Slide 1

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 2

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 3

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 4

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 5

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 6

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 7

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 8

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 9

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 10

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 11

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 12

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 13

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 14

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 15

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 16

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 17

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 18

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 19

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 20

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 21

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 22

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 23

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 24

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 25

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 26

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 27

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 28

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 29

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU


Slide 30

PYREXIA OF
UNKNOWN ORIGIN
Dr. Alaa Jumaa

 PUO

is

A Common disease presenting
ATYPICALLY

Terminology


Old Definition: Petersdorf and Beeson (1961)
1.
2.
3.



Fever higher than 38.3oC on several occasions.
Duration of fever – 3 weeks
Uncertain diagnosis after one week of study in
hospital

New Definition:


Eliminated the in-hospital evaluation
requirements → 3 outpatient visits, or 3 days in
hospital. … Ambulatory as well as in hospital

Categories of Illness Causing PUO

Infections

30 - 40 %

Malignancies

20 – 25 %

Collagen Vascular Disease

10 – 20 %

Miscellaneous

15 – 20 %

Undiagnosed

10 – 15 %

Epidemiology and Etiology


1970 → up to date:

Infection is the most frequent.
 1930 → 70% undiagnosed PUO
 2000 → 5-10% undiagnosed PUO
 Diagnostic Advances:
Modify the spectrum of PUO causing diseases:
1.
2.

Serology: HIV / Brucella / SLE
Imaging Tech: Abscesses/Solid Tumor

Geography
Malaria

Saudi (malaria area)/Africa/India

Brucella

Saudi/Gulf Area

Kala-Azar

Yemen/Sudan/India

Leprosy

Yemen/Najran…

Typhoid

India/Pakistan/Egypt/Indonesia

Histoplasmosis

USA … (West Coast)

Tuberculosis
Liver Abscess
AIDS

All over the world.

Geography
60
50
40
30
20
10
0

Infect

Neopl

CVD
India

Other

Unknown

UK
J Postgrad Med 2001; 47(2):104-107
9

DIAGNOSIS AND TREATMENT

Diagnostic Approach
 Careful

History
 Physical Examination (repeated)
 Diagnostic Testing

History


Verify the presence of fever:
 Series

of 347 patients → for prolonged fever
→ 35% were ultimately: a. No fever
b. Factitious Fever



Duration of Fever:
 The

longer the duration → the less likely to
have infection and malignancy.

History





A history of exposure to wild or domestic
animals should be solicited (zoonotic disease )
Ingestion of dirt is a particularly important clue to
infection with Toxoplasma gondii
(toxoplasmosis).
Ancestry from the Mediterranean should suggest
the possibility of familial Mediterranean fever
(FMF).

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

History


Drug and Toxin History:
 almost

all drug can cause drug fever …
 Antihistamine
 beta lactam
 anti-TB …
 Salicylates and other NSAID …
 eye drops, which may be associated with
atropine-induced fever.

History


Localizing Symptoms:
 May

Indicate the source of fever:

Bone ach

osteomylitis
Bone Metastasis

Headache

Chronic Meningitis

RUQ Pain

Liver Abscess

LUQ Pain

Splenic Abscess

Subtle changes in behavior

Granulomatous Meningitis

History


Family History:
 search

for possible infectious or hereditary
disorders
Tuberculosis
 FMF




Past Medical Condition:
Lymphoma
Rheumatic Fever

→
→

may recur
may recur

Physical Examination


Document the Fever:
 Significant



and persistent for more than ONE occasion.

Analyzing the Pattern:
 Neither

specific Nor sensitive enough to be considered
diagnostic … EXCEPT
Tertian & Quarter Pattern →
Malaria
Pel-Ebstein Pattern → Lymphoma/Tuberculosis
Pulse-Temp Dissociation → Typhoid/Brucellosis

Pattern of Fever

Physical Examination


Sweating in a febrile child should be noted
 familial




dysautonomia, or exposure to atropine.

A careful ophthalmic examination is important
Hyperemia of the pharynx, with or without
exudate, suggests
 infectious

mononucleosis, CMV infection,
toxoplasmosis, salmonellosis ,Kawasaki disease.



The muscles and bones should be palpated
carefully.

Physical Examination


Examine for Lymphadenopathy
Cervical Area
(Localized)

1. Lymphoma
2. Tuberculosis
3. Infectious Mononucleosis
4. Lymphadenitis (bacterial)

Diagnostic Testing
1.

2.
3.

CBC with a differential WBC count and a
urinalysis should be part of the initial
laboratory evaluation.
An erythrocyte sedimentation rate (ESR).
C-reactive protein is another acute-phase
reactant that becomes elevated and returns
to normal more rapidly than the ESR.

Diagnostic Testing


serology
1.
2.
3.
4.
5.
6.
7.

Anti-nuclear Antibodies
Rheumatoid Factor
CMV Antibody … IgM
Heterophile Antibody Test in children and
young adult
Tuberculin Skin Test … 5 unit ID
Thyroid Function Test
HIV Screening

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


Diagnostic Testing


Imaging Studies: … to localize
abnormalities for definite tests or treatment
 Chest

x-ray:

1. Liver
2. Spleen
3. Pancreatic
4. Subphrenic
 Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
 If CXR is (N) → Repeat on weekly basis


Atelectasis
}
↑ Hemi diaphragm } Abscess
Pleural Effusion }

Diagnostic Testing
 CT-Scan

→ CT scan chest

Mediastinal mass → Tuberculosis/Lymphoma/
Sarcoidosis
 CT-Scan Abdomen → very effective to visualize





 MRI:

All types of abscesses
Retroperitoneal tumor, lymph node or haematoma

spleen, lymph node and the brain
 Radionuclide scans

The majority of disease remaining after an
initial NEGATIVE work-up are:
1. Neoplasm
2. Seronegative Collagen Vascular Disease
3. Increasing Tuberculosis
4. Increasing Drug Addition
5. Endocarditis
6. HIV with or without infection or
malignancy
7. Implanted prosthetic devices
8. Travel … New Exposure

Therapeutic Trials


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.

Therapeutic Trials
 To

hold therapeutic trials in the early stage…
except in:
Patient who is very sick to wait.
 All tests have failed to uncover the etiology.
 Tuberculosis
 Culture-negative endocarditis.


THANK YOU