Fever is a protective response initiated by the body to fight infections. Fever of unknown origin (FUO) is defined as a temperature above 38°C for more than 3 weeks without an established diagnosis after initial investigations. Common causes of FUO include infections, malignancies, and connective tissue disorders. Evaluating a patient with FUO involves taking a detailed history, conducting a physical exam, and running diagnostic tests. Treatment focuses on identifying the underlying cause, with antipyretics used for fever control. Prognosis depends on the identified condition.

1. General Fever and FUO
RaviKumar Patel
20170646

2. Introduction
What is fever ?
• Fever is a response to cytokines and acute phase proteins
• Fever is a protective mechanism initiated by the body to destroy or
inhibit the growth of any bacteria or virus that is sensitive to
temperature changes
• Normal body temperature ranges from 36.5 – 37.5°C (37 ± 0.5) °C
.

3. Route Celsius Fahrenheit
Oral 36.8 – 37.2ºC 98.2 - 99ºF
Rectal 37.3 - 37.6ºC 99.1 - 99.6ºF
Axillary 36.4 - 36.7ºC 97.6 - 98.1ºF
Temporal 36.4 - 36.7ºC 97.6 - 98.1ºF
Tympanic 37.3 - 37.6ºC 99.1 - 99.6ºF

4. How is hyperthermia different ?
• Hyperthermia is due to Exogenous heat exposure and excessive
endogenous heat production.
• Does not involve pyrogenic molecules.
• No change in hypothalamic setpoint.
• Antipyretics cannot be used to control hyperthermia.

5. Heat production
Metabolism
• Basal rate of metabolism of all the cells of the body.
• Extra rate of metabolism caused by muscle activity including muscle
contractions caused by shivering.
• Extra metabolism caused by the effect of thyroxine
• Extra metabolism caused by the effect of norepinephrine,
epinephrine and sympathetic stimulation of cells
• Extra metabolism caused by the thermogenic effect of food.

6. Heat conservation
• Fat in subcutaneous tissue – have less heat conductive property
therefore it minimizes the heat transfer to the skin.
• Blood flow to the skin.
• Piloerection.

7. How is heat lost from the body ?
• Radiation – loss of heat from the body in form of infrared heat rays.
• Conduction – heat is conducted from body to objects in contact with
it, e.g. chair, bed, etc.
• Convection – heat is lost by the means of air currents.
• Evaporation – 0.58 calorie (2.421 joules) of heat is lost for each ml of
water that is evaporated.

8. • Respiration

9. Role of hypothalamus
• The temperature of the body is mainly regulated by the temperature
regulating centers in the hypothalamus.
• The preoptic anterior hypothalamic area and the posterior
hypothalamus work together and integrate the central and peripheral
temperature sensory signals.

11. Concept of setpoint
What is a setpoint ?
• It is a programmed optimal temperature in the hypothalamus that it
maintains.
How does it maintain ?
• When the temperature is above 37.5ºC, the rate of heat loss > the
rate of heat production.
• When temperature is below 36.5ºC, the rate of heat production > the
rate of heat loss.

12. Mechanisms initiated when the body is too hot are:
• Vasodilation of blood vessels in the skin.
• Sweating.
• Decrease in heat production.
- metabolic thermogenesis inhibited.
- shivering inhibited.
Mechanisms initiated when the body is too cold are:
• Vasoconstriction of blood vessels in the skin.
• Piloerection.
• Increase in heat production (thermogenesis)
- metabolic thermogenesis.
- shivering reflex initiated.

13. Image source: google
image.

14. Etiology
Infection Non- infectious
• Bacterial e.g. Tuberculosis
• Viral e.g. Dengue fever
• Fungal e.g. candidiasis
• Parasitic e.g. malaria
• Environmental
• Inflammation
• Autoimmune diseases e.g.
rheumatoid arthritis
• Trauma
• Drugs e.g. Methyldopa, Quinine

15. Pathogenesis

16. Phases of fever
• Prodromal phase – mild headache, fatigue, malaise
• Onset phase- characterized by chills and shivering
• Stationary phase – characterized by flushed skin and feeling hot.
• Defervescence or resolution phase – Initiation of sweating.

18. Patterns of fever
1. Continuous fever
• Temperature remains above normal throughout the day.
• Does not fluctuate more than 1⁰ C in 24 hours.
• E.g. lobar pneumonia, infective endocarditis.

19. 2. Remittent fever
• Temperature remains above normal through out the day.
• Fluctuation of temperature is more than 1⁰ C.
• E.g. viral pneumonia.

20. 3. Intermittent fever
• Temperature is present for some hours in a day and remits to normal,
e.g. miliary TB

21. 4. Relapsing fever
• Temperature rises abruptly and then falls abruptly to normal before
rising again, e.g. malaria.

22. 5. Undulant fever
• It is called undulant because the fever pattern is rising and falling like
a wave.

23. 6. Pel – Ebstein fever
A cyclic fever pattern that is occasionally seen in Hodgkin’s lymphoma
which is characterized by irregular episodes of fever of several days’
duration.

24. Exercise:
What is a pyrogen ?
A. a bacteria
B. a substance produced by the bacteria, virus, fungi and
parasite which induces fever.
C. Cytokines
D. Both b and c

25. Answer : D
A pyrogen is a fever producing agent.
two types
1. Exogenous pyrogen
• Foreign substance derived outside the host
e.g. lipopolysaccharides, endotoxins, exotoxins.
2. Endogenous pyrogen
• Produced by the immune cells that are activated in presence of infectious
agents. E.g. cytokines (IL1,IL6, TNF)

26. Fever of unknown origin
(FUO)

27. Introduction
• Fever of unknown origin (FUO) is defined as a temperature
persistently above 38.0°C for more than 3 weeks, without diagnosis
upon initial investigation done during 3 days of inpatient care or after
more than two outpatient visits.

