1. Pathogenesis of Malaria By Mohammed Mahmoud

2. Basic pathogenesis Immunological RBCs changes Parasite itself

3. Immunopathogenesis Immunity against Malaria is Premunition immunity Incomplete  reduce the severity of the attack but not to prevention infection. Takes several years to develop. Fades away quickly.

4. Immunopathogenesis APC TH1 TH2 B-cell Abs Tc NK Mq TNF ROI NO Hum CMI IL1 IL2 IFNγ IL4 IL5

5. Immunopathogenesis TH1 produces IFN γ which activates the macrophages to produce TNF, NO and ROS which help to kill the parasite, on the other hand, if these molecules are excessive tissue damage will occur.

6. Immunopathogenesis TH2 will produce IL4 & IL5  activate the B cells into plasma cells  Abs which prevent RBCs invasion by the parasite, on the other hand, if excessive Abs produces  Ag/Ab complex which deposit in tissue  activate complement  tissue damage, also Ag/Ab complexes stimulate the macrophage to release their products  more tissue damage

7. RBCs changes Cytoadherance and sequestration: Rosetting

8. RBCs changes Cytoadherance and sequestration Rosetting Deformability

9. Clinical picture Complicated Malaria (P.falciparum) Uncomplicated Malaria (other forms)

10. Uncomplicated Malaria Fever: Periodicity: Every 3 rd day  P.ovale, P. Vivax Every 4 th day  P. Malarie Irregular  P. Falciparum Classical stages: Cold stage Hot stage Sweating stage Pathogenesis: Mediated by host cytokines IL1, IL6, TNF

11. Uncomplicated Malaria Anaemia: Haemolysis of parasitized RBCs BM suppression by IL1 Splenomegly: Due to RE hyperplasia Jaundice: Due to haemlysis

12. Uncomplicated Malaria Fate of the unttt acute attack: Relapse: in case of P.vivax and ovale due to activation of the dormant hypnozoites in the liver. Recrudescence: in case of P. Malarie and falciparum due to persistance of small number of the parasites in the blood.

13. Complicated Malaria Metabolic  Acidosis, Anaemia, Hypoglycemia CNS  Cerebral Malaria CVS  Algid Malaria Lung  ARDS

14. Complicated Malaria GIT  Vomiting, diarrhea, abdominal pain Liver  hepatic failure GB  Pigmented stone Spleen  TSS, rupture spleen Kidneys  Black water fever, ARF, nephrosis Obstetric

15. Metabolic Acidosis: Due to tissue anoxia  lactic acidosis Tissue anoxia due to RBCs changes Severe anemia Hypotension (Algid malaria) Anemia More in children and pregnant women Caused by: Haemolysis BM suppresion by IL1 Autoimmune: Ab formed against parasited RBCs cross react with unparasitized RBCs 2ry hyersplenism

16. Metabolic Hypoglycaemia: More in children and pregnant women Due to: Increase consumption of glucose by: Parasites Host after quinine therapy which stimulates B cells of the pancreas Decrease production of glucose by the liver due to cytokines mediated suppresion of gluconeogenesis.

17. Cerebral Malaria Diffuse disturbance of cerebral function characterized by altered consciousness commonly accompanied by convulsions in presence of peripheral parasitaemia after exclusion of other causes of encephalopathy.

18. Cerebral malaria Pathogenesis: RBCs changes  occlusion of the cerebral mirocirculation. Immunological, excessive release of cytokines from the host cells e.g. macrophages TNFα  ++ granulocytes to release their enzymes and ROS  Enhance expression of adhesion molecules on the vascular endothelium  promote cytoadherance  ++ NO production (inhibitory neurotransmittor)

19. Algid Malaria Malaria with peripheral circulatory collapse and shock due to 2ry bacterial infection likely UTI and pneumonia (due to decreased immunity).

20. ARDS Characterized by fever, respiratory distress, hypoxemia inspite of supplemental oxygen Caused by Immunological e.g. TNF RBCs changes Lung infection 2ry to decrease immunity

21. GIT, Liver and GB GIT  vomiting, watery diarrhea & abdominal pain due to sequestration of parasitized RBCs in intestinal microcirculation. Liver  hepatic failure due to sequestration of parasitized RBCs in hepatic sinusoids GB  Pigmented stones 2ry to haemolysis.

22. Spleen Tropical splenomegly syndrome (hyperactive malarial splenomegly): Gross splenomegly, hypersplenism and polyclonal B lymphocyte proliferation  excessive high IgM level and raised titer of Ab against the present species of parasite. It is due to persistant malaria induced IgM lymphocytotoxic Ab against T suppressor cell  umcontrolled polyclonal proliferation of B cells.

23. Kidney Black water fever: More in children and non immune adults Characterized by fever, rigors, haemoglobinuria, oliguria and even anuria. Blood film is usually negative or scanty parasites Caused by massive intravascular haemlysis results from: High level of parasitaemia (> 100.000/ cmm) Insufficient and irregular ttt with quinine renders the parasitized RBCs antigenic  Ab against quinine- parasitized RBCs complex  damage of RBCs  haemolysis Primaquine in patients with G6PD deficiency

24. Kidney ARF due to sequestration of parasitized RBCs in the renal vessels. Quartan Malarial nephropathy: Intractable nephrotic syndrome with non selective protinuria Bad prognosis with no respose to steroids or antimalarial Caused by immune complex deposition

25. Obstetric Pregnancy increase the parasitaemia which can lead to: Anemia Low birth weight (packing of the placenta by the parasitized RBCs) Congenital infection: Occur in non-immune pregnant More in P.vivax than falciparum Infants present with fever, haemolytic anemia and failure to thrive.