Lecture 4 - Malaria

Question 1

Which are the two plasmodium species that cause the most cases of malaria?

Answer 1

P. falciparum

P. vivax

Question 2

Discuss transmission by female Anopheles mosquitos during the year.

Answer 2

It’s stable/year-round transmission or seasonal/unstable with epidemics.

Question 3

Name characteristics of two Anopheles species: An. gambiae and An. arabiensis.

Breeding sites, day or night biters, indoor or outdoor biters, and anthrophilic level.

Answer 3

Breeding sites: unpolluted pools, puddles, marshes, rice paddies, etc.

Night biters

Endophilic

Highly anthrophilic

Question 4

What are four factors that determine vectoral capacity?

Answer 4

1. No. of vectors per human
2. No. of human blood meals/day/vector
3. Daily survival rate
4. Extrinsic incubation period of parasite

Question 5

Where are the majority of parasites killed in anopheles mosquitoes?

Answer 5

In the midgut epithelium cells by innate immune effector genes such as TEP1.

Question 6

Explain the difference between recrudescences and relapses in human malaria.

Answer 6

Recrudescence = erythrocytic infection falls to subclinical or subpatent levels but is not eliminated, then re-appears. Is frequently associated with P. malariae.

Relapse = erythrocytic infection is eliminated. If chemotherapy to eliminate dormant hypnozoites in the liver is not performed then these can re-activate and generate new erythrocytic infection.

Question 7

Relapses in human malaria can only occur in a few plasmodium species. Which ones and why do these relapses occur?

Answer 7

This happens in P. vivax and P. ovale species.

Erythrocytic infection can only be eliminated via chemotherapy (natural immunity is unlikely to eliminate infection). If the dormant hypnozoites in the liver are not eliminated a new erythrocytic infection can occur, because these hypnozoites can be re-activated.

Question 8

There are no symptoms associated with the liver stages - symptoms begin with onset of blood stage infection (typically 7-30 days after bite).

Clinical features: describe the stages that accompany the classic symptom fever.

• Cold stage
• Hot stage
• Sweating stage

Answer 8

1. Cold stage - patient shivers, then temperature rises rapidly.
2. Hot stage - peripheral vasodilation (flushed appearance), rapid pulse and high temperature.
3. Sweating stage - copious sweating leading to a fall in temperature.

Other common systems include anaemia, splenomegaly, and jaundice.

Question 9

Can patients develop immunity against malaria?

Answer 9

Yes and no. P. falciparum can be fatal, but if the patient survives they will develop some immunity BUT repeated re-infections are required for clinical immunity.

Other species tend to cause morbidity rather than mortality.

Question 10

Cerebral malaris is a serious complication of P. falciparum infection resulting in coma. How does the brain get infected?

Answer 10

Cytoadhering of infected red cells in the brain:

Binding of PfEMP1 (encoded by var genes) to endothelia or other erytrhocytes (throughout the body).

Question 11

What is the method of choice to diagnose malaria?

Answer 11

Microscopy –> parasites shown in erythrocytes (headphones).

Question 12

Treatment of malaria consists of two components: supportive and specific.

Explain these components.

Answer 12

Supportive: manage the symptoms - reducing temperature, rehydration, blood transfusions, preventing convulsions.

Specific: eliminate the parasite - via chemotherapy, which depends on the parasite and geographical origin of infection.

Question 13

Why can a good non-toxic antimalarial like chloroquine not be used as much anymore?

What other antimalarial can be used in its place?

Answer 13

Resistance is now widespread.

Quinine is main drug used to treat severe p. falciparum in areas of chloroquine resistance.

Question 14

Which antimalarial is used mainly in combination therapies to prevent drug resistance?

Answer 14

Artemisinin. Derived from Artemisia annua (Chinese herbal remedy).

Question 15

Evolution of Plasmodium spp. and impact on human populations:

When and why did plasmodium spp. expand into human populations? What is the impact of this?

Answer 15

About 10’000 years ago. Emergence as major human pathogen coincides with the development of agriculture and resident human communities.

Impact: malaria is the strongest known selective presure in the recent history of the human genome. Different human populations have developed independent evolutionary responses to malaria: HbAS for example.

Question 16

Why is there an unusually high prevalence of HbAS in malaria endemic regions, even though the homozygous state can be lethal?

Answer 16

The heterozygous state of sickle cell gives protection against malaria. Sickled cells are more likely to be degraded by the spleen, so if malaria parasites reside in these cells they will be more likely to die.

Question 17

Malaria control happens via vector control and therapeutic drugs (e.g. chloroquine).

Name 2 ways of vector control.

Answer 17

• Indoor residual spraying (e.g. DDT).
• Insecticide treated nets (e.g. pyrethroids on bednets).

Question 18

The WHO came up with a solution to eradicate female anopheles mosquitoes: insecticide treated walls.

Why did they think this was the solution?

What were problems of this solution?

Answer 18

Development of malaria cycle takes about 12 days, during which there are about 4-6 additional feeds - this increases chance of mortality of it rests on insecticide treated walls.

Problems: vectors developed resistance to insecticides; parasites developed resistance to drugs.

Question 19

What was the main reason that eradication of malaria did not happen in sub-saharan africa?

