Pyrexia of Unknown Origin, Diseases, Yr 3, Wk 1

Question 1

Give the definition of a fever:

Answer 1

• Elevation of body temperature above normal (37 C)
• Variation of up to 0.8C daily (circadian rhythm): low in early morning, high in early evening
• Part of the systemic inflammatory response syndrome (SIRS)

Question 2

What are pyrogens

Answer 2

• Substances which CAUSE FEVER
• endogenous e.g. cytokines
• exogenous e.g. endotoxins from gram -ve bacteria
• act at hypothalamic thermoregulatory centre to cause reduced heat loss and hence fever

(pyrogens generate the production of endogenons???)

Question 3

What body structure controls the core body temperature?

Answer 3

the hypothalamus

Question 4

What mechanisms does the body perform to conserve heat?

Answer 4

shivering and vasoconstriction

Question 5

How does the body lose heat?

Answer 5

Vasodilation

Question 6

What does NEWS chart stand for?

Answer 6

National Early Warning chart

Question 7

Describe the journey from a suspected bacterial infection to septic shock:

Answer 7

suspected bacterial infection –> systemic inflammatory response syndrome –> sepsis (SIRS + evidence of bacterial infection) –> severe sepsis (organ underperfusion- oliguria, confusion, acidosis) –> septic shock (irreversible hypotension despite fluid resuscitation)

(One of the features of sepsis is an inflammatory response syndrome)
(SIRS?: Pulse >90, Temp <35 or >38, RR> 20, WCC > 12 or <5)

Question 8

Pyrexia of Unknown Origin- Definitions:

a) Give the Petersdorf and Besson (1961) definition:
b) Give the modern definition

Answer 8

a) Petersdorf and Beeson (1961): temp >38.3C, recorded on MULTIPLE occassions, present for AT LEAST 3 WEEKS, Defied diagnosis after one week of hospital evaluation

b) Modern Definition: is broader i.e. No diagnosis after
- 3 outpatient visits or
- 3 days in hospital or
- One week of outpatient investigation

(-Above 38 is relevant to our current definition

• If undiagnosed after 3 days in hospital= pyrexia of unknown origin
• It has to be going on for longer than 3 weeks and has to have defied investigations)

Question 9

Give the Definitions of Pyrexia of Unknown Origin:

Answer 9

• Classical PUO
• Nosocomial PUO: develops in hospital, undiagnosed after 3 days
• Neutropenic PUO: undiagnosed fever in patient with NEURTROPHILS <500/mm3
• HIV-associated PUO: fever in a patient with HIV infection- present and undiagnosed for more than 3 days in an inpatient or 4 weeks in an outpatient

(-nosocomial means hospital related; will probably be an infection
-Haematology patients often have neutropenic fevers- low WBCs)

Question 10

List some causes of HIV-related PUO:

Answer 10

• mycobacterium tuberculosis
• Mycobcaterium avium
• cytomegalovirus

(-often infectious but multiple infections

Question 11

List the 4 categories of causes of PUO

Answer 11

-infection
-neoplasm
-collagen
-miscallaneous
(-undiagnosed)

Question 12

List some of the:

a) Infection causes
b) Malignancy causes (neoplasm)
- Inflammatory causes
- Other causes

Answer 12

a) TB, HIV, endocarditis
b) Lymphoma, Metastatic disease, Renal Ca
c) Temporal arteritis, inflammatory bowel disease, SLE, vasculitis
d) Drug fevers, venous thrombosis, sarcoidosis

(-examples for exam questions

• TB is difficult to diagnose as it doesn’t present with a positive culture
• Any malignancy can cause fevers)

Question 13

PUO- Assessment: What should be asked about in the History that you take?

Answer 13

• Travel
• Occupation and hobbies- exposure to allergens
• Family history and age of onset- familial fevers e.g. tumour necrosis factor receptor- associated periodic syndrome- TRAPS
• PMH and surgical history
• Drug history

Question 14

What should you look at on examination?

