The document provides an overview of fever (pyrexia) including its pathophysiology, types, and differential diagnosis. It discusses how fever is regulated in the hypothalamus and the role of cytokines like interleukin and tumor necrosis factor in initiating the fever response. The document also outlines how to take a thorough history from a febrile patient to understand the biomedical and contextual perspectives of their illness.

1. 2012
School of Clinical Medicine
Clinical Skills
NRMSM UKZN
Dr RM Abraham

2. OVERVIEW
 Introduction
 Thermoregulation
 Pathophysiology of fever
 Aetiology /Differential diagnosis of fever
 Types of fever
 Pyrexia of Unknown origin(PUO)
 Factitious fever
 History taking in a febrile patient

3. INTRODUCTION
FEVER(Pyrexia)
 Is an elevation of body temperature above the normal
circadian range (daily variation) as a result of a change
in the thermoregulatory center located in the anterior
hypothalamus and pre-optic area (i.e. an increase in
the hypothalamic set point of 37 C) due to infection,
metabolic derangements or increased cell destruction.

4. THERMOREGULATION
 Body temperature is controlled in the hypothalamus,
which is directly sensitive to changes in core
temperature
 The normal 'set-point' of core temperature is tightly
regulated within 37 ± 0.5°C, as required to preserve
normal function of many enzymes and other
metabolic processes.

5. THERMOREGULATION
In a hot environment
 sweating is the main mechanism for increasing heat
loss.
 This usually occurs when the ambient temperature
rises above 32.5°C or during exercise

6. PATHOPHYSIOLOGY OF FEVER
The initiation of fever begins:
 when exogenous or endogenous stimuli are presented
to specialized host cells, principally monocytes and
macrophages ,they will then stimulate the synthesis
and release of various pyrogenic cytokines including :
1)interleukin-1, interleukin-6
2)TNF-α, and
3)IFN-γ.

7. PATHOPHYSIOLOGY OF FEVER
Exogenous pyrogens: stimuli from outside the host
like : microorganism, their products, or toxins and it is
called Endotoxin
Endotoxin : lipopolysaccharide ( LPS)
 LPS: is found in the outer membrane of all gram
negative organisms
Action :
 1) through stimulation of monocytes and macrophages
 2) direct on endothelial cell of the brain to produce
fever

8. PATHOPHYSIOLOGY OF FEVER
Endogenous pyrogens:
 polypeptides that are produced by the body ( by
monocytes and macrophages ) in response to stimuli
that is usually triggered by infection or inflammation
stimuli

9. PATHOPHYSIOLOGY OF FEVER
Pyrogens:
Substances that cause fever are called pyrogens
Cytokines :
 Cytokines are regulatory polypeptides that are
produced by
 1) monocytes / macrophages
 2) lymphocytes
 3) endothelial and epithelial cell and hepatocytes

10. PATHOPHYSIOLOGY OF FEVER
 The most important cytokines are :
 Interleukin 1 and 1 (The most pyrogenic)
 Tumor necrosis factor
 Interferon gamma
 Interleukin 6 (The least pyrogenic)
cytokines>fever develop within 1hr of infection

11. PATHOPHYSIOLOGY OF FEVER
 Cytokine-receptor interactions in the pre-optic region of
the anterior hypothalamus activate phospholipase A.
This enzyme liberates plasma membrane arachidonic acid
as substrate for the cyclo-oxygenase pathway. The resulting
mediator, prostaglandin E2, then modifies the
responsiveness of thermosensitive neurons in the
thermoregulatory centre.
 The PGE2 in the brain then stimulates the rapid release of
cAMP from glial cells, this release then induces the release
of neurotransmitters that raises the thermoregulatory set
point in the hypothalamus.
 These events then lead to increased body heat content and
fever.

12. nfection, microbial toxins,
mediators of inflammation,
immune reactions
Microbial toxins
FEVER
nocytes/macrophages,
dothelial cells, others
genic cytokines IL-1, IL-
6, TNF, IFN
Cyclic
AMP
PGE₂
Hypothalamic
endothelium
Elevated
thermoregulatory set
point
Heat conservation,
heat production
Circulation
26

13. Human Physiology 5th edition 1990
INFECTION
Monocytes, macrophages
Hypothalamus: ↑ temperature setpoint
Skeletal muscle Skin arterioles
↑ vasoconstriction
↑ heat production ↓ heat loss
Heat production > Heat loss
Heat retention
↑ Body temperature
Endogenous pyrogens (IL-1,TNF, IL-6)
shivering Curl up/add clothes

14. INFECTIONS MALIGNANCIES AUTOIMMUNE
CONDITIONS-
JOINT/CONNECT
IVE TISSUE
DISEASE
OTHERS
•Typhoid Fever
•Hepatitis A & B
•Leptospirosis
•Tuberculosis
•Malaria
•Leukemia
•Lymphoma
•Rheumatoid arthritis
•Rheumatic fever
•Systemic lupus
erythematosus
•Drug-induced
fever
14