28. Durack and street’s classification of fuo
1. Classic – 3 outpatients visits or 3 days in hospital without any
explanation of the cause.
2. Nosocomial – patient hospitalized for ≥ 24 hours but no fever or
incubating on admission
3. Neutropenic – fever on several occasions in patients whose neutrophil
count is less 500 per µL (Normal range:1500 – 8000 per µL of blood).
4. HIV associated – fever for more ≥ 4 weeks in out patients, >3 days for
inpatients with confirmed HIV infection.

29. Category Definition Aetiologies
Classic - Temperature more > 38⁰ C
- Duration of > 3 weeks
- Evaluation of at least 3 outpatient visits or 3 days in
hospital.
- Infection
- Malignancy
- Collagen vascular disease
nosocomial - Temperature more > 38⁰ C
- Patient hospitalized ≥ 24 hours but no fever or
incubating on admission
- Evaluation of at least 3 days.
- Clostridium difficile enterocolitis.
- Drug induced e.g.
- Pulmonary embolism
- Septic thrombophlebitis
- Sinusitis
neutropenic - Temperature more > 38⁰ C
- Neutrophil count < 500 per µL of blood
- Evaluation of at least 3 days.
- Opportunistic bacterial infections
- Aspergillosis
- Candidiasis
- Herpes virus
HIV
associated
- Temperature more > 38⁰ C
- Duration of ≥ 4 weeks for outpatient and > 3 days
inpatient.
- HIV infection confirmed.
Primary
- HIV
Secondary
- Cytomegalovirus
- Drug induced

30. Etiology
Class Percentage Diseases
infection 30% Abscesses, tuberculosis, HIV, infective endocarditis and
candidiasis
Malignancy 20% Lymphoma, leukemia and myeloma
Mischellanous 20% Inflammatory bowel disease, granulomatous hepatitis, drug
induced, Haemolytic anaemia,
Connective tissue
disorders
15% Still’s disease (juvenile rheumatoid arthritis), Systemic lupus
erythematosus (SLE), Temporal arteritis
Idiopathic 15%

31. Etiology
30%
20%
20%
15%
15%
infection malignanacy michellanous connective tissue diorders idiopathic

32. Approach to patient with
fever of unknown origin
(fuo)

33. 1.History taking
• Duration: when did it start ?
• Onset: acute or gradual
• Character: high grade or low grade fever
• Pattern: fever pattern, sustained or persistent.
• Associated symptoms: any joint pain, headache, chills, abdominal
pain etc.
• Past medical and surgical history: inflammatory bowel disease,
diabetes mellitus, any surgery, any operation.
• Drug history: any corticosteroids any antibiotics, etc.
• Family history: does anyone in the family has it ?

34. • Social history
- Travel history
- residential area: diseases endemic to your area.
- occupation- set of occupational diseases.
- diet history
- sexual orientation – HIV, STD’S, PID
- contact with animals

35. 2. Physical examination
HEENT
1. Central nervous system examination
- Signs
- Reflexes
- Conscious level
2. Cardiovascular examination

36. 3. Respiratory examination
4. Abdominal examination
5. Upper extremities
6. Lower extremities

37. 3. Investigations
• Full blood count
• Blood culture
• Blood smear
• Sputum culture and sensitivity
• Chest x-ray
• ECG
• Liver function test
• Urinalysis and culture
• Stool microscopy
• Lumbar puncture
• CSF analysis
• Echocardiogram
• Thyroid function test

38. Management

39. Non pharmacological treatment
• Hydration

40. • Cold sponging or tepid sponging

41. • Steam bath

42. Pharmacological treatment
• The treatment for fever of unknow origin is designed according to the
underlying diagnosis.
However;
• Empirical therapeutic trials with antibiotics, glucocorticoids, or
antituberculous agents should be avoided in FUO except when a
patient's condition is rapidly deteriorating after previous diagnostic
tests have failed to provide a definite diagnosis.

43. Antipyretics
• Paracetamol 1g Q6H PO × 3/7
mechanism of action
• Inhibits synthesis of prostaglandins.
Adverse effects:
• Liver damage (hepatotoxicity)
• NSAIDs are not the best choice for antipyretic therapy due to their
adverse effects such as GI bleeding, headache, dizziness.

44. Prognosis
• The risk of death related to FUO is dependent on the underlying
disease.
• Studies show that malignancy accounts for most FUO related deaths
compared to nonmalignant FUO where fatality rates are very low.
• The good outcome in patients without a diagnosis confirms that
potentially lethal diseases are very unusual and that empirical therapy
with antibiotics, antituberculous agents, or glucocorticoids is rarely
required in stable patients.

45. Conclusion
• Fever is both a sign and a symptom.
• Fever is a protective response initiated by the body to fight off
infections.
• The processes through which heat is lost from the body are radiation,
conduction, convection, evaporation and respiration.
• Fever results from alteration in the thermoregulatory set point.
• The best choice of antipyretic drug is paracetamol as it is better
tolerated by our body and has fewer adverse effects compared to
NSAIDs.

46. Reference
Anthony Fauci., Eugene Braunwald., Dennis Kasper., Stephen Hauser.,
Dan Longo., J. Jameson. et al. Harrison's principles of internal medicine.
19th ed. 2015.pp. 123- 141
Ralston S, Penman I, Strachan M, Hobson R, Britton R, Davidson S.
Davidson's principles and practice of medicine. 22nd ed. 2014.
Hall J. Guyton and Hall textbook of medical physiology. 12th ed.
Elsevier; 2011.pp. 867-875

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