1. Pyrexia of unknown origin Index Case Year 2 Michaelmas Term

2. 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”

3. On examination: Temp 39 0 C, 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 x10 9 /dl Bilirubin 45μMol/l

4. Differential diagnosis of PUO? History most important, Then examination Then investigations

5. PUO may be caused by: Infection Tumour Allergy Connective tissue disorders Overheating

6. 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

7. Tumour Lymphomas Renal cell carcinomas Lung cancer with secondary chest infection

8. Allergy May get eosinophilic reaction to infestation with worms

9. Connective tissue disorders SLE Dermatomyositis

10. 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

11. 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

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

13. A thick blood film, looking for infected cells

14. 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

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

16. Life cycle: sexual in mosquito and asexual in human

17. 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

18. 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

19. ?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

20. 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

21. 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

22. Prophylaxis: see http://www.traveldoctor.co.uk/malar ia.htm The Different Drug Regimens Regimen 1 Mefloquine one 250mg tablet weekly. OR Doxycycline one 100mg capsule daily. OR Malarone one tablet daily. Regimen 2 Chloroquine 300mg weekly (2x150mg tablets). PLUS Proguanil 200mg daily (2x100mg tablets). Regimen 3Chloroquine 300mg weekly (2x150mg tablets) OR Proguanil 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.

23. But drug resistance a problem:

24. 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

25. Artemisia annua