory instrumentation  Surgery  IV devices  Drugs  Immobilization

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5. 6. 7. 8. 9. 10. 11. 12.

SUBJECT: Medicine 2 DATE: July 02, 2008 TOPIC: Fever of Undetermined Origin LECTURER: Mr. Alberto Gabriel TRANSGROUP:SMV -

Fracture pelvis) ICU

in

sensitive

areas

(thigh,

IMMUNODEFICIENT FUO A. Immunosuppression  Infection  Atypical manifestation  GVHD in transplants B. Neutropenic  Bacteremia & sepsis  Fungal infection

2.

Blood or BMA C/S - 3 aerobic and anaerobic in the 1st 2 days of hospitalization 3. PPD test 4. Subsequent tests must be individualized C. Use of specific test 1. Autoantibody screening 2. Specific PCR 3. Imaging X-ray Isotope scanning 4. Tumor markers * TB – cause of prolong fever

COMMON APPROACH TO FUO

Evaluation of FUO Starts with very good history and PE 1. History – documented fever  Recent travel  Exposure to pets/animals  Work environment  Family history  Medication 2. PE – subtle signs and symptoms  Nausea  Aaaa  Oral ulcers  Fundoscopy  Petechial/splinter hemorrhages

USEFUL LABORATORY EXAMINATIONS

DIAGNOSIS • More aggressive and rapid evaluation for critically ill patients – as soon as possible • Evaluation slow and deliberate (out-patient) for the chronically ill EVALUATION OF A PATIENT WITH FUO A. No obvious cause, systemic symptoms not disabling  OPD work-ups CBC with ESR Urinalysis Chest x-ray Alkaline phosphatase, SGOT ANA, other serologic tests Blood culture Stool for guiac B. Persistence of fever or clinical deterioration – hospitalization 1. Repeat tests done in OP setting

DIAGNOSTIC ADVANCES • Ultrasonography • Echocardiography • CT scan • Magnetic Resonance Imaging (MRI) – identify which part is affected

• • • • •

Labelled WBC – Indium, Technetium Gallium scan Angiography PET scan Venous duplex imaging of LE

Table 6. Diagnostic Categories of 72 Patients with FUO at the Santo Tomas University Hospital Tuberculosis, malignancy, Chest radiograph Pneumocystis carinii pneumonia CT of abdomen or pelvis with Abscess, malignancy contrast agent Gallium 67 scan Infection, malignancy Indium-labeled leukocytes Occult septicaemia Acute infection and Technetium Tc 99m inflammation of bones and soft tissue Malignancy, autoimmune MRI of brain conditions PET scan Malignancy, inflammation Transthoracic or transesophageal Bacterial endocarditis echocardiography Venous Doppler study Venous thrombosis

TUMOR MARKERS

• •

•

Diagnostic  α feto protein (AFP)  β HCG Highly supportive  C19-9  CA125  CEA  PSA Others

NON SPECIFIC INFLAMMATORY MARKERS • Procalcitonin

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FUO General Consideration 1. Well organized systemic approach 2. Age group difference 3. Duration of fever → > 3 weeks 4. Type of hospital 5. Immune state/underlying diseases DM, collagen problem

SUBJECT: Medicine 2 DATE: July 02, 2008 TOPIC: Fever of Undetermined Origin LECTURER: Mr. Alberto Gabriel TRANSGROUP:SMV

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 Specific at high titers but not sensitive C-reactive protein  Positive for bacterial infections ESR – sensitivity 53%, Low ESR helpful to r/o bacteremia  >80-100 mm/hr useful aid and clinical marker of disease activity for CTD

INVASIVE DIAGNOSTIC PROCEDURES A. Tissue diagnosis (Biopsy) 1. Liver 2. Bone marrow 3. Lymph node 4. Skin nodule/rash and muscle 5. Temporal artery B. Angiography C. Explratory laparotomy Table 7. The Value of Exploratory Laparotomy in FUO