15. TYPES OF FEVER
The pattern of temperature changes may occasionally hint at the diagnosis:
 Continuous fever: Temperature remains above normal throughout the day
and does not fluctuate more than 1 °C in 24 hours, e.g. lobar pneumonia,
typhoid fever, urinary tract infection, brucellosis
 Intermittent fever: The temperature elevation is present only for a certain
period, later cycling back to normal(i.e. Normal temp. between fever episodes),
e.g. malaria, pyaemia, or septicemia.
Following are its types
 Quotidian fever, with a periodicity of 24 hours, typical of Plasmodium
falciparum malaria
 Tertian fever (48 hour periodicity), typical of Plasmodium vivax or Plasmodium
ovale malaria
 Quartan fever (72 hour periodicity), typical of Plasmodium malariae malaria.

16. TYPES OF FEVER
 Remittent fever: Temperature remains above normal
throughout the day and fluctuates more than 1 °C in 24
hours, e.g., infective endocarditis.
 Pel-Ebstein fever: A specific kind of fever associated
with Hodgkin's lymphoma, being high for one week
and low for the next week and so on. However, there is
some debate as to whether this pattern truly exists.

17. PYREXIA OF UNKNOWN ORIGIN (PUO)
 A common presenting problem.
 Defined as a consistently elevated body temperature of
more than 37.5 C persisting for more than 2 weeks
with no diagnosis despite one week of initial
investigations.
 The commonest cause of PUO is a common disease
presenting atypically.
 As the duration of fever increases the likelihood of an
infectious cause decreases.
 Among children, infections are the most common
causes.

18. Aetiology and Epidemiology of
PUO in developed countries
Infections (30%)
 Sepsis- Abscess at any site; Cholecystitis/ Cholangitis
Urinary tract infection
Dental and sinus infection
Bone and joint infections
 Imported infections, e.g. Malaria, Dengue, Brucellosis
 Enteric or Typhoid fever
 Infective endocarditis
 Tuberculosis (particularly extrapulmonary)
 Viral infections (cytomegalovirus-CMV, Ebstein-Barr virus-EBV, human
immunodeficiency virus-HIV), Hepatitis A and B and toxoplasmosis
 Fungal infections
Malignancy (20%)
 Lymphoma and myeloma
 Leukaemia
 Solid tumours (renal, liver, colon, stomach, pancreas)

19. Connective tissue disorders (15%)
•Vasculitic disorders (including polyarteritis nodosa
and rheumatoid disease with vasculitis)
•Systemic lupus erythematosis (SLE)
•Rheumatoid arthritis
•Rheumatoid fever
•Temporal arteritis
•Polymyositis
Miscellaneous (20%)
•Inflammatory bowel disease
•Liver disease: Cirrhosis and granulomatous hepatitis
•Sarcoidosis
•Drug reactions
•Thyrotoxicosis
•Hypothalamic lesions
•Familial meditaranean fever
No diagnosis or resolves spontaneously (15%)

20. FACTITIOUS FEVER
 This is defined as fever engineered by the patient by
manipulating the thermometer and/or temperature
chart apparently to obtain medical care.
 uncommon and typically presents in young women
with a medical and nursing background.
 Examples include The dipping of thermometers into
hot drinks to fake a fever.
 The factitious disorder is usually medical but may
relate to a psychiatric illness with reports of
depressive illness.

21. FACTITIOUS FEVER
CLUES TO THE DIAGNOSIS OF FACTITIOUS FEVER
 A patient who looks well
 Absence of temperature-related changes in pulse rate
 Temperature > 41°C
 Absence of sweating during the period of fever
 Normal ESR and CRP despite high fever
Useful methods for the detection of factitious fever
include
1) Supervised (observed) temperature measurement
2) Measuring the temperature of freshly voided urine

22. HISTORY TAKING IN FEBRILE
PATIENTS
 Using the Calgary Cambridge guide as a framework to
interviewing patients.
 The most important step is taking a meticulous detailed history
to explore the patients problems from three perspectives.
 Biomedical perspective- to understand the chronology of
symptoms, analyse each symptom and review each system to
localize the source of the fever.
 Contextual history- very important
 Patients perspective- to understand the patients interpretation
of the illness.
 Systems review- This is a guide not to miss anything. Any
significant finding should be moved to HPC or PMH depending
upon where you think it belongs.

