Infection 2) Pathogenesis of human malaria Flashcards
How many cases of malaria are there per year?
216 million
How many deaths from malaria per year?
435,000
Where do 90% of malaria cases occur?
Sub-saharan Africa
How can malaria be prevented?
Vector control
Diagnostics
Treatment
Prevention in pregnancy
What are the 5 plasmodium species in humans?
Falciparum Vivax Ovale Malaria Knowlesi
How do the species of malaria differ?
Geographical distribution
Lifecycle
Clinical features
Describe the difference in malaria severity in children and adults in endemic areas
More severe in children
More likely asymptomatic and uncomplicated in adults
How is uncomplicated malaria defined?
Parasitaemia below 2%
No schizonts
No clinical complications
How is severe malaria defined?
Parasitaemia above 2% or
Parasitaemia below 2% and schizonts or complications
Describe the plasmodium life cycle
1) Gametocytes picked up during blood meal by anopheles mosquitoes
2) Start cycle of growth and multiplication in mosquito
3) Mosquito takes another blood meal from another human
4) Infective sporozoites are injected with saliva and start another human infection by infecting liver cells
5) Enter bloodstream as merozoites
6) Enter RBC for cycles of replication within peripheral and microvasculature
7) Merozoites mature into trophozoites (ring stage)
8) Mature into schizonts which rupture and release more merozoites
How does the lifecycle of plasmodium vivax and ovale differ from the other species?
They have a dormant stage in the liver (hypnozoites) which can cause relapses by invading into the bloodstream weeks or years later
Why aren’t rapid diagnostic tests as good as microscopy?
Less sensitive by 10-100X
Can’t determine % paraistaemia or parasite stage
What do RDTs detect?
Parasite-specific antigens or enzymes produced by malaria parasite which are present in blood of infected individuals
When are RDTs falsely positive?
In patients who have been recently treated or come from malaria endemic area and have low-level asymptomatic parasitaemia
How do RDTs work?
Blood obtained by finger prick
Dye-labelled antibody binds to parasite antigen
Resultant complex is captured on strip by a band of bound antibody to form a visible line
What is the method for Giemsa-stained film?
1) take blood sample
2) drop of blood on slide and dry
3) fix with alcohol and dry
4) treat with giemsa stain and dry
5) identify under microscope
What does microscopy allow identification of?
Species
Number of parasites
Parasite stage
What is the difference between a thick and thin film?
Thick film has no fixative, RBCs lyse, increased sensitivity
Thin film has cells fixed intact in monolayer, quantification of parasites, used for plasmodium species speciation
What is the consequence of cytoadherence of infected RBCs?
Sequestration and blocking of cerebral capillaries
Describe how sequestration has a pathological base of severe manifestation of malaria
Blood flow impairment causes local hypoxia
Enhances parasite replication and sticking of infected RBCs to non-infected RBCs
Effects of parasite toxins and stimulation of host immune response is more localised causing focused production of inflammatory mediators and tissue damage
What is PfEMP-1?
Expressed by parasite on surface of infected RBC
Parasite exchanges expressed var gene causing antigenic variation allowing immune response to be escaped
What are the consequences of severe malaria in children?
Hypoglycaemia Blackwater fever Renal impairment Respiratory distress Jaundice Anaemia Cerebral malaria
Why does anaemia occur in severe malaria?
Haemolysis of infected RBC
Haemolysis of uninfected RBCs
Bone marrow suppression (dyserythropoiesis)
What is cerebral malaria?
Unarousable coma in presence of peripheral parasitaemia where other causes of encephalopathy have been excluded
Diffuse cerebral dysfunctions
Generalised convulsions
What are the differential diagnoses of cerebral malaria?
Meningitis
Encephalitis
Brain abscess
What drug used to be used to treat malaria?
IV quinine
Why is quinine no longer used?
Severe complications
Hypoglycaemia, arrhythmia, potential lethal hypotension in rapid infusion
Still had significant mortality
What drug is used to treat malaria?
IV artesunate
How does artesunate work?
Kills circulating ring-stage parasites and schizonts
Active against pathological cytoadhering stages that sequester in venues and capillaries of vital organs
How do vivax and ovale differ in their treatment compared to other species?
They need additional primaquine
What is EIR?
Number of infectious bites per person per year
What is a stable endemic transmission?
EIR > 10 per year
Severe disease in very young before acquisition of immunity
What is unstable epidemic transmission?
EIR below 1-5 per year
Severe disease is possible in all ages
What are the 2 genetic protective factors for malaria?
Sickle cell trait
Duffy negative
Why is the sickle cell trait protective against malaria?
HbS is protected
Why is Duffy negative protective against malaria?
RBCs are resistant to infection by P.vivax
Why is antimalarial drug resistance common?
Unusual genetic structural of malarial parasites
Artemisinin drug use without complementary combination treatment such as lumefantrine
Unregulated or poorly administered antimalarial drug use
Counterfeit or substandard treatments
What are some parasite factors that impact clinical outcome?
Drug resistance Multiplication rate Invasion pathways Cytoadherence Rosetting Antigenic polymorphism Antigenic variation Malaria toxin
What are some host factors that impact clinical outcome?
Immunity Proinflammatory cytokines Genetics (sickle cell trait, thalassaemia, ovalocytosis etc.) Age Pregnancy
What are some geographic and social factors that impact clinical outcome?
Access to treatment
Cultural and economic factors
Political stability
Transmission intensity
