SPR L5 Fever of Unknown Origin

Question 1

Learning Outcomes

Answer 1

• Define FUO (Classical and risk group).
• Describe the diagnostic evaluation of FUO.
• List the key pathogens in specific patient groups.
• Describe the presentation, investigation and antibiotic treatment of infective endocarditis

Question 2

What is a fever, what is it’s role?

Answer 2

Fever is the body’s response to exogenous and endogenous pyrogens. It is a common symptom and may have a protective effect.

The cause is usually immediately apparent or is discovered within a few days, or the temperature settles spontaneously.

Question 3

Fever of Unknown Origin (FUO)

Give a definition

Answer 3

if the patient’s fever is:

>38.3°C on several occasions and continues for more than 3 weeks despite 1 week of intensive evaluation

Then a provisional diagnosis of ‘fever of unknown origin’ (FUO) is made.

Question 4

1. What is the most common cause of FUO?
2. What are the important non-infectious causes?
3. The cause of fever remains undiagnosed in what percentage of FUO patients?

Answer 4

1. Infections
2. Malignancies and Autoimmune diseases.
   1. Non-infectious causes need to be differentiated from infections during the investigation of a patient with a FUO
3. 5-15%

Question 5

What are the main categories of FUO?

Answer 5

• Classical
• Nosocomial
• Neutropenic
• HIV associated

Question 6

Define the following

1. Classical FUO
2. Nosocomial (hospital acquired FUO)
3. Neutropenic FUO
4. HIV Associated FUO

What is an important consideration to be made?

Answer 6

1. –>38.3°C, several times, more than 3 weeks duration
2. –>38.3°C, several times, hospitalised
3. –>38.3°C, several occasions; neutrophil count
4. –>38.3°C, HIV positive

The classical definition of FUO requires fever >3 weeks, but in compromised patients infections frequently progress rapidly because of inadequate host defences. Consequently the pace of the investigations needs to be rapid if appropriate therapy is to be initiated.

Question 7

FUO

Give Bacterial examples

Answer 7

Tuberculosis

Enteric Fevers

Osteomyelitic

Endocarditis

Question 8

FUO

Give examples of the following causes

1. Parasitic
2. Fungal
3. Viral

Answer 8

1. Malaria - plasmodium species
2. Candidiasis - Candida Albicans
3. AIDS

Question 9

What are the two main groups that Aetiology can be divided into?

Answer 9

• infections such as tuberculosis and typhoid fever caused by specific pathogens
• infections such as urinary tract infections, biliary tract infections and abscesses, which can be caused by a variety of different pathogens.

Question 10

Significant infection may be present in the absence of fever in some groups of patient, give examples of these groups

What else needs to be looked for?

Answer 10

• seriously ill neonates
• the elderly
• patients with uremia
• patients receiving corticosteroids
• those taking antipyretic drugs continuously.

Other signs of infection

Question 11

Diagnostic evaluation of FUO

1. The list of infective agents is long - so what is the first stage of investigation to act as pointers to subsequent specific diagnostic tests?
2. History taking - what questions are important to ask?
3. Why is a travel history important?

Answer 11

1. the patient’s history and results of physical examination and screening tests
2. questions about travel, occupation, hobbies, exposure to animals and known infectious hazards, antibiotic therapy within the previous 2 months, substance misuse and other habits.
3. Some of the infections are zoonoses (e.g. leptospirosis, spotted fevers), whereas others are vector-borne (e.g. malaria, trypanosomiasis) and/or of limited geographic distribution (e.g. histoplasmosis).

Question 12

FUO

Outline the examination

Answer 12

• Search for a focus of infection
• the skin, eyes, lymph nodes and abdomen should be examined
• the heart should be auscultated.

Question 13

• *Minimum Diagnostic Evaluation Necessary
• Classical Fever Of Unknown Origin***

1. Outline the history
2. Outline the examination
3. What tests should be done?

Answer 13

1. Comprehensive history (including travel, STI risk, hobbies, pets, occupation etc.)
2. Comprehensive physical examination (including temporal arteries, ENT, rectal examination, etc.)
3. Routine blood tests (FBP, ESR,CRP)‏, Cultures of blood, urine, Chest radiograph & Abdominal ultrasound, Antinuclear and antineutrophilic cytoplasmic antibodies, rheumatoid factor

Question 14

Further evaluation

This is directed by any abnormalities detected by tests

Give examples of how further evaluation of FUO could be carried out

Answer 14

• HIV antibodies depending on detailed history
• CMV-IgM and EBV serology in case of abnormal differential WBC count
• Abdominal or chest helical CT scan
• Echocardiography in case of cardiac murmur

Question 15

FUO

Nosocomial

What are the causal agents in the following?

