Pyrexia of unknown origin

Index Case Year 2

Michaelmas Term

The case: John S, aged 28

• Home from holiday in Africa 6 weeks

• Developed ‘flu like illness and fever

• Feels ill with chills and muscle pains (rigours)

• Also developed cold sore on lip

• Admitted to hospital with “PUO”

On examination:• Temp 390C, pulse 100/min• Chest clear; HS normal• Liver and spleen palpable• No lymphadenopathy• Urine: rbc++ no positive culture• Negative bacterial culture in blood• Faecal culture unremarkable• Hb 8g/dl; MCV 90; Platelets 130 x109/dl• Bilirubin 45μMol/l

Differential diagnosis of PUO?

• History most important,

• Then examination

• Then investigations

PUO may be caused by:

• Infection

• Tumour

• Allergy

• Connective tissue disorders

• Overheating

Infection: some are difficult to diagnose:

• TB

• Sub-acute bacterial endocarditis (usually streptococcal)

• Hidden abscesses: may be post-op

• Osteomyelitis

• Brucellosis/lyme disease

• Tropical diseases

Tumour

• Lymphomas

• Renal cell carcinomas

• Lung cancer with secondary chest infection

Allergy

• May get eosinophilic reaction to infestation with worms

Connective tissue disorders

• SLE

• Dermatomyositis

How would you approach this case?

• History: travel

• Did he take antimalarial prophylaxis?

• How long did he carry on with it after returning home?

• Was he well whilst abroad? Y

• Does the fever vary in intensity? Y

• Other symptoms? Y headache, tiredness, muscle pain plus some abdominal pain

Examination and investigation?

• Pallour; tinge of jaundice• Hepatosplenomegaly• No lymphadenopathy or CNS abnormality• Urine: red cells• CXR: normal• U/S abdomen: hepatosplenomegaly X2• CT brain: normal• Blood cultures no growth

If malaria id a possibility what investigation would you ask for?

A thick blood film, looking for infected cells

Some facts about Malaria• Means “Bad Air”

• Caused by Plasmodium falciparum, vivax, ovale or malariae

• Vector: anopheles mosquito

• P falciparum most likely and most severe: 2000 case in UK annually

Geographical distribution (n.b. used to endemic in the Fens: Ague)

Life cycle: sexual in mosquito and asexual in human

Life cycle in human:

• Female anopheles mosquito injects sporozoites from salivary glands during blood meal

• Sporozoites attach to and invade liver cells• Multiplication by division to Merozoites.• Liver cell ruptures and merozoites

released• Merozoites bind and enter into rbc• Multiply and rupture with proinflammatory

cytokines

Consequences of infection:

• Cyclical recurrent fever and haemolytic jaundice

• Local vessel blockage from sequestrin production, leading to infarction in brain, liver, spleen gut

• Immune complex deposition: glomerulonephritis

?immunity

• Maternal antibodies protective to babies

• Some incomplete immunity may develop: T cell activation by liver cell stage antigens

• Immunity confounded by diversity of antigens: no cross-strain protection

Natural protection from:

• Sickle cell disease. Infection causes sickling and red cell potassium leakage kills the organism. Spleen clears affected cells

• Duffy blood type shares antigen with P vivax. Duffy negative common in Nigeria: offers protection

Prevention?

• Vector control:

• Kill mosquitos

• Spray oil on stagnant water

• Spray walls of huts

• Chemically impregnated nets

• Avoid bites with nets, staying indoors, skin sprays

Prophylaxis: seehttp://www.traveldoctor.co.uk/malari

a.htm• The Different Drug Regimens• Regimen 1 Mefloquine one 250mg tablet weekly. OR

Doxycycline one 100mg capsule daily. ORMalarone one tablet daily.

• Regimen 2 Chloroquine 300mg weekly (2x150mg tablets). PLUSProguanil 200mg daily (2x100mg tablets).

• Regimen 3Chloroquine 300mg weekly (2x150mg tablets) ORProguanil 200mg daily (2x100mg tablets).

• Regimen 4No prophylactic tablets required but anti mosquito measures such as insect repellents, mosquito nets, long sleeved clothing, etc. should be strictly observed.

But drug resistance a problem:

Treatment: see http://www.who.int/malaria/doThe

Different Drug Regimens cs/TreatmentGuidelines2006.pdf

• 1,000,000 mortality worldwide annually

• Chloroquine now ineffective for most P. falciparum

• Resistance to sulfadoxine-pyrimethamine

• NEW!! Artemisinin derivatives from China

• “ACT”- Artemisinin-based combination therapy

Artemisia annua