FEVER

CONTENTS:

• INTRODUCTION
• DEFINITION
• PHYSIOLOGY
• APPROACH TO FEVER
• INVESTIGATIONS
• MANAGEMENT
• SUMMARY
• REFERENCE
Most common presenting symptoms to clinician.

May associated with other symptoms like chills,

rigor, generalized bodyache, headache,anorexia,
etc
• Pyrexia- Greek- pyr meaning fire

• Febrile- Latin- febris meaning fever

• Fever is an elevation of body temperature that
exceeds the normal daily variation and occurs in
conjunction with increase in hypothalamic set
point.

• Normal core body temperature is 36.5-37.5 C

(97.7-99.5 F)
Variation in temperature
At 6 AM :37.O C(98.6 F)
At 6 PM :37 .6 C(99.6 F) – increased BMR and
muscle activity

An AM temperature of >37.2 c(98.9 F)

An PM temperature of >37.7 C (>99.9 F)
Defines a fever
• Body temperature have seasonal variation with low level
at 8 AM and higher level at 4 PM.
• Baseline temperature are also affected by age: lower by
0.02 for every 10 year inc in age.
• Hypothyroidism is linked to temperature lower by
0.01ºC.
• Cancer is associated with 0.02ºC higher temperature.
• In women who menstruate ,the AM temperature is generally
lower during the 2 week before ovulation: it raise by 0.6 C
(1 F) with ovulation and stays at that level until menses
occur.
NORMAL RANGE

• Orally : 97.6 – 99.6 F

• Rectal : 99.6 – 100.6 F
• Axilla :96.6 – 98.6 F
• Tympanic : same as rectal
TEMPERATURE REGULATION
• Normally heat is continuously produced in body
and being lost in surrounding.
• Rate of heat production = rate of heat loss, person
is said to be in heat balance.
• When there is disturbance of equilibrium between
the two then body temperature may rise i.e fever
or fall hypothermia.
• Body temperature is controlled by hypothalamus.
• Neurons in both anterior and posterior hypothalamus
receive two signals:
1) peripheral nerves that transmit information from
warmth/cold receptor in skin.
2) Temperature from blood bathing the region.

• These two signal are integrated by the thermoregulatory

center of hypothalamus to maintain normal body
temperature.
PATHOGENESIS
• During fever prostaglandin PGE2 level elevated in
hypothalamic tissue and third cerebral ventricle.
• PGE2 are highest near circumventricular vascular
organs- networks of enlarged capillaries surrounding the
hypothalamic regulatory centers.
• Destruction of these reduces the ability to produce fever .
• Thus both endogenous and pyrogenic cytokines interact
with these capillaries for initiating fever i.e, in raising the
set point to febrile illness.
Pyrogen
• Substance that cause fever.
• Exogenous pyrogen :like microbial product ,toxin
and microorganism.
1)Lipopolysaccharide from gram neg bacteria
2)Enterotoxins from gram positive bacteria

Endogenous pyrogen:IL 1,IL 6,TNF,interferon

PYROGENIC CYTOKINES

• Endogenous cytokines also known as pyrogenic

cytokines.

• Wide spectrum of bacterial,viral and fungal

products induce the synthesis and release of
pyrogenic cytokines.
• Fever can be present in the absence of microbial
infection.

• Example : pericarditis , trauma ,stroke and

routine immunization induce the production of IL
1 ,TNF ,IL 6 individually or combination ,these
cytokines trigger the hypothalamus to raise the
set point to febrile level.
FACTORS DETERMINING RATE OF
HEAT PRODUCTION

• BMR of body
• Muscle activity
• Effect of thyroid hormone
STAGES OF FEVER
1)Prodrome
 non specific complaints: mild headache ,fatigue,
general malaise,aches and pains.

2)Temperature raise
 generalized shaking with chills and feeling of
being cold .
 vasoconstriction, piloerection precede onset of
shivering
3)Flush
 cutaneous vasodilation occurs and skin become warm
flushed

4)Defervescence
 initiation of sweating
EFFECTS OF FEVER
• Metabolic effect
-increase need for oxygen (inc HR and respiration)
-increase use of body proteins as an energy source.

