Fever and Hyperthermia and Pyrexia of unknown origin by Dr Mohammad Hussien for Medical Student . Ass.Lecturer of Hepatogastroentrology at Kafrelsheikh University.

1. Pyrexia of unknown origin
(PUO,FUO(
Dr/ Mohammed Hussien
Assistant Lecturer of Gastroenterology & Hepatology
Kafrelsheik University
Membership at American Collage of Gastroenterology (ACG)
Membership at Egyptian association for Research and training in
Hepatogastroentrology
2017

2. → increase of body temp. > 38 degree
Types
1.Continuous → permanent fever
2.Remitant → swinging not more than 1 C
3.Intermittent or hectic → swinging more than 1 C reaching the base line at least once per 24
hours
4.Relapsing → waxes and wanes cyclically
Mechanism
1.Changing the set point in the anterior hypothalamus
-By the effect of immune system stimulation through series of reactions [infections, autoimmune reactions,
malignancy, drugs,….]
-Bacterial (lipo-polysach. Capsule, endo and exotoxins), viral and parasitic infections → exogenous pyrogens
→ stimulation of macrophages, monocytes and sensitized lymphocytes → [IL1, IL6, TNF] endogenous
pyrogens → stimulation of the endothelial cells of the brain blood vessels → PG. E1& E2 → re-setting of the
set point → fever
1.Direct effect of some drugs
-Like cocaine and phenothiazine and in some people dopamine antagonists
Definition of fever

3. 1. Dopamine level
- Affects directly the centre as occurs in neuroleptic malignant syndrome
- Neuroleptic malignant syndrome
• Occurs due to idiosyncrasy or overdose of certain drugs like haloperidol (sufenase) and
phenothiazines (e.g. chlorpromazine)
• It causes lead pipe rigidity, dystonic movements and tremors of extrapyramidal origin followed by
rise in body temp. that may lead to hypothermia
• Stupor or comma may occur
1. Other medications
- Can affect centrally the heat regulating centre like serotonin, A. choline and neuropeptides
1. CAMP and Na/Ca ion ratio may play a rule
- Malignant hyperthermia
• Disorder of the skeletal muscles in congenitally susceptible persons, initiated by halogenated
inhalation anesthesia or depolarizing agents like succenylcholine leading to generalized muscle
contraction due to increased Ca influx
• The sustained muscle rigidity leads to fever and hyperthermia
1. Disturbance of heat loss mechanism → as in heat illnesses

5. Definition it is increase of body temp. > 40.6 degree→
[elevation of core temperature without elevation of the
hypothalamic set point due to inadequate heat dissipation]
Causes
•Environmental heat stroke→
•Drug induced
Malignant hyperthermia
Neuroleptic malignant syndrome
•Infective
Cerebral malaria
Encephalitis
•Endocrinal thyrotoxic crises→
•Miscellaneous
Status epilepticus
Pontine haemorrhage
Narcotic intoxication
Serotonin syndrome
Hyperthermia

6. Original DefinitionOriginal Definition
(by(by Petersdorf and Beeson,Petersdorf and Beeson,
19611961))
• Temperatures ≥ 38.3ºC (101ºF) on several
occasions
• Fever ≥ 3 weeks
• Failure to reach a diagnosis despite 1
week of inpatient investigations or 3
outpatient visits [1 IP / 3 OP]

7. Definition of PUO
• Old Definition:
1. Fever higher than 38.3o
C on several occasions.
2. Duration of fever – 3 weeks
3. Uncertain diagnosis after one week of study in
hospital
• New Definition:
• Eliminated the in-hospital evaluation requirements
3 outpatient visits, or 3 days in hospital. …→
Ambulatory as well as in hospital

