MORTALITY & MORBIDITY CONFERENCE CASE SERIES - FUO

NERISSA ANGSORRAH FIEL BRIONES

ERICK VERANO

February 15, 2007Ledesma Hall

Objectives

To present two distinct cases of patients presenting with prolonged fever

To be able to discuss the step by step approach in the management of patients’ with fever of unknown origin

FEVER OF UNKNOWN ORIGIN

Case Presentation

General Data

I.S. 29 year old male single

Chief Complaint

Work up for on and off Fever 1 month duration

History of Present Illness

6 weeks PTA (+) intermittent fever

Tmax: 39.5ºC(-) associated signs and symptoms Temporary relief by paracetamol 500 mg PO

History of Present Illness

5 weeks PTA (+) intermittent fever

Tmax 39ºC(+) 3 episodes LBMAdmitted at a local hospitalDx Typhoid fever(+) Typhidot IgG + IgMRx Chloramphenicol x 7 days(+) fever episodesDischarged for holiday season

History of Present Illness

3 weeks PTA (+) intermittent fever

Tmax 39ºCSelf medicate

Paracetamol Cotrimoxazole Amoxicillin

No reliefReadmitted again

Diagnostics

A. Malarial Smear – NEGATIVE

B. Peripheral Smear – NORMAL

C. Blood GS – NO GROWTH

D. HIV ELISA – NON REACTIVE

E. ANA – 1.054 – WEARLY POSITIVE

F. Thyroid Fxm Test – NORMAL

G. UTZ of the abdomen – NORMAL SONOGRAPHICS

Diagnostics

H. Fecalysis – NO OVA / PARASITE SEEN

I. Urinalysis – NORMAL

J. CT of the Abdomen – RENAL CORTICAL CYST (R)

History of Present Illness

He was given ceftriaxone 3G IV OD x 3 days but developed HPS rxn

Shifted to cefixime 200 mg BID x 7 days Patient remained to have intermittent fever

Tmax 38.5º despite of antibiotic coverage Opted to be discharged Consult Admission

Past Medical History

(-) HPN (-) diabetes mellitus (-) asthma (-) Hs of other hospitalization in the past

Family History

(+) HPN mother (-) heredofamilial diseases

e.g. CA, mumps, leukemia

Personal and Social History

Non smoker Non alcoholic beverage drinker (-) history of travel

Review of System

(-) anorexia (-) weight loss (-) cough and colds (-) rashes (-) photophobia (-) alopecia (-) oral ulcers (-) bleeding tendencus

Physical Examination Conscious, coherent not in cardiorespiratory

distress BP: 120/80 mmHg, CR: 82, RR: 19, Tº: 38.9ºC Pink palpebral conjunctive, anicteric sclerae

(-) TPC, (-) CLAD ECE, (-) Retraction, Clear breath sounds (-)

crackles Adynamic precordium, normal rate regular

rhythm, (-) murmur

Physical Examination

Flat, soft abdomen, NABS, (-) masses, (-) tenderness

(-) gross deformities, full equal pulses, (-) cyanosis (-)edema

Salient Features

29 y/o male 1 month history of intermittent fever Normal physical examination Came in for work-up

Admitting Impression

Fever of unknown origin

Course in the Ward Upon admission

CBC, ESR, CRP Blood CS x 2 sites Monospot test Spec 16 Urinalysis ANA, LE panel CT of the Chest Transesophageal echocardiography Hematology referral for BMA

Laboratory ResultsCBC

Hgb – 12.5 WBC – 4690 Lymphos – 23

HCT – 39.6 Seg – 60 Platelet – 223, 000

ESR – 77 (N- 0.15) CRP – Positive up to 1.0 serum dilution

Spec 15

Na – 139 Bun – 5.0 Alb – 3.0

K – 4.5 Crea – 0.9

Monospot test – Normal

LE Panel

ANA – weakly positive Anti DNA (-) Anti SM (-) Anti RNP (-) Anti SSA (-) Anti SSB (-) Anti JO-1 (-)

Transesophageal Echocardiography

There is no echocardiography evidence of endocardial vegetation on all four cardiac valves

Thickened anterior mitral valve with mild systolic proplase

Mild posterolaterally-directed mitral regurgitation Mild tricuspid regurgitation Normal ventricular size and systolic function Ejection fraction 64%

1st Hospital Day

Patient was scheduled for BMA CT Scan of the chest

Result: INH 300 mg 1 tab OD Rif – 400 mg 1 tab OD PZA – 500 mg 3 tabs OD Ethambutol – 400 mg 3 tabs OD