• Enhance immune function

-increase activity of WBC

• Inhibits growth of microbial agents

-many microbial agents that cause infection and grow at normal
body temperature
TYPES OF FEVER
Intermittent fever:

- Temperature is present for some hours in a day and remits to

normal for remaining time.

• Daily spike- quotidian

• Every alternate day – tertian(plas. vivax, ovale)
• Every third day- quartan(plas. Malaria)
Eg: malaria , kala azar, septicemia
• Pel Ebstein fever
- Bouts of febrile and afebrile periods.
- Temperature takes 3 days to rise ,remains high for 3
days and remits in 3 days , followed by apyrexia for 9
days .
- Eg: Hodgkin lymphoma
• Low grade fever
- Temperature present daily, mainly in evening for
several days but usually does not exceed 37.8 C.
- Eg: tuberculosis
Fever of unknown origin

• Old definition (1961 by Dr Preterford and Dr Beeson) described it as

fever >38.3 C, 101 F) with minimum duration 3 weeks with 1 week
hospital stay
• New definition (Durack and street in 1991 ) divided it into four distinct
classes
1. Classic FUO
2. Nosocomial FUO
3. Neutropenic FUO
4. HIV related FUO
Definition
1. Fever> 38.3 C(>101 F)
2. Illness duration >3 weeks
3. Remains undiagnosed after 3 outpatient visits or 3 days in
hospital or 1 week of intelligent and invasive ambulatory
investigations
4. No known immunocompromised state
5. Diagnosis remain uncertain after through out history taking,
physical examinations and following obligatory
investigations: CBC, ESR, C reactive protein , electrolytes,
creatinine , LFT, ANA, RF, protein electrophoresis, urinalysis,
blood cultures, chest X-ray, abdominal ultrasonography and
tuberculin tests or interferon gamma assay
 Classification FUO
Category Definition Aetiologies
Classic • Temperature > 38.3 c (100 .9 F) • Infection
• Duration > 3 weeks • Malignancy
• Evaluation of at least 3 outpatients visits or 3 days in • Collagen vascular disease
hospital
Nosocomial • Temperature > 38.3 C • Clostridium difficile enterocolitis
• Patient hospitalized > 24 hrs but • Drug induced
• no fever at time of admission • Pulmonary embolism
• Evaluation at least 3 days • Septic thrombophlebitis
• Postoperative complication
• Sinusitis from NG, orotracheal
tubes, transfusion reaction
 Contd..
Category Definition Etiology
Immune deficient (neutropenic) • Temperature > 38.3 C • Opportunistic bacterial infections
• Neutrophil count< 500 per mm3 • Aspergillosis
• Evaluation of atleast 3 days • Candidiasis
• Herpes virus

HIV Associated • Temperature > 38.3 c • Cytomegalovirus

• Duration > 4 weeks or • Mycobacterium avium
outpatients, > 3 days for in intracellulare complex
patients • Pneumocystis jiroveci pneumonia
• HIv infection confirmed • Kaposi’s sarcoma , lymphoma
ASEPTIC FEVER:
• Malignancies
• Sarcoidosis
• Chronic renal failure
• Radiation sickness
• Acute myocardial infraction
• Post surgical patient
• Drug fever( penicillin, procainamide,propylthouracil)
Fever with relative bradycardia:

• Typhoid fever
• Meningitis
• Brucellosis
• Leptospirosis
• Drug induced fever
Fever with rigor:
• Malaria
• Kala azar
• UTI
• Septicemia
• Cholangitis
• Collection of pus in body
• Pyelonephritis
Hyperpyrexia
• When body temperature is >105 F,
• Cause:
- Pontine hemorrhage
-Rheumatic fever
-Meningococcal fever
-Septicemia
-Cerebral malaria
-Encephalitis
Approach to the patient
HISTORY TAKING

1. Onset of illness
Acute – Malaria, pyogenic infection
Gradual- TB , typhoid fever

[Link] – high grade fever : UTI, malaria

3. Pattern of fever

4. Antecedents – prior to onset of fever

Dental extractions; infective endocarditis
Urinary catheterizations : UTI , bacteraemia
Associated symptoms :