23. exploration of the patient’s problems to discover the:
 biomedical perspective  the patient’s perspective
 background information - context
providing the correct type and amount of information
aiding accurate recall and understanding
achieving a shared understanding: incorporating the
patient’s illness framework
planning: shared decision making
Initiating the session
Gathering information
Physical examination
Explanation and planning
Closing the session
Providing
structure
Building the
relationship
preparation
establishing initial rapport
identifying the reasons for the consultation
making
organisation
overt
attending to
flow
using
appropriate
non-verbal
behaviour
developing
rapport
involving
the patient
ensuring appropriate point of closure
forward planning
a

24. The content of the medical interview
Patient’s problem list
1.
2.
3.
Exploration of patient’s problems:
Biomedical perspective
sequence of events, symptom analysis, relevant systems review
Patient’s perspective
ideas, concerns, expectations, effects on life, feelings ICE
Background information - context
Past medical history
Family history
Personal and social history
Drug and allergy history
Systems review
b

25. BIOMEDICAL PERSPECTIVE
Presenting complaints of a patient with fever
 Feeling hot
A feeling of heat does not necessarily imply fever
 Rigors.
profound chills accompanied by chattering of the teeth
and severe shivering, implies a rapid rise in body
temperature. Can be produced by :
1) brucellosis and malaria
2) sepsis with abscess
3) lymphoma
 Excessive sweating.
Night sweats are characteristic of tuberculosis, but
sweating from any cause is usually worse at night.

26. BIOMEDICAL PERSPECTIVE
 Recurrent fever.
Source is often a focus of bacterial infection such as
cholecystitis or cholangitis or urinary tract infection
especially associated with an obstruction or calculi.
 Headache.
Fever from any cause may provoke headache.
Severe headache and photophobia, may suggests
meningitis.
 Delirium.
Mental confusion during fever is well described and
relatively more common in young children and in old age.
 Muscle pain. Myalgia is characteristic of viral infections
such as influenza, Malaria and brucellosis.

27. BIOMEDICAL PERSPECTIVE
Symptom analysis for fever
 Verify presence of fever- True or factitious fever
 Duration- Acute or chronic
 Mode of onset- Abrupt or gradual
 Progression- Continuous or intermittent. If intermittent
ask about frequency to determine the pattern.
 Severity- how it affects daily work/physical activities.
 Relieving and aggravating factors
 Treatment received or/and outcome
 Associated symptoms- Localizing symptoms may
indicate the source of fever.

28. BIOMEDICAL PERSPECTIVE
 Respiratory tract symptoms:
1) Sore throat, nasal discharge, sneezing-URTI
2) Sinus pain and headache-suggests sinusitis
3) cough, sputum, wheeze or breathlessness-suggests a LRTI
 Genitourinary symptoms:
1) Frequency of micturition, dysuria, loin pain, and vaginal or
urethral discharge-suggesting
a) Urinary tract infection,
b) Pelvic inflammatory disease and
c) Sexually transmitted infection (STI)

29. BIOMEDICAL PERSPECTIVE
 Abdominal symptoms: diarrhea, with or without blood, weight loss and
abdominal pain -suggesting
a) Gastroenteritis,
b) Intra-abdominal sepsis,
c) Inflammatory bowel disease,
d) Malignancy
 Skin rash: enquire about appearance and distribution as it may provide clues
to the diagnosis-
1) Macular- Measles,Rubella,toxoplasmosis
2) Haemorrhagic- Meningococcal infections, viral haemorrhagic fever.
3) Vesicular- Chickenpox, Shingles, herpes simplex
4) Nodular- Erythema nodosum( TB and Leprosy)
5) Erythematous- Drug rashes, Dengue fever

30. BIOMEDICAL PERSPECTIVE
 Joint symptoms: joint pain, swelling or limitation of
movement is suggestive of active arthritis.
A) distribution : mono , oligo or poly arthritis
B) appearance : fleeting
1) infective arthritis- oligoarthritis
2) collagen vascular disease-fleeting
3) reactive arthritis

31. BIOMEDICAL PERSPECTIVE
Constitutional symptoms:
 Weakness
 Fatigue
 Anorexia
 Change of weight
 Fever/chills
 Lumps
 Night sweats

32. CONTEXTUAL HISTORY
Past Medical /Surgical History
Start by asking the patient if they have any medical
problems
 IHD/DM/Asthma/HT/RHD, TB/Jaundice/Fits e.g. if diabetic- mention time of
diagnosis/current medication/clinic check up
Past surgical/operation history
 E.g. time/place/ what type of operation.
 Note any blood transfusion / blood grouping.
 H/O dental extractions/circumcision & any excessive bleeding during these
procedures.
Patient known to have rheumatic heart disease is at risk to develop infective
endocarditis if not given prophylaxis
 Any minor operations or procedures including endoscopies, dental
interventions, biopsies.
History of trauma/accidents
 E.g. time/place/ and what type of accident
 History of tattoo piercing

33. CONTEXTUAL HISTORY
Drug and allergy History
 dosage, timing &how long.
 Drug fever is uncommon and therefore easily missed-The
culprits include :
penicillin and
cephalosporin
sulphonamide
anti tuberculous agents
anticonvulsants particularly phenytoin
 OCT/Vitamins/Traditional /Herbal medicine & alternative
medicine such as acupuncture.
 Blood transfusion.
 Immunization against Hepatitis A &B, Typhoid fever.
 Malaria prophylaxis

34. CONTEXTUAL HISTORY
Family History
 Any familial disease/running in families e.g. breast
cancer, IHD, DM, Asthma, Arthritis
 Infections running in families as TB, Leprosy.
 Cholera, typhoid in case of epidemics.