Answer 14

• Examination- be thorough:
• Including skin, eyes, oral cavity, nails and lymph nodes
• Repeated examination often worthwhile

(-Travel history for something like relapsing malaria
-TRAPs results in periods of high fever due to cytokine problem at the receptors)

Question 15

PUO- List some of the initial investigations that you would carry out:

Answer 15

• Simple things first:
• CXR,
• Urinanalysis and urine microscopy,
• FBC and differential WCC
• C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR)
• Blood cultures taken at times of fevers
• Urea, creatinine, electrolytes, Liver function tests

(-Blood in the urine may indicate inflammation of small vessels in the renal capillary circulation

• CRP and ESR are both very sensitive for inflammation
• High ESR: temporal arteritis
• Prolonged blood cultures)

Question 16

PUO - further investigations:
I will not list some indications for further investigations and I would like you to answer with the Investigations that you would carry out with each indication:

(Histories may guide the investigations that you choose to do. A new murmur should prompt you to look for endocarditis)

a) Tropical travel
b) New murmur
c) Headaches
d) Micro. Haematuria
e) TB contact
f) Drug misuse

Answer 16

a) Tropical travel: -Blood for malarial parasites, dengue; less likely if > 21 days since return
- HIV, bone marrow for leishmaniasis

b) New murmur: echocardiography (trans-oesophageal echo may be needed)
c) Headaches: Temporal artery biopsy (TA) or CT PET
d) Micro. Haematuria: Auto-antibodies +/- renal biopsy, (polyarteritis) ultrasound (renal Ca)
e) TB contact: Sputum smear, bone marrow, mantoux
f) Drug misuse: Screen for blood-borne viruses

Question 17

Describe the use of imaging techniques in PUO:

Answer 17

• more valuable if they have some “direction”
• cannot always differentiate between infection and inflammation
• anatomical changes may not develop in immunocompromised hosts (e.g. neutropenic patients and abscesses)

Question 18

Give an imaging technique used in PUO-

Answer 18

CT PET scan

(-CT- Positron emission tomography

• Way to monitor patients response to chemo and useful in diagnosis of PUO
• The arrows = hot spots, where the contrast has been taken up more and thus it is at subclavian artery and thus shows arteritis (this is in reference to a picture of a PET CT scan on slide 18 of the PUO lecture)

Question 19

List some invasive investigations that can be used in PUO:

Answer 19

• obtain tissue for culture and histology
• bone marrow biopsy (lymphoma) and liver often examined as part of blind investigation: malignancy, TB, lymphoma
• Diagnostic laparotomy (rarely necessary)

Question 20

List some of the treatments used in PUO:

Answer 20

• Therapeutic trial: rarely used, suspected mycobacterial infection (anti-tuberculous therapy), suspected vasculitis or conn. tissue disorder (steroids)
• Diagnosis of Mtb unlikely if no response to chemotherapy within 2 weeks
• Response of temproal arteritis to steroids is dramatic- usually within 48 hrs

(-therapeutic trial still used in TB infection- anti-tuberculous therapy
-Steroids in temporal arteritis)

Question 21

Describe Fabricated Fever:

Answer 21

• fever is real but self-induced
• self injection common
• microbiology may be strongest clue e.g. multiple different organisms on blood culture at different times
• Patient often continues despite being very sick
• Psychiatric expertise should be sought rather than direct confrontation

Question 22

PUO- Outcomes: Expand:

Answer 22

• Spontaneous resolution of PUO: commoner in young compared with old patient
• Some patients with no diagnosis respond to NSAIDs or steroids (steroid responsive PUO)
• Regular re-appraisal required (the answer may not become apparent for many months)

Question 23

Give a summary of PUO:

Answer 23

-PUO- fevers >38C need to be present repeatedly for weeks

-Infection only accounts for less than 1 in 4 cases
:malignancy, inflammatory and other causes

• Imaging techniques and blood tests may NOT yield the diagnosis
• Spontaneous recovery more likely in younger patients