1. Vascular-line related
2. Cholecystitis and pancreatitis
3. Pneumonia (related to assisted ventilation
4. Postoperative abscesses eg. intra-abdominal

Answer 15

1. Staphylococci
2. Gram-negative rods
3. Gram-negative rods, including Pseudomonas
4. Gram-negative rods and anaerobes

Question 16

• *FUO**
• Neutropenic*
• What are the typical causal agents in the following?*
  1. Vascular-line related
  2. Oral infection
  3. Pneumonia
  4. Soft tissue, e.g. perianal abscesses

Answer 16

1. Staphylococci
2. Candida, herpes simplex virus
3. Gram-negative rods, Candida, Aspergillus, CMV
4. Mixed aerobes and anaerobes

Question 17

FUO

• HIV Associated*
• What are the typical causal agents in the following?*
  1. Respiratory tract
  2. Central nervous system
  3. Gastrointestinal tract
  4. Genital tract

Answer 17

1. Pneumocystis, Mycobacterium
2. Toxoplasma
3. Salmonella, Campylobacter, Shigella
4. Treponema pallidum, Neisseria gonorrhoeae

Question 18

Endocarditis

1. Outline the pathogenesis of endogenous infection
2. What is the most common cause?
   
   1. How does this arise?
3. Describe the pathological processes involved?

Answer 18

1. endogenous infection acquired when organisms entering the bloodstream establish themselves on the heart valves.
2. Most commonly streptococci from the oral flora enter the bloodstream,
   
   1. for example during dental procedures or vigorous teeth cleaning or flossing
3. fibrin-platelet vegetations are present on damaged valves before the organisms implant,

organisms multiply and attract further fibrin and platelet deposition.

Question 19

• *Infective endocarditis**
• Clinical presentation*

1. What do the majority of patients have?
2. What can cause this condition?

Answer 19

1. The majority of patients have a pre-existing heart defect, either congenital or acquired (e.g. as a result of rheumatic fever), or a prosthetic heart valve in situ. However, the patient may be unaware of any defect before the infection.
2. Almost any organism can cause endocarditis, but native valves are usually infected by oral streptococci and staphylococci

Question 20

• *Infective endocarditis**
• Clinical presentation*

1. Give the most common clinical findings
2. What four processes do the varied signs and symptoms relate to?
3. Give examples of S+Ss that may be seen in addition to the ones mentioned above

Answer 20

1. A patient with infective endocarditis almost always has a fever and a heart murmur

2.

• the infectious process on the valve and local intracardiac complications
• septic embolisation
• bacteremia, often with metastatic foci of infection
• circulating immune complexes and other factors.

3.

• may also complain of non-specific symptoms such as anorexia, weight loss, malaise, chills, nausea, vomiting and night sweats, symptoms that are common to many of the causes of FUO listed in.
• Peripheral manifestations may also be evident in the form of splinter hemorrhages and Osler’s nodes
• Microscopic haematuria due to immune complex deposition in the kidney is characteristic.

Question 21

Infective Endocarditis

1. Why was the mortality rate so high in previous years?
2. What is the mortality rate currently?
3. What is an issue?
4. How long does eradication take?
   
   1. outline some of the difficulties

Answer 21

1. Before the advent of antibiotics infective endocarditis had a mortality of 100%.
2. The mortality of infective endocarditis is 20-50% despite treatment with antibiotics
3. Antibiotic resistance has become an increasing issue
4. Even with appropriate treatment, eradication takes several weeks to achieve, and relapse is not uncommon.
   
   1. inaccessibility of the organisms within the vegetations (both to antibiotics and to host defenses)
   2. the organism’s high population density and relatively slow rate of multiplication
   3. Antibiotics work best on rapidly dividing bacteria

Question 22

Infective Endocarditis - Organisms

Outline the main organisms involved

Answer 22

• native valve
  
  • oral streptococci (viridans group) such as Streptococcus sanguis, Strep. oralis and Strep. mitis and by Staph. aureus.
  • Intravenous drug misusers have the added complication of infection due to organisms they inject into themselves. (gram negatives)‏
• early prosthetic valve
  
  • Coagulase-negative staphylococci are common causes of endocarditis and are probably acquired at the time of surgery.
• Late prosthetic valve
  
  • more than 3 months after cardiac surgery
  • like those causing native valve endocarditis

Question 23

Infective endocarditis investigation

1. What is the most important test?
   
   1. How should this be carried out?
2. What is important in investigation to ensure that antibiotic susceptibility tests can be performed and optimum therapy prescribed?

Answer 23

1. Blood culture
   
   1. Ideally, three separate samples of blood should be collected within a 24-h period and before antimicrobial therapy is administered.
2. ​Isolation of the causative organism

Question 24

Culture negative endocarditis

Outline some of the issues

Answer 24

• Difficult to grow organisms
• Antibiotic presence
• Q fever (Coxiella burnetii) - was quite common in NI
• Long list of others

Question 25

Typical antibiotic treatment of infective endocarditis

1. What does the antibiotic treatment depend upon?
2. What two levels is this guided by?
3. Outline treatment for the following
   
   1. Viridans streptococci
   2. Enterococci
   3. Staphylococci
4. How long is treatment for?
   
   1. What needs to be monitored?

Answer 25

1. depends upon the susceptibility of the organism
2. MBC and MIC​
3. Treatment
   
   1. For penicillin-susceptible streptococci, high dose penicillin is the treatment of choice.

Penicillin and aminoglycoside

2. Amoxicillin and aminoglycoside
3. Flucloxicillin and aminoglycoside

Vancomicin

4. Treat for 4 weeks (6 weeks if prosthetic valve)
   
   1. monitor CRP for response to treatment

Question 26

Case

75 years-old lady presents with

–1 week of Malaise, nausea, loss of appetite

–Past history of aortic valve surgery

On examination, Flushed, temp=38.2oC, Systolic murmur

What investigations?

Answer 26

Systemic symtoms, Fever, Old murmor?

Blood cultures – 3 sets within 24 hrs before antibiotics are started

Depending how well she is, could delay starting antibiotics until sensitivities have been carried out

Want to take these when she has a fever, and when it has just started (if the fever is coming and going)

Big priority – blood culutres taken and taken well, taken when febrile. Can provide tailoring of antibiotic therapy