35. CONTEXTUAL HISTORY
Personal and Social History
 Smoking history - amount, duration & type- strong risk factor for IHD
 Alcohol history - amount, duration & type-Unhealthy alcohol use is
associated with cardiomyopathy, CVA, liver cirrhosis, alcoholic
hepatitis, hepatocellular carcinoma.
 Occupation, social & education background, family social support&
financial situation, Social class.
 Home conditions-Water supply, Sanitation status in his home &
surrounding, Geographic area of living, fresh-water swimming.
 Animals / birds in his/her house- exposure to birds (psittacosis) or
animals (toxoplasmosis, brucellosis, leptospirosis)
 Consumption of unpasteurized milk or milk products (tuberculosis,
brucellosis and Q fever).
 Sexual History- Unprotected exposure to sexual partner with STI, HIV
 Illicit drug usage- injections and sharing of needles (HIV, hepatitis B
&C, infective endocarditis), site of injection (e.g Femoral vein-septic
arthritis, ilio-psoas abscess)

36. CONTEXTUAL HISTORY
Travel History
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- Malaria, Dengue, Salmonella
 10 –21Days-Malaria,Typhoid,Brucella,HepatitisA
 Weeks-Months- Amoebiasis, HIV, Hepatitis
Vital questions-(Always ask about foreign travel).
a) Where have you been? …Endemic area or not ?
b) What have you done?
C) How long were you there?
d) Did you have insect bites or contact with animals?
e) Did you take precautions/prophylaxis against malaria?
If the patient has been in an endemic area
The most common diagnoses :Malaria, Typhoid fever, Viral hepatitis,
Dengue fever
Malaria must be excluded whatever the presenting symptoms

37. PATIENTS PERSPECTIVE
Always ask the patient how he/she feels/thinks about
the illness by analysing
 Ideas
 Concerns
 Feelings
 Expectations
 Effects on daily living

38. SYSTEMS REVIEW
 General
• Weakness
• Fatigue
• Anorexia
• Change of weight
• Fever/chills
• Lumps
• Night sweats

39. SYSTEMS REVIEW
Cardiovascular
• Chest pain
• Paroxysmal Nocturnal Dyspnoea
• Orthopnoea
• Short Of Breath(SOB)
• Cough/sputum (pinkish/frank blood)
• Swelling of ankle(SOA)
• Palpitations
• Cyanosis

40. SYSTEMS REVIEW
Gastrointestinal
• Appetite (anorexia/weight change)
• Diet
• Nausea/vomiting
• Regurgitation/heart burn/flatulence
• Difficulty in swallowing
• Abdominal pain/distension
• Change of bowel habit
• Haematemesis, melaena
• Jaundice

41. SYSTEMS REVIEW
Respiratory System
• Cough(productive/dry)
• Sputum (colour, amount, smell)
• Haemoptysis
• Chest pain
• SOB/Dyspnoea
• Tachypnoea
• Hoarseness
• Wheezing

42. SYSTEMS REVIEW
Urinary System
• Frequency
• Dysuria
• Urgency
• Hesitancy
• Terminal dribbling
• Nocturia
• Back/loin pain
• Incontinence
• Character of urine: color/ amount (polyuria) & timing
• Fever

43. SYSTEMS REVIEW
Nervous System
• Visual/Smell/Taste/Hearing/Speech problem
• Head ache
• Fits/Faints/Black outs/loss of consciousness(LOC)
• Muscle weakness/numbness/paralysis
• Abnormal sensation
• Tremor
• Change of behaviour or psyche.
• Paresis.

44. SYSTEMS REVIEW
Genital system
• Pain/ discomfort/ itching
• Discharge
• Unusual bleeding
• Sexual history
• Menstrual history – menarche/ LMP/ duration &
amount of cycle/ Contraception
• Obstetric history – Para/ gravida/abortion

45. SYSTEMS REVIEW
Musculoskeletal System
• Pain – muscle, bone, joint
• Swelling
• Weakness/movement
• Deformities
• Gait

46. THE END: REFERENCES
 Guyton's Textbook of Medical Physiology
 Davidson's Principles & Practice of Medicine
 Hutchinson's Clinical Methods
 Harrison’s Principles of Internal Medicine
 Google images