Fever and Febrile syndromes

 Thermoregulation Pathogenesis of
fever
o Fever only
 Fever and Fever Rush Lymphadenopathy
and
 Mechanisms of Heat Regulation
To raise Body Temperature
To lower Body Temperature
To raise Body Temperature
Heat generation:
 Obligate heat production
 Muscular work
 Shivering
Heat conservation :
Vasoconstriction
Heat preference
To lower Body Temperature
Heat loss
Obligate heat loss
Vasodilatation
Sweating
Cold preference
MAJOR THERMOREGULATORY PATHWAYS I.

Skin temperature Core

temperature

Peripheral Central
thermoreceptors thermoreceptors
(in skin) (in hypothalamus, other areas
of CNS and abdominal organs)

Hypothalamic thermoregulatory
integrating center
 MAJOR THERMOREGULATORY PATHWAYS II.
Hypothalamic thermoregulatory integrating center

Behavioral
il Motor
t Sympathetic
t ti Sympathetic
t ti
adaptations
t tis neuronss nervous
rs s system
st nervous
rs s system
st

Sceletal Skin Skin

muscles blood vessels sweat glands

Muscle tone, Skin Sweating

shivering vasoconstriction,
vasodilataion
Control of Control of
heat production heat Control of Control of
or loss production heat loss heat loss
 Normal Body Temperature
• For healthy individuals 18 to 40 years of age, the
mean oral temperature is 36.8° ± 0.4°C (98.2° ±
0.7°F)
• Low levels occur at 6 A.M. and higher levels at 4 to
6 P.M.
• The maximum normal oral temperature is 37.2°C
(98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.
• These values define the 99th percentile for healthy
individuals.
 FEVER—A DEFENSE MECHANISM
 Indicator of disease in body • Pathogens
release toxins
 Toxins affect hypothalamus • Temperature is
increased
 Rest decreases metabolism and heat production by the body

PATTERNS OF FEVER:
SUSTAINED- remains above normal with little change
RELAPSING – periods of febrile episodes interspersed with acceptable temp values
INTERMITTENT—varies from normal to above normal to below normal (may have a fairly
predictable pattern)
REMITTENT—fever spikes and falls w/o a return to normal temp values
 Fever versus Hyperthermia
• Fever: resetting of the thermostatic set-point in the anterior hypothalamus and
the resultant initiation of heat-conserving mechanisms until the internal
temperature reaches the new level.
• Hyperthermia: an elevation in body temperature that occurs in the absence of
resetting of the hypothalamic thermoregulatory center

 Fever > 37.8 °C (100.2°F) Elevated body temperature

mediated by an increase in the hypothalamic heat-
regulating set point

 Hyperthermia - Increase in body temp. (> 41°C) that

overrides or bypasses the normal homeostatic
mechanisms
 Mechanisms of Hyperthermia and
Associated Conditions
1. Excessive heat production: exertional hyperthermia,
thyrotoxicosis, pheochromocytoma, cocaine,
delerium tremens, malignant hyperthermia
2. Disorders of heat dissipation: heat stroke, autonomic
dysfunction
3. Disorders of hypothalamic function: neuroleptic malignant
syndrome, CVA, trauma
PATHOGENESIS OF FEVER
Hypothetical Model for the Febrile Response
Interleukin-1 β and TNF-α play prominent roles in fever production by
stimulating the release of cyclic AMP from the glial cells and activating
neuronal endings from the thermoregulatory center that extend into the
area.

Bacterial Pyrogens:
Lipopolysaccharide (LPS) endotoxin
Endotoxin binds to LPS-binding protein and is transferred to CD14 on
macrophages, which stimulates the release of TNFα.
• Staphylococcus aureus enterotoxins
• Staphylococcus aureus toxic shock syndrome toxin (TSST)
Both Staphylococcus toxins are superantigens and activate T cells
leading to
the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon
(IFN)-gamma in large amounts
• Group A and B streptococcal toxins
Exotoxins induce human mononuclear cells to synthesize not only TNFα
but also IL1 and IL-6

CAUSES OF FEVER:
 Infection
 Tissue injury - infarction, trauma Malignancy
 Drugs
 Immune-mediated disorders Other inflammatory
disorders Endocrine disorders
 Factitious or self-induced fever
 Infections presenting as fever
without localizing signs or symptoms
Viral Rhinovirus, adenovirus, parainfluenza
Enterovirus, ECHO
Influenza
EBV, CMV
Colorado tick fever

Bacterial Staphylococcus aureus

Listeria monocytogenes
Salmonella thyphi, S. parathyphi
Streptococci

Post animal exposure

Coxiella burneti (Q fever)
Leptospira interrogans
Brucella species
Ehrlichia chaffeensis

