3. Pathogenesis of human malaria

Question 1

Malaria’s burden to global health

Answer 1

219 million cases a year
435000 deaths
91 countries ongoing transmission
Disproportionate burden in subsaharan Africa w 90% of cases and 92% of deaths

Question 2

What age range do malaria deaths occur in the most?

Answer 2

More than 2/3 (70%) of all malaria deaths occur in under 5s

1 child dies every 2 minutes from malaria

Question 3

Incidence and mortality of malaria

Answer 3

21% global decrease in malaria incidence and 29% decrease in mortality between 2010 and 2015

Question 4

What led to the big decrease in incidence and mortality in malaria?

Answer 4

VECTOR CONTROL
insecticide treated mosquito nets
indoor residual spraying
diagnostics
treatment
prevention in pregnancy

Question 5

Malaria in the UK

Answer 5

single most common imported infection in travellers
1683 UK cases in 2018

6 deaths a year

ALWAYS ask patients where they’ve been - not just last place, ask patients to list places they’ve been

Question 6

What is the vector for malaria?

Answer 6

female anopheles mosquito

males drink tree sap and females drink blood

Question 7

What do the different species of malaria differ in?

Answer 7

Geographical distribution
lifecycle
clinical features
demographics
reservoir

Question 8

Malaria Species and fever paroxysms

Answer 8

P. falciparum - malignant tertian
P. vivax - Benign tertian
P. ovale - tertian
P. malarie - quartan
P. knowlesi - quotidian

Question 9

Plasmodium spp. life cycle

Answer 9

Plasmodium first infects the liver where it forms merozoites Merozoites then emerge from liver and enter rbcs, where they mature into trophozoites (Ring stage), which mature into schizonts, which then rupture releasing more merozoites, also into the blood. This carries on in a cycle. Some merozoites become gametocytes which are taken up during a blood meal by a Anopheles mosquito, where it replicates inside the mosquito, and then gets transmitted to another human when the mosquito goes to take another blood meal, again first infecting the liver.

Question 10

Which stage parasites of malaria cause symptoms?

Answer 10

Blood stage parasites

Question 11

What are hypnozoites?

Answer 11

They are dormant stagesof P. vivax and P. ovale which can persist in the liver and cause relapse by invading the bloodstream weeks or even years later

Question 12

Outcome of most childhood Plasmodium falciparium malaria?

Answer 12

Mostly asymptomatic, and uncomplicted, minority severe

Question 13

Adult in endemic area with p. falciparum malaria

Answer 13

Very small minority have severe disease. Mostly asymptomatic or uncomplicted disease

Question 14

Adult or child not living in endemic area with P. falciparum malaria

Answer 14

Some severe, rarely asymptomatic, mostly uncomplicated

Question 15

Which malaria type is most common in the UK?

Answer 15

P. falciparum malaria is the most common in the UK

Question 16

Diagnosis of malaria

Answer 16

Giemsa-stained blood film
Rapid diagnostic tests (RDTs) - alternative to clinical diagnosis/microscopes. Useful when good quality microscopy cannot be provided

Question 17

Diagnosing malaria - thick film

Answer 17

no fixative
RBCs lyse
increased sensitivity

Question 18

Diagnosing malaria - thin film

Answer 18

Cell fixed intact in a monolayer
Quantifies parasites
Used for P. spp speciation

Question 19

Microscopy to diagnose malaria

Answer 19

Should report:
species (can be more than one)
Parasitaemia (density)
Paraste stage (presence of schizonts in peripheral film is significant)

Question 20

Diagnosis of malaria by antibody-based dipsticks

Answer 20

Malaria rapid diagnostic tests detect specific antigens produced by malaria parasites present in infected or recently infected individuals. Some RDTs can detect only one spp

Usually obtain blood for it by finger prick

Dye-labelled antibody binds to parasite antigen, and resultant complex is captured on the strip by a band of bound antibody to form a visible line

Question 21

RDT problems

Answer 21

1. Less sensitive than microscopy by 10-100x
2. Detect parasite antigen rather than live parasite - so can be positive in patients who’ve recently treated (up to 2 weeks) or come from endemic area and have low level of asymptomatic parasitaemia
3. Not possible to determine the % parasitaemia or stage of parasite

Question 22

Uncomplicated malaria definition

Answer 22

Parasitaemia <2%
No Schizonts
No clinical complications

Question 23

Severe malaria definition

Answer 23

Parasitaemia >2%
OR
Parasitaemia <2% plus either schizonts reported on blood film or complications

Question 24

Multi system disease

Answer 24

Rapid progression to death
mortality 10-40% in first 24hrs

Malaria is a MEDICAL EMERGENCY

Question 25

Sequestration and rosetting

Answer 25

Parasite sequestration is believed to be responsible for malaria's severe manifestations, including cerebral mlaria. It causes blood flow impairment which leads to local hypoxia. It also enhances parasite replication and rosetting, which is the sticking of infected red blood cells to non-infected red blood cells. Furthermore, when the parasites sequester their toxin's effects are more localised. They also stimulate the host immune response which causes increased production of inflammatory mediators resulting in tissue damage

Question 26

What is rosetting

Answer 26

When infected red blood cells stick to non-infected red blood cells, causing a rosette clump

Question 27

How do infected red blood cells affect cerebral capillaries?

