Pathogenesis of human malaria Flashcards
Which age group has the highest mortality rate due to malaria in areas with high transmission rates
- In areas with high transmission of malaria, children under 5 are particularly susceptible to infection, illness and death; more than 70% of all malaria deaths occur in this age group
Actions we have taken to reduce malaria transmission rates
- Insecticide treated mosquito nets
- Indoor residual spraying
- Diagnostics
- Treatment
- Prevention in pregnancy
Vector for malaria
- Female anopheles mosquito
How do the malaria causing species differ
- Geographical distribution
- Lifecycle
- Clinical features
- Demographics
- Reservoir
At which life cycle stage do parasites of malaria cause symptoms
- Blood stage
Relevance of parasite life cycle to malaria
- When gametocytes are picked up during a blood meal by anopheles mosquitos, they start another cycle of growth and multiplication in the mosquito
- When the mosquito takes another blood meal from another human, the infective sporozites are injected with the saliva, and start another human infection by infecting the liver cells first
- From here, they enter the blood stream as merozites, and then enter red blood cells for cycles of replication within the peripheral and microvasculature
- Merozites infect rbcs, these mature into trophozites(ring stage), which mature into schizonts, which then rupture releasing more merozoites
Diagnosis of malaria - blood film
- Take blood sample
- Drop of blood on a slide, dry, fix with alcohol, dry, treat with giemsa stain to stain parasites, dry then look at through a microscope
- Can then identify species, no. of parasites
Diagnosis of malaria - rapid diagnostic testing
- Detects parasite specific antigens or enzymes
- Less sensitive than microscopy, but useful if a skilled microscopist is not available
Malaria - thick film
- No fixative
- RBCs lyse
- Increased sensitivity
Malaria - thin film
- Cell fixed intact in a monolayer
- Quantification of parasites
- Used for P.spp. speciation
What should be reported after microscopic investigation of malaria
- Species (may be multiple)
- Parasitemia (density)
- Parasite stage (presence of schizonts in peripheral film is significant)
Diagnosis of malaria antibody-based ‘dipsticks’
- Variations occur between malaria RDT products, though the principles of the tests are similar
- Malaria RDTs detect specific antigens(proteins) produced by malaria parasites, that are present in the blood of infected or recently infected individuals
- Soms RDTs can detect only one spp.
- Blood for the test is commonly obtained from a finger prick
- With malaria RDTs, the dye-labelled antibody first binds to a parasite antigen, and the resultant complex is captured on the strip by a band of bound antibody, forming a visible line
Problems with RDTs
- They are less sensitive by 10-100x than microscopy
- Detect parasite antigen rather than live parasite (may therefore be positive in patients who have been recently treated - up to 2 weeks. or come from a malaria endemic area and have a low level of asymptomatic parasitaemia
- Not possible to determine the percentage parasitaemia or stage of parasite
Classification of malaria
Uncomplicated:
parasitaemia <2% and no schizonts and no clinical complications
Severe:
Parasitaemia > 2%
or
Parasitaemia <2% plus…either schizonts reported on blood film or complications
What is pfemp1
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of proteins present on the membrane surface of red blood cells (RBCs or erythrocytes) that are infected by the malarial parasite Plasmodium falciparum.
Role of pfemp1 in malaria
Pfemp1 also has a role in cytoadherence of Infected Red Blood Cells to endothelia of cerebral capillaries
Cytoadherence of IRBC leads to sequestration and blocking of cerebral capillaries
Rosette formation of Uninfected Red Blood Cells contributes to sequestration
Systemic production of cytokines enhances cytoadherence of IRBC
Effect of parasite sequestration
Parasite sequestration is thought to be the pathological basis of the severe manifestations of malaria, including cerebral malaria.
It causes blood flow impairment leading to local hypoxia.
It enhances parasite replication and the sticking of IRBC to non-infected red blood cells (rosetting, see below).