2nd Hospital Day

CXR PA Lateral view Result

CD4 CD8 Post Bone marrow aspiration biopsy

3rd Hospital Day

Vit A 2500 ml 2 tabs 4 x a day x 8 doses

4th Hospital Day

Bone marrow aspiration GS – No growth Bone marrow aspiration biopsy – normal

Normal cellular component Normal megakaryocytes, erythroid and myeloid

cells No abnormal tumor cells

5th – 7th Hospital Day

Afebrile

8th Hospital Day

Discharged Take home medications c/o DOTS

FINAL DIAGNOSIS

Miliary Tuberculosis

Temperature Pattern

35

36

37

38

39

40

41

42

43

CASE NO. 2

G. F.,a 64 year-old female

Chief complaint: fever

HISTORY OF PRESENT ILLNESS

3 weeks PTA intermittent fever (Tmax 38.8 0C)

(+) loose watery stools x 5 days after taking

Dulcolax

generalized crampy abdominal pain

HISTORY OF PRESENT ILLNESS

admitted at Asian Hospital Dx: Diverticulitis, sigmoid,(confirmed by CT- scan), Infectious diarrhea and UTIgiven Metronidazole and

Ciprofloxacin x 10 dayspending urine C/S

HISTORY OF PRESENT ILLNESS

1 week PTA recurrence of fever(Tmax 39 0C), chills

(+) hypogastric pain, dysuria

CBC: Hgb 11.8 Hct 0.35wbc 9.3 seg 80 lym 11mon 8 plt 533,000

HISTORY OF PRESENT ILLNESS

Urinalysis: rbc: 3-5 wbc: >150bacteria: +1

fecalysis: color: greenish brown

consistency: semi-formed

rbc: 1-2/hpf wbc: 2-4/hpf

ova/parasites: none

HISTORY OF PRESENT ILLNESS3 days PTA persistence of symptoms

ID consult Dx: Diverticulitis vs UTI

given Cotrimoxazole

2 days PTA urine C/S: 1.E.coli 25,000 cfu/mL resistant to Ciprofloxacin2. Klebsiella pneumonia 15,000 sensitive to Ciprofloxacin

ADMISSION

REVIEW OF SYSTEMS

No headache

No alopecia, rash, photophobia

No night sweats

No oral ulcers

No cough, colds, dyspnea

No chest pain, palpitations

(+) weight loss of 10 lbs

No bleeding tendencies

PAST MEDICAL ILLNESS

(+) HPN – 5 months, on Losartan 50mg OD

UBP 120-130/80 HBP 150/80

(-) DM, BA, PTB

Post colonoscopy , November 2006 - normal

Post appendectomy – 15 years old

FAMILY HISTORY

(+) HPN, CVA, CA (breast) – mother

(+) DM – paternal side

PERSONAL & SOCIAL HISTORY

Non smoker

Non alcoholic beverage drinker

No history of travel

PHYSICAL EXAMINATION

Conscious, coherent, not in cardio-respiratory distress

BP 120/70 CR 89bpm RR 18 T 37.7 0C

Wt: 57kg Ht: 156cm BMI 23.4kg/m2

Pink palpebral conjunctivae, anicteric sclerae

Moist buccal mucosae, non- hyperemic posterior pharyngeal walls, tonsils not enlarged

Supple neck, no palpable cervical lymphadenopathies

PHYSICAL EXAMINATION

Symmetrical chest expansion, no retractions, clear lungs

Adynamic precordium, AB 5th LICS MCL, no murmurs

Flabby abdomen, normoactive bowel sounds, soft, non-tender, no hepatosplenomegaly, no CVA tenderness

No edema, no cyanosis, pulses full and equal

IMPRESSION

Fever of Unknown Origin

LABORATORY

Hgb 11.2

Hct 35

WBC 9750

Segmenters 70

Lymphocytes 20

Monocytes 10

Platelets 464,000

CRP Positive up to 1:16 dilution

ESR 125

LABORATORY

Urinalysis: rbc 3.4 WBC 6.3 epi cells 0.7

bacteria: 323.9

Urine C/S: no growth

Fecalysis: color: brown consistency: soft

Pus cells: 8-10/hpf mucus: moderate

Ova/parasite: none

Stool C/S: normal flora

Blood C/S: no growth

LABORATORY

ANA Negative

LE panel Negative

VDRL Negative

CA 125 20.447

CA 19-9 0

2-D ECHO

Normal left ventricular dimension with normal wall thickness, wall motion and contractility. Normal EF 65%. No preicardial effusion nor evidence of vegetation.