8. Aetiology

9. Definition Expansion
1. Classical PUO
2. Nosocomial PUO
3. Neutropenic PUO
4. HIV-Associated
5. Transplant

10. Classification of PUOClassification of PUO
Category Definition Aetiologies
Classic • Temperature >38.3°C (100.9°F) ;
• Duration of >3 weeks
• Evaluation of at least 3 outpatient
visits or 3 days in hospital
• Infection
• Malignancy
• collagen vascular disease
Nosocomial • Temperature >38.3°C
• Patient hospitalized ≥ 24 hours but no
fever or incubating on admission
• Evaluation of at least 3 days
• Clostridium difficile enterocolitis
• drug-induced
• pulmonary embolism
• septic thrombophlebitis,
• sinusitis
Immune
deficient
(neutropenic)
• Temperature >38.3°C
• Neutrophil count ≤ 500 per mm3
• Evaluation of at least 3 days
• Opportunistic bacterial infections,
• aspergillosis,
• candidiasis,
• herpes virus
HIV-
associated
• Temperature >38.3°C
• Duration of >4 weeks for outpatients,
>3 days for inpatients
• HIV infection confirmed
• Cytomegalovirus,
• Mycobacterium avium-intracellulare
complex,
• Pneumocystis carinii pneumonia,
• drug-induced,
• Kaposi’s sarcoma, lymphoma

11. COMMON CCOMMON CAUSESAUSES OF PUOOF PUO

12. Classic PUOClassic PUO
3 common etiologies which account for the
majority of classic PUO:
•Infections
•Malignancies
•Collagen Vascular Disease
Others/Miscellaneous which includes drug-
induced fever.

13. InfectionsInfections
• Bacterial: abscesses, TB, complicated UTI, endocarditis, osteomyelitis,
sinusitis, Lyme disease, prostatitis, cholecystitis, empyema, cholangitis,
brucellosis, typhoid, leptospirosis, Q fever, etc.
• Viral: CMV, infectious mononucleosis, HIV, etc.
• Parasite: Malaria, toxoplamosis, leishmaniasis, extraintestinal amebiasis.
• Fungal: histoplasmosis, etc.

14. MalignanciesMalignancies
• Haematological
• Lymphoma
• Chronic leukemia
• Non-haematological
• Renal cell cancer
• Hepatocellular carcinoma
• Pancreatic cancer
• Colon cancer
• Sarcomas

15. Collagen vascular disease /Collagen vascular disease /
Autoimmune diseaseAutoimmune disease
 Adult Still's disease
 Temporal arteritis
 Rheumatoid arthritis
 Rheumatic fever
 Inflammatory bowel disease
 Reiter's syndrome
 Systemic lupus
erythematosus
 Polyarteritis nodosa
 Vasculitis

16. Others/miscellaneousOthers/miscellaneous
 Drugs: penicilin, phenytoin, captopril, allopurinol,
erythromycin, cimetidine, etc.
 Hyperthyroidism
 Familial mediterranian fever
 Sarcoidosis
 Factitious fever :more in female by malingerers
 Deep Venous Thrombosis
 Hypothalamic lesions

17. Unknown causes
• In about 10% of cases despite workup.

18. Nosocomial PUONosocomial PUO
• More than 50% of patients with nosocomial PUO are due to infection.
• Focus on sites where occult infections may be sequestered, such as:
- Sinusitis of patients with NG or oro-tracheal tubes.
- Prostatic abscess in a man with a urinary catheter.
• 25% of non-infectious cause includes:
- Acalculous cholecystitis,
- Deep vein thrombophlebitis
- Pulmonary embolism.

19. Neutropenic PUONeutropenic PUO
• Patients on chemotherapy or immune deficiencies are susceptible to:
- Opportunistic bacterial infection
- Fungal infections such as candidiasis
- Infections involving catheters
- Perianal infections.
• Examples of aetiological agent:
- aspergillus
- Candida
- CMV
- Herpes simplex

20. HIV-associated PUOHIV-associated PUO
• HIV infection alone may be a cause of fever.
• Common secondary causes include:
- Tuberculosis
- Toxoplasmosis
- CMV infection
- P. carinii infection
- Salmonellosis
- Cryptococcosis
- Histoplasmosis
- Non-Hodgkin's lymphoma
- Drug-induced fever

21. Rule out the little 3Rule out the little 3
• • Rule out factituous fever:
• document the fever.
• • Rule out habitual hyperthermia :
• temperature chart & settings
• • Rule out drug fever:
• stop all nonessential medications

22. HistoryHistory TakingTaking
History of Presenting Illness (HOPI)
1 。 Onset
 - acute: Malaria, pyogenic infection
 - gradual: TB, thyphoid fever
2 。 Character
 high grade fever: UTI, TB, malaria, drug
3 。 Pattern
 sustained/persistent: Thyphoid fever, drugs

23.  intermittent fever:
Daily spikes: Abscess, TB,
Twice-daily spikes: Leishmaniasis
Saddleback fever: Leptospirosis, dengue,
 -relapsing/ recurrent fever: , Brucellosis, Hodgkin’s
lymphoma(pel-Ebstein fever).
4 。 Antecedents
- prior to onset of fever:
 dental extraction: Infective endocarditis
 Urinary catherization: UTI, bacteremia.

