Seminar

1. Maj (Dr) Manoj Balachandran
Medical Officer
Army Medical Corps

2.  Consistently elevated body temperature of
more than 37.5 degree celsius for more than
2 weeks with no diagnosis after initial
investigation (e.g. after a week’s appraisal in
the hospital. (Davidson)
 1) Fever higher than 101 degree F on several
occasions. (2) A duration of more than 3
weeks. (3) Failure to reach a provisional
diagnosis after one week of inpatient
investigations or by three outpatient visits.
(Petersdorf and Beeson, 1961)

3.  Fever persisting for more than 3 weeks
 Documented temperature of more than 101
degree F on several occasions.
 Uncertain diagnosis after extensive evaluation
in hospital for 1 week.
 PUO of 2 weeks no diagnosis could be made.

4.  Types:
 A. Pyrexia of Unknown Origin:
 1. Daily or Intermittent Fever >= 38.3 C (101F)
 2. Duration for three consecutive weeks
 3. No source by clinical evaluation
a. Hospital evaluation for 3 days (previously 7)
or
b. Intensive outpatient evaluation for 7 days or
c. Three outpatient visits

5.  B. Nosocomial Fever or Unknown
Origin:
 1. Daily or Intermittent Fever >= 38.3 C (101F)
 2. Hospitalized >1 day without fever on
admission
 3. Fever evaluation of 3 days or more
 C. Immune-Deficient Pyrexia of
Unknown Origin:
 1. Daily or Intermittent Fever >=38.3 C (101F)
 2. Neutrophil count < 500 per mm3
 3. Fever evaluation of 3 days or more

6.  D. HIV-Associated Fever of
Unknown Origin:
 1. Daily or Intermittent Fever >= 38.3 C
(101F)
 2. Outpatient Fever >4 weeks or
 3. Inpatient fever >3 days

9.  Infections (30%)
 a) Sepsis- Intra-abdominal abscess,
cholecystitis/cholangitis, Urinary tract
infection, prostatitis, Dental and sinus
infections, Bone and joint infections
 b) Infectious diseases, e.g. malaria, dengue,
brucellosis
 c) Enteric fevers
 d) Infective endocarditis
 e) Tuberculosis (particularly extrapulmonary)

10.  f) Viral infections (CMV, Epstein-Barr
virus(EBV), HIV and toxoplasmosis
 g) Fungal infections

11.  Malignancy (20%)
 a) Lymphoma and myeloma
 b) Leukaemia
 c) Solid tumours (renal, liver, colon, stomach,
pancreas)

12.  Connective tissue disorders (15%)
 a) Rheumatic fever
 b) Vasculitic disorders (incl. polyarteritis
nodosa and rheumatoid disease with
vasculitis)
 c) Temporal arteritis/ polymyalgia rheumatica
 d) Systemic lupus erythematosis (SLE)
 e) Still’s disease
 f) Polymyositis

13.  Miscellaneous (20%)
 a) Inflammatory bowel disease
 b) Liver disease: cirrhosis and granulomatous
hepatitis
 c) Sarcoidosis
 d) Drug reactions
 e) Atrial myxoma
 f) Thyrotoxicosis
 g) Hypothalamic lesions
 h) Familial Mediterranean fever
 No diagnosis or resolves spontaneously (15%)

14.  Major infectious diseases in India- (i) Food or
waterborne diseases: Bacterial diarrhoea,
Hepatitis A and E and Typhoid fever. (ii)
Vectorborne diseases: Dengue fever, Japanese
encephalitis and malaria (iii) Water contact
disease: Leptospirosis (iv) Animal contact
disease: Rabies.
 Personal and social history- Sexual history,
illicit drug usage (injection)- HIV, hepatitis B
and C, infective endocarditis.

