Fever of unknown origin: case presentation
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38950.394340.68 (Published 31 August 2006) Cite this as: BMJ 2006;333:484All rapid responses
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I agree with all of the above and that the rash is most likely a drug
eruption. Top
of my list for next Ix is
1)ESR
2)Mantoux
3)Don't forget Lyme titres (it doesn't always present with classical ECM
rash and
just like SLE and Syphillis has earned the right to be called "the great
pretender".
4)Isotope bone scan will probably show the knee to be a "hot spot" but
would it
advance us any further towards a diagnosis
The hardest thing to cope with from both physician and family point of
view is
that after all Ix have been completed there still may be no answer and the diagnosis may finally end up as being Pyrexia of UNKNOWN Origin.
At what stage do we decide to stop doing tests?
I have mixed emotions as my heart goes out to this unfortunate young
woman
and her family but my head loves a puzzle and I will follow progress with
much
interest.
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1.What differential diagnoses would you consider ?
A/ Still's disease, adult type/most probable diagnosis/
B/ Osteomyelitis /less likely/
C/ Another collagen disease /less likely/
D/ Malignancy /highly unlikely, thank God/
2. What further investigations should be carried out ?
It seems to me that this young lady has been thoroughly and
meticuously investigated. There are not many, if at all any test(s) that
have not been done. Looking at the all the investigations ordered and done, she
was probably initially admitted under Infectious Disease team. They did
rule out most of the infective causes. It must be probably them who started
IV antibiotic treatment on the background of what was initially looking as
a positive blood culture. Most of other potential causes (malignancy, collagen vascular disease) have been almost ruled out as
well. Internal Medicine team seems to be very good and well coordinated in
that hospital. I have feeling that Rheumatology team made important input
to the final diagnosis for this young lady.
The only test that I would consider adding is X-ray of the right knee
joint and distal femur. Just to rule out osteomyelitis or any other
unexpected joint/bone problem in that area that is already clinically
tender.
ESR will definitely be high and I would not be pushing very hard for it. I
do not think joint aspiration is necessary.
3. What would you tell the patient and her parents given that tests
have not revealed a clear diagnosis at this stage ?
I would tell them that at this stage the definitive diagnosis is not
clear yet. However, their daughter may be having rare type of disease
called Still's disease. But before we definitely confirm it as a such (this is diagnosed after other disease are excluded), it is important to
get joint opinion from Rheumatology and Infectious Disease team. The
answer is probably somewhere there....
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1/ Dengue Fever is diagnosis
diagnosis may be masked by antibiotics
negative blood firm does not exclude malaria
negative blood cultures do not exclude septicaemia such as meningococcal
or pneumococcal
2/ detection of specific antibodies
significanl rise in serial Dengue antibody titres
platelet count checked for significant thrombocytopenia
3/She is well on way to recovery which will be complete leaving no after
effects. Full recovery often takes 6 months and can by accompanied with
depression.
Natural that family feel frustrated since they need a specific doctor
for help, encouragement and supervision.
No aspirin or non-steroidal inflammatory drugs since bleeding tendency. US
use guaiac test for occult blood.
Mussolini banished malaria from Italy by drainage of extensive
swamps. A remarkable feat but global warming has
brought the mosquito back. World maps do not show the return
but the shape does not allow vivid illumination
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19 F with fever, raised inflammatory markers and hypocomplementemia-
Differential diagnosis here are-
1. Immune complex disease- SLE or glomerulonephritis
2. Most common infections have been ruled out- however consideration
should be given to tuberculosis, intrabdominal collections and pelvic
inflammatory disease, gonorhoea etc (sexual hx should be taken again)
3. Lymphomas
4. Adult onset Still's disease (cannot explain low complement levels)
Investigations suggested-
1. Urine for microscopy and culture
2. Cervical culture
3. CXR
4. CT scan abdomen/Pelvis
5. Ferritin
Obviously distressing time for everyone but would not discuss cancer
at this stage.
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Patients with FUO are elusive and challenging clinical cases.
FUO is an illness of greater than 3 week's duration.
Fever higher than 38.3oC on several occasions.
No diagnosis established despite 1 week of intensive evaluation.
Common causes:
Infections cause 30-40% of the cases of FUO. Most common cause.
Neoplasms cause 20-30% of the cases of FUO.
Rheumatologic diseases cause 10-20% of the cases of FUO.
Miscellaneous conditions cause 15-20% of the cases of FUO.
5-15% of FUO's remain undiagnosed. Usually these FUO's resolve on their
own. Most of these patients have a relatively good prognosis
A thorough history is very important. This history should include
information concerning alcohol consumption, medications, occupational
history, pets, travel, familial disorders, and previous illnesses.
Examples of diseases for which clues are provided include:
Amoebiasis- leading to liver abscess, foreign travel has usually occurred
in the recent past
Mediterranean fever- family history is very helpful
Psittacosis- patient has mentioned contact with parakeets.
Metastatic cancer- patient mentions previous cancer or cancer treatment.
Drug fever- patient mentions the use of various medications.
Prior inflammatory processes in the abdomen can lead to intraabdominal
abscesses- patient with Crohn's disease or prior episode with
cholecystitis, diverticulitis, or appendicitis.
Comprehensive History
Repeated Physical Examinations
Complete blood count, including differential and platelet count
Routine blood chemistry, including lactate dehydrogenase, bilirubin, and
liver enzymes.
Urinalysis, including microscopic examination
Antinuclear antibodies
Rheumatoid factor
Angiotensin converting enzyme
Routine blood cultures (X3) while not receiving antibiotics.