CT SCAN OF THE CHEST

Minimal fibrosis, both apices otherwise normal CT of the chest

MRI OF THE WHOLE ABDOMEN

Diverticulitis, ascending and recto-sigmoid colon.

Complex pelvic fluid collections as described. Consider pelvic abscess probably secondary to ruptured diverticulitis.

CT SCAN OF THE WHOLE ABDOMEN

Primary consideration is sigmoid diverticulitis with fistula formation. No discrete abscess formation but no intravenous contrast given.

FEVER PATTERN

35

36

37

38

39

40

41

Co- amoxiclav

Cefuroxime Cefuroxime

Pip- Tazo

FEVER OF UNKNOWN ORIGIN

DISCUSSION

FEVER OF UNKNOWN ORIGIN

Definition: Fever higher than 38.3ºC (100.9°F) on several occasions Duration of fever for > 3 weeks Failure to reach a diagnosis despite 1 week of inpatient

investigation

…by Petersdorf and Beeson from a prospective analysis of 100 cases, which has become the clinical standard

• Petersdorf, RG, Beeson, PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961; 40:1.

Classification of Fever of Unknown Origin

Minimal diagnostic work ups to qualify as FUO: History Physical examination Complete blood count, including differential and

platelet count Routine blood chemistries, including liver enzymes

and bilirubin Hepatitis serology (if liver tests abnormal) Urinalysis, including microscopic examination, and

urine culture Chest radiograph

FEVER OF UNKNOWN ORIGIN

Risk Factors

History of travel Current medications (including antimicrobials) Immunocompromised state

(Collagen vascular disease /Cancer/ HIV/AIDS) Current or recent hospitalization

FEVER OF UNKNOWN ORIGIN

The percentage of patients with fever of unknown origin by cause during four decades   Adapted from Mourad, O, Palda, V, Detsky, AS. Arch Intern Med 2003; 163:545. Adapted from Mourad, O, Palda, V, Detsky, AS. Arch Intern Med 2003; 163:545.

Common Etiologies of Fever of Unknown Origin

Infections Tuberculosis (especially

extrapulmonary) Abdominal Abscesses Pelvic Abscesses Dental Abscesses Endocarditis Osteomyelitis Sinusitis

Cytomegalovirus Epstein Barr Virus Human immunodeficiency

virus Lyme disease Prostatitis Sinusitis Fungal disease

Malignancies Chronic Leukemia Lymphoma Metastatic cancers Renal cell carcinoma Colon carcinoma Hepatoma Myelodysplastic

syndromes Pancreatic carcinoma Sarcomas

Collagen-Vascular Dse Adult Still’s disease Polymyalgia rheumatica Temporal arteritis Rheumatoid arthritis Rheumatoid fever Inflammatory bowel dse Reiter’s syndrome SLE Vasculitides

Common Etiologies of Fever of Unknown Origin

Miscellaneous

Drug-induced fever Complications from cirrhosis Factitious fever Hepatitis

(alcoholic, granulomatous or lupoid) Deep venous thrombosis Sarcoidosis

Common Etiologies of Fever of Unknown Origin

DRUG FEVER

DIAGNOSTIC APPROACH

FEVER OF UNKNOWN ORIGIN

DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN

Fever > 38.30C x 3 weeks;

1 week of “intelligence and invasive investigation”

Physical Exam

CBC, ESR, CRP, urinalysis, liver function tests, electrolytes, blood culture, urine culture, PPD skin test, chest radiograph

Order appropriate follow up and diagnostic testing Positive

NO

CT scan of the chest/ abdomen/pelvisWith contrast

DIAGNOSTIC APPROACH

Erythrocyte sedimentation rate — One study reviewed elevations above 100 mm/h

among 263 patients with FUO: 58 percent had malignancy, most commonly

lymphoma, myeloma or metastatic colon or breast cancer

25 percent had infections such as endocarditis, or inflammatory diseases like rheumatoid arthritis or giant cell arteritis

Zacharski, LR, Kyle, RA. Significance of extreme elevation of erythrocyte sedimentation rate. JAMA 1967; 202:264

DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN

CT scan of the chest/ abdomen/ pelvis

with IV/PO contrast

Needle biopsy/ Invasive testing

Radionuclide scanning procedures (67Ga scan, 111 In PMN scan)(to identify/ localize inflammatory processes)