24. 5 。 Associated symptoms
 Chills & rigors
 bacterial, rickettsial and protozoal disease,
 influenza, lymphoma, leukaemia, drug-induced
 Night sweats
 TB, Hodgkin’s lymphoma
 Loss of weight
 Malignancy, TB
 Cough and Dyspnoea
 Miliary TB, multiple pulmonary emboli, AIDS patient with PCP, CMV.
 Headache
 Giant cell arteritis, typhoid fever, sinusitis
 Joint pain
 RA, SLE, vasculitis

25. • Abd. Pain
• Cholangitis, biliary obstruction, perinephric
abscess, Crohn’s disease, dissecting aneuryms,
gynaecological infection
• Bone pain
• Osteomyelitis
• Sorethroat
•IM, retropharyngeal abscess, post-Streptococcal
infection
• Dysuria, rectal pain
• Prostatic abscess, UTI
• Altered bowel habit
• IBD, thyphoid fever,amoebiasis
• Skin rash
• Gonococcal infection, PAN ， NHL, dengue
fever

26. • Past Medical History
• Malignancy = leukemia, lymphoma,
• HIV infection
• DM
• IBD
• collagen vascular disease-SLE, RA, giant cell arteritis
• TB
• Heart disease: valvular heart disease
• Past Surgical History
• Post splenectomy/ post- transplantation
• Prosthetic heart valve
• Catheter, AV fistula
• Recent surgery/ operation
• Drug History
• Immunosuppressive drug/ corticosteroid
• Anticoagulants: accumulation of old blood in closed space e.g. retroperitoneal,
perisplenic
• Family History
• Anyone in family has similar problem: TB, familial Mediterranian fever

27. • Social History
• Travel
• amoebiasis, typhoid fever, malaria,
• Residental area
• malaria, leptospirosis, brucellosis
• Occupation
• farmers, veterinarian, slaughter-house workers = Brucellosis
• workers in the plastic industries = polymer-fume fever
• Contact with domestic / wild animal / birds :
• Brucellosis, psittacosis (pigeons), Leptospirosis, Q fever, Toxoplasmosis
• Diet history
• unpasteurized milk/cheese = Brucellosis
• poorly cooked pork = Trichinosis
• IVDU = HIV-AIDS related condition, endocarditis
• Sexual orientation = HIV, STD, PID
• Close contact with TB patients.

28. • General
Pattern of fever (continous, intermittent, relapsing)
Ill/not ill
Weight loss (chronic illness)
Skin rash
ExaminationExaminationExaminationExamination

29. HandsHands
• Stigmata of Infective Endocarditis
• Vasculitis changes
• Clubbing
• Presence of arthropathy
• Raynaud’s phenomenon

31. ArmsArms
Drug injection sites (ivdu)
Epitrochlear and axillary nodes (lymphoma, sarcoidosis, focal
infection)
• Head & neckHead & neck
• Feel temporal arteries (tender & thicken)
• Eyes – iritis/conjuctivitis (CT disease – reiter syndrome)
• Jaundice (ascending cholangitis)
• Fundi – choroidal tubercle (miliaryTB), roth’s spot (IE) and retinal haemorrhage
(leukaemia).
• Lymphadenopathy

32. Face & mouthFace & mouth
• Butterfly rash
• Mucous membranes
• Seborrhoic dermatitis (HIV)
• Mouth ulcers (SLE)
• Buccal candidiasis
• Teeth & tonsils infection (abscess)
• Parotid enlargement
• Ears – otitis media

33. Chest
• Bony tenderness
• Cvs – murmurs (IE, atrial myxoma), rubs
(pericarditis)
• Resp – signs of pneumonia, TB, empyema and
lung cancer