Granulomatous infection Mycobacterium tuberculosis

Histoplasma capsulatum
Infections producing Fever and Rush
1. Maculopapular Erythematous
Enterovirus
EBV, CMV, Toxoplasma gondii
HIV
Colorado tick fever
Salmonella thyphi
Leptospira interrogans
Measles virus
Rubella virus
Hepatitis B virus
Treponema pallidum
Parvovirus B19
Human herpesvirus 6
Infections producing Fever and Rush
2. Vesicular
Varicella-zooster
Herpes simplex virus
Coxackie A virus
Vibrio vulnificus

Cutaneous petechiae
Neisseria gonorrhoea
N. meningitidis
Rickettsia rickettsii (RMSF)
Ehrlichia chaffeensis
Echoviruses
Viridans-streptococci (endocarditis)
Infections producing Fever and Rush
3. Diffuse erythroderma
Group A streptococci (scarlet fever, toxic shock syndr.)
Staphylococcus aureus (toxic shock syndr.)
Distinctive rush
Ecthymia gangrenosum – Pseudomonas aeruginosa
Erythema chronicum migrans – Lyme disease
Mucous membrane lesions
Vesicular pharyngitis – Coxackie A virus
Palatal petechiae – rubella, EBV, Scarlet fever
Erythema – toxic shock syndr.
Oral ulceronodular lesion – Histoplasma capsulatum
Koplik’s spots – measles virus
Infections with Fever and Lymphadenomegaly
(generalized)
Viral Measles
Rubella
Hepatitis B
Bacterial Scarlet fever
Brucellosis
Leptospirosis
Tuberculosis
Syphilis
Lyme disease
Infections with Fever and Lymphadenomegaly
(regional)
Pyogenic infection Sta. aureus, Stre.
Tuberculosis Scrofula (tbc. Cervical adenitis)
Cat-scratch disease Bartonella
Ulceroglandular fever Tularemia
Oculoglandular fever Tul., sporotrichosis, etc.
Inguinal lymphadenopathy Syphilis, herpes
Plague Yersinia pestis
 DEFINITION OF FUO
1.Fever ≥ 38.3°C (>101°F) on several occasions
2. Duration ≥ 3 weeks
3. Failure to reach a diagnosis despite
1 week appropriate in-hospital investigation or 3
outpatient visits
DEFINITIONS
Classical FUO
Nosocomial FUO
Neutropenic FUO
HIV-associated FUO
 NOSOCOMIAL FUO
• Hospitalized patient
• Fever ≥ 38.3°C (>101°F) on several
occasions • Infection not present or
incubating on
admission
• Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of microbiological cultures)
Examples: Septic thrombophlebitis, sinusitis,
Clostridium difficile colitis, drug fever
 NEUTROPENIC FUO
• Less than 500 neutrophils mm-3
• Fever ≥ 38.3°C (>101°F) on several
occasions • Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of
microbiological cultures)
Examples: Perianal infection, aspergillosis, candidemia
 HIV-associated FUO
• Confirmed HIV infection
• Fever ≥ 38.3°C (>101°F) on several
occasions • Duration of ≥4 weeks (outpatients) or
≥4 days in hospitalized patient
• Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of
microbiological cultures)
Examples: M. avium/M. intracellulare infection, tuberculosis, non-Hodgkin's
lymphoma, drug fever
 Classification
li ii of causative
i diseases
i
Major disease categories
Infections
Neoplastic diseases
Non-infectious inflammatory diseases (NIID)
Minor categories
Factitious fever
Drug-related fever
Habitual hyperthermia
(should always be considered before starting FUO work-up)
 INFECTIONS 1.
Systemic infections
Most common:
Tuberculosis and endocarditis
Less common:
- Epstein-Barr virus and cytomegalovirus
- toxoplasmosis, brucellosis
- Q fever, cat-scratch disease, malaria
- HIV or opportunistic infections associated with AIDS
 INFECTIONS 2.
Localized infections
Most common:
Occult abscess (liver, spleen, kidney, brain, bone)
Less common:
- Cholangitis
- Osteomyelitis
- Urinary tract infection
- Paranasal sinusitis
 CAUSES OF FUO
• • NEOPLASTIC DISEASES
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other

Solid tumors:

 Renal carcinoma
 Colon
 Liver
 NEOPLASMS
Most common:
- lymphoma (both Hodgkin's and non-Hodgkin's)
- leukemia
Less common:
- Primary and metastatic tumors of the liver
- Renal cell carcinomas
- Atrial myxoma
- Chronic lymphocytic leukemia
- Multiple myeloma
 NIID - AUTOIMMUNE DISORDERS
• NON-INFECTIOUS INFLAMMATORY DISEASES
Collagen diseases, autoimmune dis., vasculitides, Crohn d.
Most common:
- systemic lupus erythematosus
- cryoglobulinemia
- polyarteritis nodosa
Less common:
- Giant cell arteritis
- Polymyalgia rheumatica
 MISCELLANEOUS CAUSES
Granulomatous, Whipple d.,Cardiac myxoma,
Castleman dis.,etc.