Order appropriate follow up/diagnostic testingspecific therapy

Positive

NO

No diagnosis

positive

Empiric therapy (anti-TB / anti microbial)

Watchful waiting

DIAGNOSIS OF FEVER OF UNKNOWN ORIGINCT scan of abdomen/pelvis

With contrast

Assign to most likely category

29 years old male6 weeks intermittent fever Tmax 39.5

Treated as a case of typhoid feverCT Scan abdomen: renal cortical cyst

Cervical lymph node

CBC, ESR (77), CRP, urinalysis, liver function tests, electrolytes, blood culture, urine culture, monospot test, ANA, Lupus panel

CT scan of the chest - positive

AFB sputum smear negative x 3 days and AFB culture pending

Bone marrow biopsy for TB culture - pendingHIV test – negative

CD4 count-252

Positive

CASE 1 - SUMMARY

64 years old female3 weeks intermittent fever Tmax 38.8

abdominal pain and loose stoolsTreated as UTI and diverticulitis

Essentially normal PE

CBC (leukocytosis), ESR (125), CRP(1:16), urinalysis, liver function tests, electrolytes,

blood culture, urine culture, stool culture – no growthANA, Lupus panel - negative

CT scan of the chest – minimal fibrosis both apicesMRI of the abdomen – diverticulitis, complex fluid collections

t/c pelvic abscesses 20 to ruptured diverticulitis

CT scan of the abdomen- sigmoid diverticulitis with fistula formation

Exploratory laparotomy- phlegmon

Positive

CASE 2 - SUMMARY

Among infections, tuberculosis and abscesses are the most common etiologies.

Tuberculosis single most common infection in most FUO

series. Presentations of TB, which escape early

detection, are either extrapulmonary, miliary, or occur in the lungs of patients with significant preexisting pulmonary disease.

FEVER OF UNKNOWN ORIGIN

Abscess Usual location of occult abscesses -abdomen or pelvis

Underlying conditions which predispose to abscess formation –cirrhosis,steroid or immunosuppressive medications, recent surgery, and diabetes.

Abscesses arise when there has been disruption of a barrier such as the bowel wall in appendicitis or diverticulitis. The rupture often seals off spontaneously and local peritonitis is converted to an abscess by host defense mechanisms.

FEVER OF UNKNOWN ORIGIN

Therapeutic trials of antimicrobials or corticosteroids, rarely establish a diagnosis.

Antimicrobial agents could be expected to suppress, but not cure, an infectious process such as an occult abscess since adjunctive drainage would usually be required.

A trial of corticosteroids for an inflammatory process should not replace relevant biopsies for steroid responsive diseases; and a careful evaluation for infection should precede such a trial

FEVER OF UNKNOWN ORIGIN

SUMMARY

Fever of unknown origin (FUO) is defined as fever higher than 38.3ºC on several occasions lasting for at least three weeks without an established etiology despite intensive evaluation and diagnostic testing

Three general categories of illness account for the majority of "classic" FUO cases and have been consistent through the decades. These categories are infections, malignancies, and

collagen vascular diseases.

The most important aspects of the evaluation of a patient with FUO are to take a careful history, perform a detailed physical examination, and to reassess the patient frequently.

We recommend the following minimum diagnostic evaluation: blood cultures, erythrocyte sedimentation rate, lactate dehydrogenase, HIV antibody test and viral load, rheumatoid factor, heterophile antibody test, antinuclear antibodies, tuberculin skin test, and CT scan of abdomen and chest

SUMMARY

Diagnostic workup may fail to identify an etiology in as many as 30 to 50 percent of patients.

Most adults who remain undiagnosed have a good prognosis.

SUMMARY AND RECOMMENDATIONS

References De Kleijn, EM, Vandenbroucke, JP, van der, Meer JW. Fever of

unknown origin (FUO). I A. prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group. Medicine (Baltimore) 1997; 76:392.

Knockaert, DC, Vanneste, LJ, Bobbaers, HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc 1993; 41:1187.

Miller, RF, Hingorami, AD, Foley, NM. Pyrexia of undetermined origin in patients with human immunodeficiency virus infection and AIDS. Int J STD AIDS 1996; 7:170.

Mourad, O, Palda, V, Detsky, AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med 2003;163:545

Petersdorf, RG, Beeson, PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961; 40:1.2.

Vanderschueren, S, Knockaert, D, Adriaenssens, T, et al. From prolonged febrile illness to Fever of unknown origin: the challenge continues. Arch Intern Med 2003; 163:1033.12