Internal Medicine Course for 6th Year

Waleed Abdurrab Hafiz, MD

February 19, 2018
You are evaluating a 35-year-old Ethiopian driver in your internal medicine clinic for evaluation of
fever. He has been suffering from fever for the past 24 days. He has no other symptom.

You have seen him twice in your clinic over the past 2 weeks, and you requested minimal initial
diagnostic workup, all of which came back negative.

He is febrile (Temp 38.6 oC). His temperature over the past 2 weeks has been > 38.3 oC. The rest of his
vital signs are normal and his exam is otherwise unremarkable.

Can we label this patient’s fever as fever of unknown origin (FUO)?

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

- Introduction

- Causes of FUO

- Diagnosis of FUO

- Initial treatment of FUO

- Prognosis of FUO
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- Mortality in rheumatoid arthritis. Rheumatology 2007.

What is the normal human body temperature?

- For a healthy person, 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 6 P.M.

- The maximum normal oral temperature is

- 37.2°C (98.9°F) at 6 A.M.
- 37.7°C (99.9°F) at 6 P.M.

- These values define the 99th percentile for healthy individuals

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

What is the normal human body temperature?

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

Fever
- Elevation of body temperature that exceeds the normal daily variation

- Occurs when IL-1, IL-6, TNF-ά or other cytokines are released from monocytes and macrophages
in response to a stimulus

- Most fevers are short lived and do not require diagnostic investigation or specific therapy

- Some are due to serious illnesses, most of which can be diagnosed and effectively treated

- A small but important subgroup of fevers are both persistent and difficult to diagnose
1- Mortality in rheumatoid arthritis. Rheumatology 2007.
1- Mortality in rheumatoid arthritis. Rheumatology 2007.
 Fever of Unknown Origin (FUO)

- Defined in 1961 by Petersdorf and Beeson as the following:

(1) a temperature greater than 38.3°C (101°F) on several occasions,

(2) more than 3 weeks' duration of illness,
(3) failure to reach a diagnosis despite 1 week of inpatient investigation

1- Mortality
Petersdorf and Beeson. Medicine in 1961
rheumatoid arthritis.
1961;1;40, 1 Rheumatology
30. 2007.
You are evaluating a 35-year-old Ethiopian driver in your internal medicine clinic for evaluation of
fever. He has been suffering from fever for the past 24 days. He has no other symptom.

You have seen him twice in your clinic over the past 2 weeks, and you requested minimal initial
diagnostic workup, all of which came back negative.

He is febrile (Temp 38.6 oC). His temperature over the past 2 weeks has been > 38.3 oC. The rest of his
vital signs are normal and his exam is otherwise unremarkable.

Can we label this patient’s fever as fever of unknown origin (FUO)?

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

 Fever of Unknown Origin (FUO)

In response to the new evolving environment, cases of FUO are currently

codified into four distinct subclasses of the disorder:

(1) Classic FUO,

(2) Nosocomial FUO,
(3) Immune-deficient FUO,
(4) HIV-related FUO

1- Mortality
D.T. Durack & A.C. Street. in rheumatoid
Curr Clin arthritis.
topics Infect Dis Rheumatology
1991; 35-; 11,2007.
35
 Category Nosocomial Neutropenic HIV-associated Classic
Hospitalized, acute care, Neutrophil count either All others with
Patient’s Confirmed HIV-
and no infection when <500/µL or expected to reach fevers for ≥3
situation positive
admitted that level in 1-2 days weeks

Duration of
3 daysb (or 4 weeks as 3 daysb or 3+
illness while 3 daysb 3 daysb
outpatient) outpatient visits
investigated
Infections,
Septic thrombophlebitis, MAIc infection, TB, malignancy,
Perianal infection,
Examples sinusitis, C. difficile colitis, non-Hodgkin’s inflammatory
aspergillosis, candidemia
drug fever lymphoma, drug fever diseases, drug
fever
aAllrequire temperatures of ≥38.3°C (101°F) on several occasions.
bIncludes at least 2 days’ incubation of microbiology cultures.
cM. avium/M. intracellulare.