- drug-induced fever
- sarcoidosis
- Whipple's disease
- familial Mediterranean fever
- recurrent pulmonary emboli
- alcoholic hepatitis
- Thyroiditis
- Castleman disease
- factitious fever
Agents commonly associated with drug-induced fever

Allopurinol Meperidine
Captopril Methyldopa
Cimetidine Nifedipine
Clofibrate Nitrofurantoin
Erythromycin Penicillin
Heparin Phenytoin
Hydralazine Procainamide
Hydrochlorothiazide Quinidine
Isoniazid
Distribution of the different disease categories

Shift in the relative proportion of specific

disease categories during the last decade:
Infections  tumors  NIID  Undiagnosed 

Geographical differences
In developing countries, tropical area:
more infections
 TEN LEADING CAUSES OF CLASSIC FUO
among Adults at Community Hospitals in the USA
Lymphoma 16 %
Collagen vascular disease 16 %
Abscess 13 %
Undiagnosed cause 9%
Solid tumor 8%
Thrombosis or hematoma 7%
Granulomatous disease, nonmycobacterial 5%
Endocarditis 5%
Mycobacterial disease 5%
Viral disease 5%
Remaining causes 11 %
MINIMUM DIAGNOSTIC EVALUATION 1.
1. Comprehensive history
including travel history, risk for
venereal diseases, hobbies, contact with pet animals and
birds, etc.
2. Comprehensive physical examination
including temporal arteries, rectal digital examination, etc.
3. Routine blood tests
complete blood count including differential, ESR or CRP,
electrolytes, renal and hepatic tests, creatine phosphokinase,
lactate dehydrogenase
4. Microscopic urinalysis
 5. Cultures of blood, urine
and other normally sterile compartments if
clinically indicated, e.g. joints, pleura, cerebrospinal fluid
6. Chest radiograph
7. Abdominal (including pelvic) ultrasonography
8. Autoantibodies
ANA, Reumatoid factor, etc.
9. Tuberculin skin test
10. Serological tests directed by local epidemiological data
DIAGNOSTIC IMAGING IN PATIENTS WITH FUO
Imaging Possible diagnoses
Chest radiograph Tuberculosis, malignancy,
Pneumocystis carinii pneumonia
CT of abdomen or pelvis with contrast Abscess, malignancy
agent
Gallium 67 scan Infection, malignancy
Indium-labeled leukocytes Occult septicemia
Technetium Tc 99m Acute infection and inflammation of
bones and soft tissue
MRI of brain Malignancy, autoimmune conditions
PET scan Malignancy, inflammation
Transthoracic or transesophageal Bacterial endocarditis
echocardiography
Venous Doppler study Venous thrombosis
Roth AR and Basello GM. : Approach to the Adult Patient with Fever of Unknown Origin Am Fam Physician. 2003;68:2223-8. Review.
 Physical Exam

• Facial/Sinus Tenderness  Sinusitis

• Temporal Artery TendernessTemporal Arteritis
• Tenderness of a Tooth Periapical Dental Abscess
• Roth Spots on Fundoscopic ExamEndocarditis
• Enlarged Tender Thyroid Thyroiditis
• Murmur Endocarditis
• Perirectal Tenderness/Fluctuance Perirectal Abscess
• Prostatic Tenderness Prostatitis or Prostate Abscess
• Splenomegaly Lymphoma, Endocarditis, Leishmaniasis
• Lymphadenopathy Lymphoma, HIV, Tuberculosis
• Calf Tenderness DVT
 Algorythm forltftiif
the Diagnosis of FUO
Complete history and physical assesment
Positive findings Order appropriate and specific
diagnostic testing
No

CBC, electrolytes, LFT, blood culture, urinalasysis, urine

culture, ESR, PPD skin test, chest radigraph

Positive results Order appropriate follow-up

diagnostic testing
No

CT of abdomen / pelvis with contrast

Assign most likely category

Infection Malignancies Autoimmune (NIID) Miscallenous
 Liver Biopsy and Bone Marrow
Biopsy
• Diagnostic yield of liver • The diagnostic yield of bone
biopsy has ranged from 14% marrow cultures in
to 17%. immunocompetent individuals
• Physical exam finding of has been found to be 0% to
hepatomegaly or abnormal 2%
liver profile are not helpful in
predicting abnormal biopsy
result.
• Complication rate is 0.06% to
0.32%
 Prognosis
• Prognosis is determined primarily by the
underlying disease.
• Outcome is worst for neoplasms.
• FUO patients who remain undiagnosed after
extensive evaluation generally have a favorable
outcome and the fever usually resolves after 4-5
weeks.
 Summary
• FUO is often a diagnostic dilemma
• Infections comprise ~30% of cases
• Bone marrow biopsies are of low diagnostic
yield
• Diagnostic approach should occur in a step-wise
fashion based on the H&P
• Patient’s that remain undiagnosed generally
have a good prognosis