15.  Common diseases: UTI, Amoebic abscess,
Tuberculosis
 Occupational or recreational exposure-
birds(psittacosis) or animals (toxoplasmosis,
Q fever, brucellosis, leptospirosis) and
consumption of unpasteurised milk or milk
products (brucellosis and Q fever)

16.  Intermittent- Fever is present only for several
hours and always touches the baseline sometime
during the day. It has three subdivisions:
 (i) Quotidian- The paroxysm of fever occurs daily
e.g. Double infection of P. vivax, Pent-up pus
anywhere in the body, Tuberculosis.
 (ii) Tertian- When the paroxysm occurs on
alternate days (ie, a gap of 48 hours ) e.g. Benign
tertian malaria, Malignant tertian malaria.
 (iii) Quartan- When two days intervene between
consecutive paroxysmal attacks (ie, a gap of 72
hours) e.g. Quartan malaria (P. malariae)

17.  Continued- Fever does not fluctuate more
than 1 degree C (1.5 degree F) during the 24
hours period and never touches the baseline.
E.g. Lobar pneumonia, Second week of
enteric fever, Miliary tuberculosis,
Meningococcal meningitis, Rheumatic fever.
 Remittent- Daily fluctuation of fever is more
than 2 degree C (3 degree F) and it never
touches the baseline. E.g. Amoebic liver
abscess, sometimes in urinary tract infection,
Acute bronchopneumonia, Acute tonsillitis,
Bacteraemia, septicaemia, pyaemia.

18.  Rash or skin nodules
 a) Vasculitic lesions: cutaneous or systemic
vasculitic disorders, granulomatous disease,
lymphoma, acute endocarditis and drug
reactions
 b) Nodular skin lesions: disseminated fungal
infection and malignancy. Cancers of the
colon, bladder and ovary often metastasise to
the abdominal wall; nodules on the scalp or
chest wall- breast or bronchial primary.
Leukaemia and lymphoma- papules, nodules
and plaques.

19.  Eyes
 a) Red eye: conjunctivitis, scleritis or uveitis.
Immune complex disorders, connective tissue
disease, Reiter’s syndrome, reactive arthritis
etc.
 b) Conjunctival petechiae: endocarditis
 c) Proptosis: Thyroid eye disease. If unilateral,
orbital infiltration by malignancy or
granulomatous disease

20.  Optic fundi- haemorrhages and exudates
(vasculitis), Roth’s spots (endocarditis),
choroidal tubercles and disseminated fungal
lesions
 Upper airways- nasal obstruction or bleeding,
sinus pain or swelling (granulomatous
disease, malignancy)
 Rectal examination- Perianal disease (
inflammatory bowel disease), Local sepsis or
abscess, Rectal carcinoma, Prostatic
malignancy or prostatitis

21.  In order of increasing complexity and
invasiveness.
Tests used in the first week of investigating PUO
•Full blood count and differential
•Erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP)
•Serum ferritin
•Urea, creatinine and electrolytes
•Liver function tests and gamma-glutamyl transferase
•Blood glucose
•Bone biochemistry
•Creatinine phosphokinase
•Malaria blood films (if travel history)
•Urinalysis
•Midstream urine (MSU) for microscopy and culture.

22. •Faeces culture
•Sputum for routine microscopy and culture, and microscopy
and culture for mycobacteria
•Blood cultures (3)
•Chest radiograph
•Ultrasound examination of abdomen
•Electrocardiogram (ECG)

23. Serological investigations in the management of PUO
Viral- CMV, EBV, HIV, Hepatitis A, B and C, Parvovirus
If travel history: Arbovirus
Bacterial- Chlamydia, Q fever, Brucellosis, Mycoplasma,
Syphilis, Leptospirosis, Lyme disease, Yersinia,
Antistreptolysin O (ASO) titre
If travel history: Rickettsia, Meliodosis, Relapsing fever,
Bartonella
Fungal- Cryptococcus (antigen detection)
If travel history: Histoplasmosis, Coccidiodomycosis
Protozoan and parasitic- Toxoplasmosis
If travel history: Schistosomiasis, Amoebiasis, Leishmaniasis,
Trypanosomiasis

24. Further Non-invasive investigations in the management
of PUO
Nucleic acid detection (polymerase chain reaction, PCR)
•Increasingly used e.g. for TB, herpes simplex virus
(HSV), CMV, HIV, parvovirus, dengue, Toxoplasma,
Whipple’s disease
Immunology
• Autoantibody screen, including anti-double stranded
DNA, anti-neutrophil cytoplasmic antibody (ANCA)
•Immunoglobulins
•Compliment (C3 AND C4) levels
•Cryoglobulins
Tuberculosis screening tests
•Tuberculin (Mantoux) test
•Early morning specimen of urine (EMSU) (3) for
mycobacterial microscopy and culture
Imaging techniques
•Ultrasound of abdomen- Liver tumour or metastasis,
liver abscess, Dilated intrahepatic bile ducts, Renal
tumour, abscess or hydronephrosis, Ascites