• Chills and rigor-bacterial ,rickettsial, protozoal disease , influenza,

lymphoma, leukaemia ,drug induced

• Night sweats-TB, Hodgkin lymphoma

• Loss of weight- Malignancy, TB

• Cough and dyspnoea: Miliary TB, pulmonary emboli, aids pt with

PCP
• Headache: Giant cell arteritis , typhoid, sinusitis

• Joint pain: RA , SLE , Vasculitis

• Abdomen pain: Cholangitis, biliary obstruction ,perinephric abscess, Crohn’s

• Bone pain: osteomyelitis, lymphoma

• Skin rash :Gonococcal infection , NHL , dengue

Past medical history

• Malignancy – Leukaemia ,lymphoma, HCC

• HIV infection , DM , IBD , Collagen vascular disease , RA , giant cell
arteritis , TB , Valvular heart disease

Past surgical history – Post transplantation ,Av fistula, recent surgery/

operation

H/o blood transfusion

 Drug history – Immunosuppressive drugs/ corticosteroids .

Family history :anyone with similar problems- TB

Travel history : travel to endemic- amoebiasis , typhoid , malaria , schistosomiasis

Residential area- malaria, leptospirosis , brucellosis

DRUGS CAUSING FEVER

• Antimicrobial agents – Acyclovir , carbapenems , cephalosporins

and tetracyclines
• Anticonvulsant – Barbiturate , Carbamazepine , phenytoin
• Antineoplastic agents- Interferons , 6 mercaptopurine, bleomycin
• Cardiovascular drugs – Clofibrate, furosemide , Heparin
• Histamine 2 blockers – cimetidine
• Immunosuppressants – Azathioprine
• NSAIDs – ibuprofen , salicylates
• Occupation – farmers, veterinarian – brucellosis

• Contact with domestic animals/birds – Brucellosis ,

psittacosis(pigeons) , leptospirosis, Q fever (cattle , sheep, goats),
toxoplasmosis(cat)

• Diet history – unpasteurized milk/cheese- brucellosis

• Poorly cooked pork- trichinosis ,raw egg- salmonella

• IVDU- HIV aids related condition, infective endocarditis

• Sexual hx – HIV ,STD , PID

• Close contact with TB patient

GENERAL EXAMINATION
• Vitals

• Temperature

• Pulse
• Weak or absent pulse - Takayasu's arteritis

• Rate

• Physiologically, fever is accompanied by tachycardia.

• Relative bradycardia (Faget's sign) - legionellosis, brucellosis,

psittacosis, leptospirosis, typhoid
SKIN:

• Janeway lesions -infective endocarditis

• maculopapular, vesicular, or petechial rash -typhus

• Swollen lymph nodes –Lymphadenopathy -reactive lymphoid

hyperplasia (suggestive of inflammation or infection) or underlying
malignant processes such as lymphoma

• Macules, papules, and nodules on the trunk and extremities in

meningococcemia
Head
• Temporal artery tenderness with weak pulse : temporal arteritis
• Sinus tenderness : in sinusitis

Eyes
• Roth's spots : infective endocarditis
• Photophobia or ocular pain on palpation suggestive of uveitis -
Wegener's granulomatosis, Bechet syndrome
Mouth
• Oral thrush -candidiasis - HIV/AIDS
• Oral ulcers –SLE, Crohn's disease
• Petechiae on the palate -infective endocarditis.
• Parotid gland enlargement and tenderness in infections (e.g.,
Staphylococcus aureus, tuberculosis, mumps, HIV), Sjogren's
syndrome, or sarcoidosis.

Neck
• Cervical lymph nodes -inflammation, infection, lymphoma
• Enlargement of the thyroid gland may be present in thyroiditis
Arms – drug injection site

Lungs
• Rales or rhonchi - pneumonia.
• Fremitus with diminished breath sounds- pneumonia.

Heart
• Heart murmurs - IE , SLE (Libman-Sacks endocarditis), or chronic
diseases (pericarditis)
Abdomen
• Abdominal tenderness, rebound tenderness , guarding - intra-
abdominal infections.
• Flank pain -perinephric abscess, or pyelonephritis.
• An inguinal mass -psoas muscle abscess.