Answer 27

Infected red blood cells (IRBCs) undergo cytoadhesion to the endothelia of cerebral capillaries via Pfemp1, which leads to the sequestration and blocking of cerebral capillaries. This is contributed to by rosetting of uninfected RBCs. Systemic cytokine production increases cytoadherance.

Question 28

What is PfEMP-1

Answer 28

An adhesive molecule called plasmodium falciparum erythrocyte membrane protein - Pfemp1 - which is found on the surface of IRBCs encoded by a family of 60 var genes, with a single ell only expressing one of these at a time

Question 29

What leads to antigenic variation in plasmodium?

Answer 29

plasmodium parasites regularly exchange their expressed var genes leading to antigenic variation. As an antibody response forms to 1 PfEMP, there is a switch of expression to alternative PfEMPs, so it escapes the immune response and maintains infection

Question 30

Malaria parasite sequestration in brain and lungs

Answer 30

Sepsis leads to proinflammatory cytokines which result in the activation of vascular endothelial cells which leads to augmented expression of adhesion molecules and adherence of IRBCs, leading to endothelial dysfunction and tissue inflammation

Question 31

Endothelial dysfunction in malaria pathogenesis

Answer 31

coagulation and disruption of vascular endothelial cells leading to vascular leakage and pergusion abnormalities, leading to tissue inflammation

Question 32

Tissue inflammation in malaria

Answer 32

leukocyte infiltration into the tissue parenchyma

Question 33

Types of malaria disease presentation

Answer 33

cerebral malaria placental malaria acute respiratory distress renal impairment and metabolic acidosis

Question 34

Renal impairments and metabolic acidosis in malaria

Answer 34

increased glycolysis and lactic acid accumulation hypoxia hyperventilation

Question 35

How does malaria cause sepsis?

Answer 35

sepsis which affects the spleen, and infected or altered RBCs result in macrophage activation and cytokine production (the cytokines then result in all the systemic effects e.g. parasite sequestration, endothelial dysfunction, tissue inflamamtion etc)

Question 36

Systemic effects of severe malaria

Answer 36

``` Sepsis Proinflammatory cytokines Parasite sequestration (brain and lungs) Endothelial dysfunction Tissue inflammation Cerebral malaria placental malaria Acute respiratory distress Renal impairment and metabolic acidosis Anaemia Impaire erythropoiesiss Fever ```

Question 37

How does malaria cause anaemia?

Answer 37

Sepsis in the spleen results in pro-inflammatory cytokines which cause adhesion and rupture of infected and altered RBCs resulting in anaemia. Plus there is also impaired erythropoiesis (bone marrow)

Question 38

Severe malaria effects

Answer 38

``` Cerebral malaria Anaemia Jaundice Respiratory distress Renal impairment Blackwater fever Hypoglycaemia ```

Question 39

What is cerebral malaria?

Answer 39

unrousable coma in presence of peripheral parasitaemia where other causes of encephalopathy have been excluded Clinician must be alert to any alteration in consciousness Diffuse cerebral dysfunctions and generalised convulsions Focal neruologic signs and brainstem signs (abnormal oculo-vestibular reflexes) Abnormalities of posture and muscle tone

Question 40

Differentials for cerebral malaria

Answer 40

Meningitis (including TB), encephalitis, brain abscess

Question 41

How is cerebral malaria assessed in children?

Answer 41

Using the Blantyre coma score A total score of 3 or less is cerebral malaria score is based on eye movement, verbal response and best motor response

Question 42

Severe malarial anaemia pathogenesis

Answer 42

Haemolysis of iRBC Haemolysis of uninfected RBCs Bone marrow suppression (dyserythropoiesis)

Question 43

management of severe malaria

Answer 43

medical emergency Primary objective of antimalarial treatment in severe malaria is to prevent death untreated mortality almost 100% but falls to 15-20% with effective antimalarial treatment Cerebral malaria: prevention of neurological deficit is important Severe malaria in pregnancy: saving life of mother is primary objective

Question 44

Problem with IV quinine

Answer 44

Previously IV quinine BUT hypoglycaemia, arrhythmias, potentally lethal hypotension in rapid infusion AND significant mortality still: cerebral malaria has a treated mortality rate of 15-20%

Question 45

What is used to treat malaria?

Answer 45

IV artesunate Safer and easier to administer And reduces parasite burden more rapidly than quinine

Question 46

Where in lifecycle does artesunate act?

Answer 46

Ring stage and Mature schizont

Question 47

What should be used in addition to artesunate in vivax and ovale malaria?

Answer 47

Need to add primaquine because need specific treatment aimed at eradicating liver hypnozoite stage, if not, hypnozoites can reactivate and cause disease relapse much later

Question 48

Acquired immunity

Answer 48

Antibody mediated depends on local pattern and intensity of transmission - vary within countries e.g. Ethiopia EIR= entomological incoulation rate (no. of infectious bites per person per year) Stable endemic transmission (EIR>10/y) severe disease in v young Unstable epidemic transmission (EIR <1-5/y) severe disease possible in all

Question 49

Genetic protective factors

Answer 49

Sickle cell trait | duffy negative

Question 50

Sickle cell trait

Answer 50

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.

Question 51

Duffy negatibe

Answer 51

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.

Question 52

Key drivers of antimalarial drug resistance

Answer 52

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

Question 53

What factors lead to malarial clinical outcome?

Answer 53

Parasite factors Host factors Geographic and social factors