25. Echocardiogram
•Vegetations
•Atrial myxoma
•Intracardiac thrombus
CT/MRI of thorax and abdomen
•Enlarged lymph nodes
•Organomegaly
•Lung and liver metastasis/ primary tumours
•Tumours and abscesses
Limited skeletal survey
•Multiple myeloma
•Bone metastases
Isotope bone scan
•Malignancy
•Osteomyelitis/ septic arthritis
Labelled white cell scan
•Abscesses/local sepsis
•Inflammatory bowel disease

26. Factitious fever
Fever or appearance of fever, which is engineered by
the patient. The desired effect is usually
accomplished by manipulating the thermometer
and/or temperature chart, or by inducing infection by
the self injection of contaminated materials.
Female patients, those with medical and nursing
background, Munchausen’s syndrome.

27. CLUES TO THE DIAGNOSIS OF FACTITIOUS FEVER
•A patient who looks well
•Bizarre temperature chart with absence of diurnal variation and/or
temperature-related changes in pulse rate
•Temperature >41 degree C
•Absence of sweating during defervescence
•Normal ESR and CRP despite high fever
•Evidence of self-injection or self harm
•Useful methods for the detection of factitious fever include supervised
(observed) temperature measurement, and measuring the temperature of
freshly voided urine

28.  Liver biopsy- Tuberculosis, Lymphoma, or
granulomatous disease including Sarcoidosis.
Biopsy material to be sent for culture.
Serological diagnosis is preferred in Glandular
fever syndromes, Q fever and Syphilis.
 Bone marrow biopsy- Diagnostic yield 15%.
Haematological malignancy, Myelodysplasia,
Tuberculosis, Brucellosis, Enteric fever or
Visceral Leishmaniasis. Culture and
microscopy.

29.  Temporal artery biopsy- Patients >50 years,
if ESR is not significantly elevated. 5 cm
section of artery for better diagnostic yield.
Prognosis in PUO
 Overall mortality is 30-40%
 <55 years: 5%
 >55 years: 30%. Malignancy
 If no cause is found: mortality low and fever
settles spontaneously.

30. Case history
A 25-year-old male is seen in the A&E department, at the
request of his doctor, with a history of fever, anorexia and
malaise. He had returned the previous week from a month’s
backpacking trip around India, where he had lost 5 kg in
weight. The casualty officer asks you to see this patient with
PUO. The preliminary blood investigations by the GP were
normal.
On examination, the patient was found to be febrile with a
temperature of 39.5°C. He had no lymphadenopathy or pallor
of mucous membranes.
BP 110/70; pulse 90; heart sounds normal.
Chest: clinically clear.
Examination of abdomen: slight generalised tenderness.
Liver, kidneys and spleen not palpable. Examination of CNS:
unremarkable.

31. Where would you manage this patient?
Admit to a MAU side room until an infectious aetiology has been ruled
out. Results in this patient
•
WCC: slightly raised at 12 000 × 109/L
•
ALT: 92 iu/L (normal range 5–40 iu/L)
•
Alkaline phosphatase: 190 iu/L (normal range 25–115 iu/L)
•
All other initial investigations were normal.
What should you do now?
•
Recheck his history of travel
•
Recheck his risk factors for hepatitis and HIV
•
Send blood for viral markers for hepatitis
•
Arrange a liver ultrasound.

32. The ultrasound shows a liver abscess in the
right lobe and, in view of his travel, an
amoebic abscess is a strong possibility.
Fortunately, you had sent off an amoebic CFT
sample and you ring the reference laboratory
urgently. The test is positive (usually positive
with an amoebic liver abscess).
Treatment
Treat with metronidazole 800 mg × 3 daily
for 10 days followed by diloxanide furoate
500 mg × 3 daily for 10 days. Aspiration of
the abscess is only required with failure of
medical therapy.

34.  Q: What is the recommended weight to lose
per week when you start a diet or a weight
loss program?

35.  Ans: 0.45 – 0.9 Kg. Anything above that can
have other implications to your health and
normal body functioning.