• Splenomegaly -infectious mononucleosis, splenic abscess, or hepatitis

• Renal enlargement – renal cell ca
Genitourinary

• Prostatic enlargement -prostatic abscess

• Epididymal nodule ---epididymitis.
• Testicular nodule -polyarteritis nodosa.
• Penis/scrotum- pus/discharge
• Vaginal examination – collection pelvis pus/PID
Extremities:

• Osler's nodes - infective endocarditis.

• Swollen joints with effusion - infectious arthritis or rheumatic

diseases.

• Splinter haemorrhage - infective endocarditis.

• Limb tenderness along deep veins -deep vein thrombosis or

thrombophlebitis.
Neurologic examination:

• Cranial nerve deficits - cerebral vasculitis associated with

systemic lupus erythematosus.

• Signs of meningism – Chronic tb meningitis

• Focal neurological signs – brain abscess , mononeuritis

multiplex in PAN
• Initial diagnostic tests (stage 1)

i. CBC with differentials

ii. ESR and CRP
iii. LFT
iv. 3 set of blood cultures( from 3 different sites, several hrs apart
prior antibiotic therapy)
v. Chest radiograph
vi. Serum virology
vii. Urine analysis and culture
viii. Sputum c/s
ix. Abdominal ultrasound
x. Mantoux test
• CBC –anaemia suggest serious underlying disease
• Leukocytosis with bands – occult bacterial infection
• Leucopenia and lymphopenia – Advanced HIV
• Thrombocytopenia – Malaria/ Leukemia
• Peripheral blood - Malaria
• ESR
• If elevated- significant inflammatory process , if high -> 100 mm /h ….
• Tuberculosis , Myeloma , Temporal arteritis
• High ESR lacks specificity – in drug rxn, Thrombophlebitis , nephrotic
syndrome

• CRP – closely associated with inflammatory process

• ESR and CRP elevated in
1. Bacterial infection
2. Immunological mediated inflammatory states
3. Neoplasms
4. Tissue infraction

MORE SPECIFIC AND SENSITIVE IS ACUTE PHASE PROTEINS

• Imaging studies.. Chest Xray
• Miliary shadows – disseminated TB
• Mediastinal mass – Lymphoma/ Tuberculosis
• In abscess in liver / Spleen or pancreatic and subphrenic abscess –
Atelectasis and elevation hemidiaphragm
• If CXR normal , repeat weekly basics
Stage 2
• Repeat history and examination
• Protein electrophoresis
• CT ( chest , Abdomen , Pelvis)
• Autoantibody screening
• Electrocardiogram
• Bone marrow examination
• Lumber puncture
• Temporal artery biopsy
• Hiv test counselling
• Mediastinal mass – Tuberculosis /Lymphoma/sarcoidosis
• Dorsal spine – spondylitis and disc space disease
• CT scan abdomen – effective to visualize abscess ,
retroperitoneal tumor and hematoma
Stage 3
i. Echocardiogram
ii. Barium studies
iii. IVU
iv. Liver biopsy
v. Exploratory laparotomy
vi. Bronchoscopy
Nuclear medicine

• Fluorodeoxyglucose positron emission tomography (FDG-PET/CT)

– highly sensitive diagnostic technique for anatomic localization of
infectious, inflammatory or neoplastic processes , although
nonspecific but guide for further definitive test like biopsy or
aspiration
• Gallium and indium labelled leukocyte studies sensitive not
specific, localize the involved site for a targeted evaluation with
CT scan, indium scans however has high rate of false negative
with bone infections.
Stage 4
• Treat TB
• Endocarditis
• Vasculitis
• Trial of aspirin /steroids
 Imaging studies
• Chest radiograph – Tuberculosis , malignancy , pneumocystis carinii
pneumonia

• CT abdomen/ pelvis with contrast – Abscess , malignancy

• Gallium 67 scan – Infection , malignancy

• Indium labelled leukocytes – Occult septicemia
• Technetium Tc 99m – acute infection and inflammation bone and soft tissue

• MRI brain – Malignancy , auto immune disease

• Transthoracic or transesophageal echocardiography – Bacterial endocarditis

• Venous doppler studies – Venous thrombosis

Invasive test
• Done only when clinical picture and initial test require
histopathological evaluation

• Used to diagnose commonly malignancy, certain infections,

myeloproliferative disorder and inflammatory condition .