Operative findings in 70 FUO cases Number (%) Malignant 21 (30.0) Specific infection 21 (21.4) Indeterminate disease 14 (20.0) Miscellaneous 6 (8.6) Nothing found 14 (20.0) Source: Mayo clinic ESR • • • •



Liver and bone marrow biopsy

SELECTED CAUSES OF FUO (Mandell) • Disseminated granulomatosis • Lymphoma • Thromboembolic disease • Endocarditis • Adult Still’s disease • Drug fever • Temporal arteritis and PMR

EVALUATION OF A PATIENT WITH FUO REQUIRES: • Knowledge of those disorders that produce this syndrome (FUO) • Recognition of the potential significance of subtle findings in the history and physical examination • Awareness of the value in the clinical setting of specific diagnostic procedures

NOSOCOMIAL INFECTION

Sensitivity 53% Specificity 33% (-) PPV for bacteremia 94% ↓ ESR (<20 mm/hr) helpful to r/o bacteremia

DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN * see last page

EMPIRIC TREATMENT

TREATMENT AND MANAGEMENT • Non-specific treatment is rarely curative and may delay diagnosis • NSAIDS – Ibuprofen, Indomethacin, Naproxen

 • •

EMPIRIC STEROIDS • Seldom indicated • Consider cryptic TB  Difficult to exclude

Response to ASA & NSAIDS – may mask fever of infection Naproxen test Therapeutic trial

THERAPEUTIC TRIAL • Specific therapy – specific goal and hypothesis • Time limit • Regular, reliable observation of vital signs and clinical conditions • Use drugs with limited spectrum • May delay diagnosis • Only for seriously ill patients – nosocomial FUO, febrile neutropenia • Some FUO may resolve spontaneously

DEFINITION Nosocomial infection – are infectious which are the result of treatment in a hospital or a healthcare service unit. they appear as fever after 48 hours or more after hospital admission or within 30 days after discharge Other known as: “Hospital-acquired infection” “Healthcare-associated infection” COMMON CAUSES • Urinary tract infection • Surgical sites • Pneumonias TRANSMISSION • Contact (direct or indirect) transmission • Droplet transmission • Airborne transmission • Common vehicle-borne transmission • Vector-borne transmission PREDISPOSITION INFECTION • Host factors – poor state of health, advanced age, prematurity, immunodeficiency • Invasive devices – intubation tubes, catheters, surgical drains • Host treatments – immunosuppressive, antimicrobials or recurrent blood transfusion

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SUBJECT: Medicine 2 DATE: July 02, 2008 TOPIC: Fever of Undetermined Origin LECTURER: Mr. Alberto Gabriel TRANSGROUP:SMV

PREVENTION • Isolation • Handwashing and gloving • Aprons • Masks

DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN Complete history and physical assessment Positive findings

No CBC, electrolytes, LFT, blood culture, urinalysis, urine culture, ESR, PPD skin test, chest radiograph Positive results

No

CT of abdomen/pelvic with contrast

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Assign to most likely category

SUBJECT: Medicine 2 DATE: July 02, 2008 TOPIC: Fever of Undetermined Origin LECTURER: Mr. Alberto Gabriel TRANSGROUP:SMV

No

Lumbar puncture, gallium 67 scan, sinus films (radiography or CI)

Autoimmune conditions Rheumatoid factor, ANA

Malignancie

Hematologic Peripheral smear, serum protein electrophoresis Diagnosis clear ?

NonHematologic Mammography, chest CT with contrast, upper/lower endoscopy, bone scan, gallium 67 scan

No

Miscellaneous Order appropriate diagnostic tests based on information from the history

Temporal artery biopsy, lymph node biopsy

No No Bone marrow MRI of the brain, biopsy of suspicious skin lesions or lymph nodes, liver biopsy, diagnostic laparoscopy

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Infection Urine and sputum cultures for AFB, VDRL, HIV test; serology for CMV, EBV, ASO titer (geographically specific testing)