Modified from DT Durack, AC Street,

1- Mortality in JS Remington,
in rheumatoid arthritis.MN Swartz (eds):
Rheumatology Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.
2007.
You are evaluating a 35-year-old Ethiopian driver in your internal medicine clinic for evaluation of
fever. He has been suffering from fever for the past 24 days. He has no other symptom.

You have seen him twice in your clinic over the past 2 weeks, and you requested minimal initial
diagnostic workup, all of which came back negative.

He is febrile (Temp 38.6 oC). His temperature over the past 2 weeks has been > 38.3 oC. The rest of his
vital signs are normal and his exam is otherwise unremarkable.

Can we label this patient’s fever as fever of unknown origin (FUO)?

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

Infections
(e.g. abscesses, endocarditis, tuberculosis, complicated urinary tract infections)

Neoplasms
(e.g. lymphomas, leukemias)

Connective tissue diseases

(e.g. temporal arteritis, polymyalgia rheumatica, Still’s disease, systemic lupus erythematosus)

Miscellaneous disorders
(e.g. alcoholic hepatitis, granulomatous conditions)

Undiagnosed conditions

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

The single most common cause of pyrexia of unknown origin is:

a) Mycobacterium tuberculosis
b) Salmonella typhi
c) Brucella sp.
d) Salmonella paratyphi A

Correct answer : a) Mycobacterium tuberculosis

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

1- Mortality in rheumatoid arthritis. Rheumatology 2007.
Drug fever:

- Almost any drug can cause fever

- Patho-etiology:
- Contamination of the drug with a pyrogen or microorganism
- Related to the pharmacologic action of the drug itself (e.g., amphotericin B)
- Allergic (hypersensitivity) reaction to the drug

- Fever out of proportion to clinical picture

- Associated findings: rigor (43%), myalgia (25%), rash (18%), headache (18%), leukocytosis (22%),
eosinophilia (22%), serum sickness (fever, swelling, rash, LN enlargement), proteinuria, abnormal liver
function test

- Onset: Typically occur 7 to 10 days (can be up to 21 days) after initiation

- Resolves within 48 hours after discontinuation of the drug (depending on the half-life of the drug)
1- Mortality in rheumatoid arthritis. Rheumatology 2007.
1- Mortality in rheumatoid arthritis. Rheumatology 2007.
Factitious fever:

- Diagnosis should be considered in any FUO, especially in young women

- Medical and paramedical staff

- Patients are clinically well

- Absence of the normal diurnal pattern

- Many have features of Munchausen syndrome

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

You are evaluating a 35-year-old Ethiopian driver in your internal medicine clinic for evaluation of
fever. He has been suffering from fever for the past 24 days. He has no other symptom.

You have seen him twice in your clinic over the past 2 weeks, and you requested minimal initial
diagnostic workup, all of which came back negative.

He is febrile (Temp 38.6 oC). His temperature over the past 2 weeks has been > 38.3 oC. The rest of his
vital signs are normal and his exam is otherwise unremarkable.

Comprehensive history and physical exam  80% of the

diagnostic process

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

Minimal Initial Diagnostic Workup For FUO
• CBC + differential
• Blood film reviewed by hematopathologist
• ESR and CRP
• 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)
• Chest radiography
• Hepatitis serology (if abnormal LFTs)

Further testing should always be directed by history and physical exam findings
1- Mortality in rheumatoid arthritis. Rheumatology 2007.
What is the best therapy for FUO patient?

- Hold therapeutic trials in the early stage… except in:

- Patient who is very sick to wait
- All tests have failed to uncover the etiology

- 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- Mortality in rheumatoid arthritis. Rheumatology 2007.

- 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 fever usually resolves after 4-5 weeks

1- Mortality in rheumatoid arthritis. Rheumatology 2007.

- FUO is often a diagnostic dilemma

- Infections comprise ~30% of cases

- Diagnostic approach should occur in a step-wise fashion based on the history and physical exam

- Patient’s that remain undiagnosed generally have a good prognosis

1- Mortality in rheumatoid arthritis. Rheumatology 2007.