34. AbdomenAbdomen
 Rose coloured spot
(typhoid fever)
 Hepatomegaly (, hepatic
cancer, metastasis)
 Splenomegaly
(haemopoietic
malignancy, IE, malaria)
 Renal enlargement
(renal cell ca)
 Testicular enlargement (seminoma)
 Penis & scrotum – discharge/rash
• Per rectal exam – mass/tenderness
in rectum/pelvis (abscess, ca,
prostatitis)
• Vaginal Examination – collection of
pelvic pus/ Pelvic Inflammatory
Disease

35. Central Nervous System
• Signs of meningism (chronic TB meningitis)
• Focal neurological signs (brain abscess)

36. Stage 1: Laboratory investigations
Stage 1: (screening tests)
1. Full blood count
2. ESR & CRP
3. LFTs
4. Blood culture
5. Malta &widal
6. Serum virology
7. Urinalysis and culture
8. Sputum culture and sensitivity
9. Stool analysis and occult blood
10. CXR
11. Tuberculin skin test.
Investigatio
n

37. Stage 2:
1. Repeat history and examination
2. Protein electrophoresis
3. CT (chest, abdomen, pelvis)
4. Autoantibody screen (ANA, RF, ANCA, anti-dsDNA)
6. Bone marrow examination
7. Lumbar puncture
8. Consider PSA, CEA
9. Temporal artery biopsy in+50
10. HIV test counselling
Stage 2: Laboratory investigations

38. Stage 3:
1. Echocardiography
2. Radioactive
scan(Indium-labelled
WC scan – IBD,
abscesses, local sepsis)
3. Barium studies
4. IVU
5. Liver biopsy
Stage 3: further investigations
6. Exploratory laparotomy
7. Bronchoscopy

39. • Despite a diligent workup of FUO, as many as 30% of
cases remain unsolved at time of discharge.Clinicians
are then faced with the question of whether empiric
treatment is necessary. In a study looking at 199 cases
of FUO, 61 patients (30%) were discharged without a
causal diagnosis. Thirty-one of these unsolved cases had
subsidence of fever by the time of discharge.
Stage 4: theraputic trials

40. • . At 5–year follow-up, only 2 of the 61 patients had died
secondary to the FUO, pointing to the generally
favourable prognosis of untreated FUO. For this reason,
there is little role for empiric treatment of FUO. Current
literature supports empiric treatment in only three
specific situations: cases suggestive of culture–negative
endocarditis, cryptic disseminated tuberculosis &
temporal arteritis that impair vision.

41. Imaging Studies

42. Degree Illness Defination Thermoregulatory mechanisms
Mild - Sweat rash
- Heat syncope
- Heat edema
- Heat tetany
- Heat cramps
An erythematous rash due to excessive
sweating
standing for long time in hot weather
respiratory alkalosis that may occurs secondary
to hypercapnia leading to precipitation of
ionized calcium
Contraction of one muscle without relaxation of
the opposite one
Intact
Moderate Heat exhaustion Moist and clammy skin Intact
Severe Heat stroke a failure of thermoregulatory mechanisms due to hot
wet weather leading to increase in body temperature to
a lethal level > 40.6 C
Failed
Various heat illneses
Various heat illneses

43. Fever with epistaxis
1.Acute typhoid fever
2.Acute rheumatic fever
3.Infective endocarditis
4.Acute leukemia
5.Lymphoma
6.Vasculitis
7.Hemorrhagic forms of exanthemata
-Spirochetal diseases (leptospirosis, Lyme disease and relapsing fever)
-Viral hemorrhagic fever
Fever with herpes labialis
•Common cold and influenza
•Malaria
•Meningococcal meningitis
•Pneumonia

44. Fever with headache
• Meningitis and encephalitis → headache usually occipital and severe
• Influenza and common cold
• Typhoid fever → headache usually frontal dull aching
• Rift valley fever and dengue
• Malaria
Fever presenting by pains
• Eye pains → mostly viral in origin
• Backache
• Influenza
• Meningitis, encephalitis and meningoencephalitis
• Rift valley fever
• Brucellosis
• Chest pain
• Influenza
• Broncho or lobar pneumonia
• Pleurisy (FMF)

45. Fever with pallor
•Infective endocarditis
•Acute rheumatic fever
•Hemolytic crisis
•Malaria
•Malignancies e.g. acute leukemia
•Abdominal pain
•Typhoid perforation and peritonitis
•TB peritonitis
•Amoebic hepatitis
•Rift valley fever
•Referred from lobar pneumonia esp. in children