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BSMS302 > 3. Pathogenesis of human malaria > Flashcards

3. Pathogenesis of human malaria Flashcards

1
Q

Malaria’s burden to global health

A

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

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2
Q

What age range do malaria deaths occur in the most?

A

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

1 child dies every 2 minutes from malaria

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3
Q

Incidence and mortality of malaria

A

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

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4
Q

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

A 
VECTOR CONTROL
insecticide treated mosquito nets
indoor residual spraying
diagnostics
treatment
prevention in pregnancy
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5
Q

Malaria in the UK

A

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

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6
Q

What is the vector for malaria?

A

female anopheles mosquito

males drink tree sap and females drink blood

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7
Q

What do the different species of malaria differ in?

A 
Geographical distribution
lifecycle
clinical features
demographics
reservoir
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8
Q

Malaria Species and fever paroxysms

A 
P. falciparum - malignant tertian
P. vivax - Benign tertian
P. ovale - tertian
P. malarie - quartan
P. knowlesi - quotidian
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9
Q

Plasmodium spp. life cycle

A

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.

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10
Q

Which stage parasites of malaria cause symptoms?

A

Blood stage parasites

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11
Q

What are hypnozoites?

A

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

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12
Q

Outcome of most childhood Plasmodium falciparium malaria?

A

Mostly asymptomatic, and uncomplicted, minority severe

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13
Q

Adult in endemic area with p. falciparum malaria

A

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

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14
Q

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

A

Some severe, rarely asymptomatic, mostly uncomplicated

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15
Q

Which malaria type is most common in the UK?

A

P. falciparum malaria is the most common in the UK

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16
Q

Diagnosis of malaria

A

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

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17
Q

Diagnosing malaria - thick film

A

no fixative
RBCs lyse
increased sensitivity

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18
Q

Diagnosing malaria - thin film

A

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

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19
Q

Microscopy to diagnose malaria

A

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

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20
Q

Diagnosis of malaria by antibody-based dipsticks

A

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

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21
Q

RDT problems

A
  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
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22
Q

Uncomplicated malaria definition

A

Parasitaemia <2%
No Schizonts
No clinical complications

23
Q

Severe malaria definition

A

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

24
Q

Multi system disease

A

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

Malaria is a MEDICAL EMERGENCY

25
Q

Sequestration and rosetting

A

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

26
Q

What is rosetting

A

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

27
Q

How do infected red blood cells affect cerebral capillaries?

A

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.

28
Q

What is PfEMP-1

A

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

29
Q

What leads to antigenic variation in plasmodium?

A

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

30
Q

Malaria parasite sequestration in brain and lungs

A

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

31
Q

Endothelial dysfunction in malaria pathogenesis

A

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

32
Q

Tissue inflammation in malaria

A

leukocyte infiltration into the tissue parenchyma

33
Q

Types of malaria disease presentation

A

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

34
Q

Renal impairments and metabolic acidosis in malaria

A

increased glycolysis and lactic acid accumulation
hypoxia
hyperventilation

35
Q

How does malaria cause sepsis?

A

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)

36
Q

Systemic effects of severe malaria

A 
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
37
Q

How does malaria cause anaemia?

A

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)

38
Q

Severe malaria effects

A 
Cerebral malaria
Anaemia
Jaundice
Respiratory distress
Renal impairment
Blackwater fever
Hypoglycaemia
39
Q

What is cerebral malaria?

A

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

40
Q

Differentials for cerebral malaria

A

Meningitis (including TB), encephalitis, brain abscess

41
Q

How is cerebral malaria assessed in children?

A

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

42
Q

Severe malarial anaemia pathogenesis

A

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

43
Q

management of severe malaria

A

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

44
Q

Problem with IV quinine

A

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%

45
Q

What is used to treat malaria?

A

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

46
Q

Where in lifecycle does artesunate act?

A

Ring stage
and
Mature schizont

47
Q

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

A

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

48
Q

Acquired immunity

A

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

49
Q

Genetic protective factors

A

Sickle cell trait

duffy negative

50
Q

Sickle cell trait

A

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.

51
Q

Duffy negatibe

A

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.

52
Q

Key drivers of antimalarial drug resistance

A

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

53
Q

What factors lead to malarial clinical outcome?

A

Parasite factors
Host factors
Geographic and social factors

BSMS302 (10 decks)

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