• Liver biopsy- granulomatous hepatitis, rheumatic inflammatory

disorder
• Lymph node biopsy- LGV , toxoplasmosis
• Bone marrow biopsy- neoplastic disorder, Miliary tb
TREATMENT
• DECISION TO TREAT FEVER
- Fever itself is not a disease.
- It is the ordinary response of host.
- Most fever are associated with self limited infection i.e
viral illness.
- Use of antibiotics are not contraindicated in such patient
.
- Treatment of fever with routine antipyretics does not
harm and does not slow down the resolution of
common viral and bacterial infections.
• However , in bacterial infection with holding of
antipyretics therapy can be helpful in evaluating the
effectiveness of particular antibiotics , especially in
absence of positive culture of infective organism.

• The routine use of antipyretics can mask an

inadequately treated bacterial infection.
Mechanism of antipyretics
• Empiric antibiotics not indicated unless patient is neutropenic and
condition is deteriorating .
• antibiotic delay the diagnosis of occult infection
• Empiric glucocorticoids not indicated unless strong clinical
suspicion for a specific rheumatological diagnosis
• If patient condition deteriorating therapeutic trials of antibiotic,
steroids or anti tuberculous agent is considered.
• Oral aspirin and acetaminophen(PCM) are equally
effective in reducing fever.
• Aspirin dose (325-1000mg)
• Pcm dose 500 -1000mg
• NSAIDS – ibuprofen inhibit COX-2 are excellent
antipyretics.
• Glucocorticoids( act in two level)
-inhibit PG synthesis by inhibiting phospholipase A2
activity
-also block transcription of the Mrna for the pyrogenic
cytokines.
Regimens for the treatment of fever
• Objective for treating fever are :
1) reduce hypothalamic set point
2) facilitate heat loss

• Reducing fever also reduces the systemic symptoms like

headache, myalgias and arthralgias.
• Oral aspirin and NSAIDS effectively reduces the fever but
effect platelets and GI tract.
• So acetaminophen is preferred antipyretics.
• If patient cannot take oral antipyretics then iv and rectal
suppositories can be given.
• Antitubercular drugs-if granulomatous disease present

• If fever doesn’t respond after 6 weeks of antituberculous treatment, another

diagnosis considered

• Colchicine , NSAID and glucocorticoids

Other exceptions to start antibiotic or steroid treatment
• Culture negative endocarditis
• Cryptic disseminated TB
• Temporal arteritis with suspected vision loss – use glucocorticoids
• Anakinra
• A recombinant form of naturally occurring IL 1 antagonist.
• Block activity of IL1 , effective in auto inflammatory syndrome.
Naproxen for suspected neoplastic fever
• Naproxen test done to differentiate infectious and neoplastic etiology

• Naproxen 250mg is given orally every 8 hourly for 3 days, in which patient
temperature is measured

• If temperature decrease substantially-malignant/ neoplastic etiology

• If temperature constant/minimal decrease – infectious cause
• Treatment of fever in some patient is recommended because
fever increases the demand of oxygen( ie for every 1 C over 37 C ,
there is 13 % inc in oxygen consumption) and aggravate the
patient condition with preexisting impairment of
cardiac ,pulmonary and CNS function)
Summary

• The most common cause is infections, followed by connective tissue disorder and
neoplasms.
• However, it is not uncommon to never come to a definitive diagnosis.
• Diagnostic approach includes history to determine the fever pattern, associated
complaints, exposures as well as physical examination, including general assessment
of vital signs and , skin, eyes, sinuses, mouth , lymph nodes,lungs liver, spleen and
limbs.
• Diagnostic tests include CBC and peripheral smear, ESR and CRP, blood cultures,
urinalysis and urine culture, chest radiograph, tuberculin skin testing,
serum electrolytes, BUN, creatinine, and liver enzymes and HIV serology.
• Additional lab and imaging tests might be also ordered depending on the history,
examination, and initial tests findings.
• Empiric treatment with anti inflammatory medications or antibiotics is generally not
recommended.
REFERENCE
• HARRISONS 21ST EDITION
• DAVIDSONS 23rd EDITION
THANK YOU