Moreover, when parasites sequester, the effects of parasite toxins are more localized
They also the stimulate the host immune response, which may cause a focused production of inflammatory mediators and tissue damage
What is PfEMP-1 encoded by
- This is encoded by a family of 60 var genes (variant antigenic region proteins)
- A single cell only expresses one of these at any time - a single PfEMP-1 phenotype
- The parasite regularly exchanges the expressed var gene, leading to antigenic variation
- As an antibody response forms to 1 PfEMP, there is a switch of expression to alternative PfEMPs, escaping the immune response and maintaining infection
How does malaria cause tissue inflammation
Pro-inflammatory cytokines –> Activation of vascular endothelial cells –> augmented expression of adhesion molecules and adherence of infected RBCs (parasite sequestration in brain and lungs) –> coagulation and disruption of vascular endothelial cells –> vascular leakage and perfusion abnormalities (endothelial dysfunction) –> Leukocyte infiltration into the tissue parenchyma (tissue inflammation)
What can tissue inflammation in malaria lead to
- Cerebral malaria
- Placental malaria
- Acute respiratory distress
- Renal impairment and metabolic acidosis
What causes fever in malaria
- Pro-inflammatory cytokines
Effect of sepsis
Sepsis(spleen) uptake of infected or altered RBCs resulting in macrophage activation and cytokine production -destruction of RBCs-> pro-inflammtory cytokines –> adhesion and rupture of infected and altered RBCs(anaemia) -low levels of RBCs-> increased glycolysis and lactic acid accumulation, hypoxia, hyperventilation (renal impairment and metabolic acidosis)
Main complications of severe malaria
- Hypoglycaemia
- Cerebral malaria
- Anaemia
- Jaundice
- Respiratory distress
- Renal impairment
- Blackwater fever
Cerebral malaria
- Unarousable coma in the presence of peripheral parasitaemia where other causes of encephalopathy have been excluded
Scoring system used in children for cerebral malaria
- Blantyre coma score (total score of 3 or less -> CM)
- Clinician must be alert to any alteration in consciousness
Presentation of cerebral malaria malaria
- Diffuse cerebral dysfunctions - generalised convulsions
- Focal neurologic signs and brainstem signs (abnormal oculo-vestibular reflexes)
- Abnormalities of posture and muscle tone
Cerebral malaria - differential diagnosis
- Meningitis (including TB) .
- Encephalitis
Severe malarial anaemia pathogenesis
- Haemolysis of IRBC and URBC
- Bone marrow suppression (dyserythropoiesis)
- Parasitised red cells rupture caused by plasmodium cycles and clearance of deformed parasitised and un-parasitised erythrocytes are the principal causes of malarial anaemia
Previous treatment for malaria
IV quinine
Why was IV quinine discontinued
- Hypoglycaemia
- Arrhythmias
- Potentially lethal hypotension in rapid infusion
- Significant mortality still - cerebral malaria has a treated mortality rate of 15-20%
Current treatment of malaria
- IV artesunate
- Safer and easier to administer
- Reduces parasite burden more rapidly
Artesunate vs Quinine
- Artesunate kills circulating ring-stage parasites as well as schizonts whereas quinine does not
- Both artesunate and quinine are active against the more pathological cytoadhering stages that sequester in the venules and capillaries of vital organs
- Thus, artesunate prevents maturation of the younger parasite stages and thereby prevents sequestration, which reduces consequent microcirculatory obstruction
Erythrocytic schizogony
Merozoites -> Infected red blood cell -> ring stage -> trophozoite -> immature schizont -> mature schizont -> rupture cell -> merozoites
Why is it important to target the liver hypnozoite stage in treating malaria
- If this is not targeted, the hypnozoites may reactivate and cause disease relapse much later
SO - Add primaquine to your management plan for vivax and ovale
Acquired immunity - malaria
- Thought to be antibody mediated
- Depends on local pattern and intensity of transmission
What is EIR
- Entomological inoculation rate - number of infectious bites per person per year
Stable vs unstable transmission
- Stable endemic transmission (EIR > 10/y) - severe disease in very young
- Unstable epidemic transmission (EIR < 1-5/y) - severe disease possible in all
Sickle cell trait - HbS relatively protected
Because P. falciparum malaria has been a leading cause of death in Africa since remote times, the sickle cell trait is now more frequently found in Africa and in persons of African ancestry than in other population groups.
Duffy negative
Persons who are negative for the Duffy blood group have red blood cells that are resistant to infection by P. vivax. Since the majority of Africans are Duffy negative, P. vivax is rare in Africa south of the Sahara, especially West Africa.
Key drivers of antimalarial drug resistance
Unusual genetic structure of malaria parasites in regions known for antimalarial drug resistance
Artemisinin drug use without a complementary combination treatment, such as lumefantrine. ACT= artemisinin combination therapy
Unregulated or poorly administered antimalarial drug use
Counterfeit or substandard treatments: cause 25% of all malaria deaths
Malaria causing species
P. falciparum, P. vivax, P. ovale, P. malarie, P. knowlesi