Cytomegalovirus IgM antibodies or virus detection in blood.
Heterophile antibody test in children and young adults.
Tuberculin skin test.
CT of abdomen or radionuclide scan.
HIV antibodies or virus detection assay.
Further evaluation of any abnormalities detected by above tests.
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if in doubt sbe, stop antiobiotics, repeat echos
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The definite features here are:
1. Documented persistent fever
2. Elevated inflammatory markers
3. Low C3/lowish C4
4. Mild liver function derangement
Differential diagnosis of fever of unknown origin can be divided
into:
Infection
Malignancy
Autoimmune
Miscellaneous, to include drug induced, hepatitis, sarcoidosis
In terms of infection, the pretreatment with antibiotics makes
culture results difficult to interpret, but most things have already been
considered. One would have to think about TB and HIV, but neither of these
would explain the complement levels. I note there are no urine culture
results.
Malignancy must be considered, but imaging is all normal and this
wouldn't explain the complement levels either.
The low complement levels suggest complement activation which
therefore makes a rheumatological cause seem most likely. Autoantibody
screen is negative which rules out most common things, but returning to
the history this episode was preceded by a sore throat, which makes a post
-streptococcal syndrome a strong possibility. ASOT can be negative in
these cases early on and therefore might be worth repeating. The addition
of an anti-DNAse B or anti-hyaluronidase test might be of use. Urinalysis
might also be of use.
Even if all tests were negative, the prognosis is frequently good, as
far as I am aware.
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In essence this is a 19 year old girl with:
Persistent fever, transient rash and monoarthralgia.
Elevated acute phase reactants ( C-Reactive Protein, Neutrophilia).
Raised Gamma Glutamyl Transferase(GGT) with otherwise normal liver
function.
Low complement levels.
Differential Diagnosis:
Running this across the classical diagnostic sieve:
1. Infection: Most of the common infections have been ruled out.
Others that could be considered include:
• Tuberculosis: not a typical clinical picture and no h/o contact ,
but needs to be considered.
• A mild case of “chronic” meningococcemia cant be ruled out,
although 3 weeks is long enough for the disease to either worsen or
resolve
• Rubella: fever, rash and arthralgia , but rash not typical
.Prolonged fever unlikely.
• Hepatitis/Cholangitis; could explain fever and elevated GGT, but no
abdominal symptoms or jaundice.
• Some cases of Enteric fever may not have positive blood cultures.
Other “exotic” infections don’t seem to fit the bill.
2. Connective tissue/auto-immune disease:
• Juvenile Rheumatoid Arthritis is a strong possibility. The
evanescent rash is typical. However conventional wisdom dictates that when
there is rash, there is usually polyarthralgia.
• Systemic Lupus Erythematosus(SLE): Also a strong contender. The
altered liver function and the low complement levels are consistent with
SLE.
• Auto-immune Hepatitis
• Sclerosing cholangitis: can explain fever and altered GGT.
3. Immune deficiency: Possible coagulase-negative staphylococcal
sepsis in association with low complement levels warrant further testing.
4.. Maligancies: Hodgkins and pre-leukaemic leukaemia can present
like this with a normal blood film as can some renal tumours
5. Endocrine: Thyrotoxicosis should be considered in view of
tachycardia. Can be associated with auto-immune diseases
6.. Others: Familial Mediterranean fever
Juvenile Rheumatoid Arthritis (Systemic Onset) and SLE are highest on
the list of possibilities.
Further investigations:
1. ESR
2. PCR for Meningococcus
3. Mantoux Test
4. Urine dipstick /microscopy to look for haematuria/casts.
5. Renal function tests
6. Thyroid Function Test
7. Chest X ray
8. Abdominal Ultrasound.
9. Immune studies:A repeat auto-immune screen , also looking at anti-LKM
antibodies;
10. Complement pathway and immunoglobulins
11. If remains febrile: Bone marrow aspirate may be considered. Bone
marrow can also be cultured for Salmonella
What to tell the patient/parents
This is obviously a distressing time for the patient and her parents.
I would tell them that many of the common causes of fever have been ruled
out and that we are giving her adequate antibiotic cover for most of the
bacteria. We might need to do more specialised tests to find out the exact
cause. As always this is more likely to be an uncommon presentation of a
common disease than vice versa. If all tests are negative, a bone marrow
aspiration may have to be considered. Possibility of occult malignancy,
though frightening has to be mentioned.
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One classical cause of PUO from the Mediterranean area not yet
excluded is typhoid/paratyphoid, and the appropriate serology is needed.
The initial antibiotics would probably render blood cultures falsely
negative and the rash could well be simply drug-associated. A history of
mosquito bites is probably a red herring as malaria is now very unusual in
Italy and the syptoms/signs are not those of more recent exotic diagnoses
such as viral haemorrhagic or encephalitic fevers.
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PUO
The following would be my diffrential diagnosis, in the order of
priority.
1) Still's disease (young girl, spiking fever, arthralgia,
neutrophilia, negative antibodies). Very high serum ferritn would be
complementary. After ruling out infection a trial of steroids after
discussion with the family.
2) I would rule out osteomyelitis by considering MRI of the knee joint
and femur / white cell scan, especially in view of neutrophilic
leucocytosis, staphylococcus in blood culture and knee tenderness before
starting steroid trial.
3) I would do ultrasound of abdomen /CT abdomen to rule out occult
collection, adenopathy or hepatosplenomegaly.
4) Auto immune processs is my last consideration and therefore if the
liver abnormalities are persistent liver biopsy.
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