General information about the
fever
Fever is due to a rise of a new “set point” of
body temperature in the hypothalamus induced
by pyrogenic cytokines. These cytokines include
IL-1, TNF, interferon- gamma, and IL-6.
The elevation in temperature results from
either:
• increased heat production (eg, shivering) or
• decreased heat loss (eg, peripheral
vasoconstriction).
Hyperthermia—
it not mediated by cytokines—occurs when:
1-there is excessive body metabolic heat production (as in
thyroid storm) or
2-environmental heat load exceeds normal heat loss capacity
or when there is impaired heat loss (eg, heat stroke).
in hyperthermia, there is no diurnal variation and
temperature may rise to levels (more than 41.1°C)
capable of producing irreversible protein
denaturation and resulting in brain damage.
also it does not respond to antipyretic drug.
Body temperature in cytokine-induced fever (
hyperpyrexia) seldom exceeds 41.1°C unless
there is structural damage to hypothalamic
regulatory centers, responding to antipyretics
The average normal oral body
temperature taken in mid- morning is
36.7°C (range 36–37.4°C).
(normal diurnal temperature
variation is 0.5–1°C).
The normal rectal or vaginal temperature
is 0.5°C higher than the oral temperature,
and the axillary temperature is 0.5°C
lower.
rectal temperature is more
reliable than an oral
temperature
inflammation of unknown origin (IUO)
it is defined as the presence of elevated inflammatory
145 parameters (CRP or ESR) on multiple occasions
for a period of at least
3 weeks in an immunocompetent patient with normal
body temper- ature, for which a final explanation is
lacking despite history-taking, physical examination,
and the obligatory tests
Diagnostic criteria for FUO
FUO categories
1-Hospital-associated FUO
• hospitalized patient with fever of 38.3°C or higher on several
occasions
• due to a process not present or incubating at the time of admission,
• in whom initial cultures are negative
• the diagnosis remains unknown after 1 week of investigation
2-Neutropenic FUO includes
• patients with fever of 38.3°C or higher on several
occasions
• Less than 500 neutrophils per microliter
• in whom initial cultures are negative .
• the diagnosis remains uncertain after 3 days
3-HIV-associated FUO
• patients with HIV and fever of 38.3°C or higher
• who have been febrile for 4 weeks or more as an outpatient or 3
days as an inpatient,
• the diagnosis remains uncertain after 3 days of investigation
with at least 2 days for cultures to incubate
FUO in solid organ transplant
recipients
FUO in the returning traveler
factitious FUO
Approximately 50% of cases remain
undiagnosed but have a benign course
with eventual resolution of symptoms.
Most cases represent unusual manifestations of
common diseases:
Brucellosis, typhoid fever, tuberculosis, endocarditis,
gallbladder disease, abscesses, rheumatology
diseases, malignant tumors
Classification of Causes of FUO
1. Infection—Both systemic and localized infections
can cause FUO. Tuberculosis and endocarditis are the
most com- mon systemic infections associated with
FUO, but mycoses, viral diseases (particularly infection
with Epstein-Barr virus and CMV), toxoplasmosis,
brucellosis, Q fever, cat- scratch disease,
salmonellosis, malaria, and abscesses.
2. Neoplasms—Many cancers can present as FUO. The
most common are lymphoma (both Hodgkin and non-
Hodgkin) and leukemia. Posttransplant
lymphoprolifera- tive disorders may also present with
fever.
3-Autoimmune disorders—Still disease, SLE,
cryoglobuli- nemia, and polyarteritis nodosa are
the most common causes of autoimmune-
associated FUO. Giant cell arteritis and
polymyalgia rheumatica are seen almost
exclusively in patients over 50 years of age
4. Miscellaneous causes:
thyroiditis, sarcoidosis, Whipple disease, familial
Mediterranean fever, recurrent pulmonary emboli,
alcoholic hepatitis, drug fever, and factitious fever.
Post-transplantation fever
Approach to patients with FUO
first it is necessary to document the
presence of fever by a digital
thermometer in more than one occasion
Diagnosis of the cause of FUO:
1-comprehensive history
2-clinical examination
3-investigation
Full clinical examination
Fever in the injection drug-user
Investigation
Complete routine investigation
BB,CBC,ESR ,LFT,RFT,TFT,CRP,GUE,
etc.
Culture
Blood culture and sensitivity
Other body fluid and sputum
-
serological test
Serological tests for connective tissue disorders:
Autoantibody screen
Complement levels Immunoglobulins Cryoglobulins
Immunological tests
• Serology (antibody detection) for viruses, including HIV-1,
and some bacteria
• Interferon-gamma release assay ( IGRA):
for diagnosis of exposure to tuberculosis (but note this will
not distinguish latent from active disease and can only be
used to trigger further investigations of active disease)
blood smears for malaria
Antigen detection
• Blood, e.g. HIV p24 antigen, cryptococcal antigen, Aspergillus galactomannan
ELISA and for Aspergillus and other causes of invasive, fungal infection (1,3)-β-D-
glucan
• CSF for cryptococcal antigen
• Bronchoalveolar lavage fluid for Aspergillus galactomannan
• Nasopharyngeal aspirate/throat swab for respiratory viruses, e.g. IAV, RSV
• Urine, e.g. for Legionella antigen, pneumococcal Ag
Nucleic acid detection ( PCR)
• Blood for Bartonella spp. and viruses
• CSF for viruses and key bacteria
(meningococcus, pneumococcus,
Listeria monocytogenes)
• Nasopharyngeal aspirate/throat swab for
respiratory viruses
PCR
Sputum for Mycobacterium tuberculosis (MTB) and
rifampicin (RIF) resistance with geneXpert MTB/RIF
cartridge-based nucleic acid amplification test
• Bronchoalveolar lavage fluid, e.g. for respiratory
viruses
• Tissue specimens, e.g. for T. whipplei
• Urine, e.g. for Chlamydia trachomatis, Neisseria
gonorrhoeae • Stool, e.g. for norovirus, rotavirus
Imaging studies
CXR
US
CT scan
Echocardiography
Biopsy
Lymph node
Bone marrow
Liver
Cytology
ascites, pleural effusion, CSF
When to Refer the patient:
• Any patient with FUO and progressive weight loss and
constitutional signs.
• Any immunocompromised patient (eg, transplant recipients
and patients with HIV).
• Infectious diseases specialists may also be able to coordinate
and interpret specialized testing (eg, Q fever serologies) with
outside agencies, such as the US CDC.
When to Admit the patient to the hospital
• Any patient rapidly declining with weight loss
• If FUO is present in immunocompromised patients, such as those who
are neutropenic from recent chemotherapy or those who have
undergone transplantation (particularly in the previous 6 months).
Treatment of FUO is according
to the etiology
Empirical therapeutic trials with antibiotics,
glucocorticoids, or antituberculous agents should be
avoided in FUO except when a patient’s condition is
rapidly deteriorating after the aforementioned diagnostic
tests have failed to provide a definite diagnosis.
Thank you so much