Answer 19

Technical challenges of executing the strategy:

• Eradication was not sustainable (too expensive)
• Vertical programme (disease-specific)
• No eradication –> donors withdrew their money

Question 20

What are some factors that helped the spread of chloroquine resistance?

Answer 20

• Exposure of parasites to sub-therapeutic dose of drug
• Incomplete compliance because of sharing the drugs
• Parasites not killed gave them an opportunity to become resistant

Question 21

What is ‘Roll Back Malaria’?

What are 4 of its aims?

Answer 21

Global partnership of national governments, NGOs, academia, etc. with aims:

1. Access to effective treatment
2. Promotion of ITNs and improved vector control
3. Prevention and management of malaria in pregnancy
4. Improving the prevention of and response to epidemics and malaria in complex emergencies

Question 22

What is the ‘Global Malaria Programme’ responsible for?

• Malaria … and … formulation
• … support & capacity …
• Coordination of … to fight malaria
• Convenes experts to …, set global …
• Focus on providing … solutions to the various … and operational challenges

Answer 22

• Malaria policy and strategy formulation
• Operations support & capacity development
• Coordination of WHO’s global efforts to fight malaria
• Convenes experts to review evidence, set global policies
• Focus on providing integrated solutions to the various epidemiological and operational challenges

Question 23

There no vaccine against malaria. Name the three main challenges why there isn’t.

Answer 23

1. Choosing the right antigens (> 5000 genes)
2. Generating strong enough immune responses
3. Avoiding immune escape mechanisms

Question 24

Name three things that would make the ideal anti-malaria vaccine.

Answer 24

• Effective against all life cycle stages & against disease - contains multiple antigens
• Generate appropriate immune responses - antibody and cell-mediated
• Tailored for both host AND parasite genotypes

Question 25

What are requirements for public health vaccine?

Answer 25

Must be cheap, stable, single shot, effective in infants, aim to reduce illness, not prevent all parasitaemia.

Question 26

RTS,S/AS02 vaccine is a … candidate based on P. … surface antigen. It’s an excellent antibody induction against … .

Answer 26

RTS,S/AS02 vaccine is a pre-erythrocytic vaccine candidate based on P. falciparum surface antigen. It’s an excellent antibody induction against sporozoites.

Question 27

Malaria life cycle in human:

Malaria is transmitted in blood during feeding. The … seek out and invade hepatocytes and then multiplu. The period within the hepatocytes is termed … schizogony, in which … are developed.

After about a week the hepatic schizonts burst and the liberated … invade erythrocytes and begin the asexual cycle (… schizogony). The growing intra-erythrocytic parasite consumes the erythrocyte’s …, changes the cell membrane to facilitate importation of …, and disposis of the potentially toxic … waste product.

6-8 days after emerging from the liver, when parasite levels have reached roughly 100 million in the blood, they become detectable by … or rapid diagnostic tests and the … stage of infection begins.

By the end of the intra-erythrocytic lifecycle, the parasite has consumed most of the erythrocyte contents and several … have taken place. The erythrocytic schizonts then bursts and releases between 6-30 daughter …, each of which can invade erythrocytes and repeat the cycle.

Some blood-stage parasites develop into longer-lived … forms (…) that can transmit malaria to mosquitoes.

Answer 27

Malaria life cycle in human:

Malaria is transmitted in blood during feeding. The sporozoites seek out and invade hepatocytes and then multiplu. The period within the hepatocytes is termed exo-erythrocytic schizogony, in which merozoites are developed.

After about a week, the hepatic schizonts burst and the liberated merozoites invade erythrocytes and begin the asexual cycle (erythrocytic schizogony). The growing intra-erythrocytic parasite consumes the erythrocyte’s contents, changes the cell membrane to facilitate importation of nutrients, and disposis of the potentially toxic haem waste product.

6-8 days after emerging from the liver, when parasite levels have reached roughly 100 million in the blood, they become detectable by microscope or rapid diagnostic tests and the blood-stage of infection begins.

By the end of the intra-erythrocytic lifecycle, the parasite has consumed most of the erythrocyte contents and several nuclear divisions have taken place. The erythrocytic schizonts then bursts and releases between 6-30 daughter merozoites, each of which can invade erythrocytes and repeat the cycle.

Some blood-stage parasites develop into longer-lived sexual forms (gametocytes) that can transmit malaria to mosquitoes.

Question 28

No infectious disease has shaped the human genome more than malaria has. What are the malaria protective mechanisms of these diseases:

• HbAS
• HbAC, HbCC + HbAS
• Ovalocytosis
• G6PD deficiency
• HbAE

Answer 28

HbAS = parasite growth at low oxygen tensions

HbAC, HbCC + HbAS = reduced cytoadherance

Ovalocytosis = reduced invasion

G6PD deficiency = reduced parasite densities

HbAE = reduced multiplication at high densities

Question 29

Name the reasons behind these clinical symptoms of severe malaria:

• Severe anaemia
• Acidosis
• Hypoglycaemia
• Acute respiratory distress syndrome
• Acute kidney injury
• Severe jaundice

Answer 29

• Severe anaemia = destruction of blood cells by spleen and by parasites.
• Acidosis = accumulation of organic acids - ketoacidosis, kidney injury.
• Hypoglycaemia = failure hepatic gluconeogenesis, increase in glucose consumption.
• ARDS = increased pulmonary capillary permeability.
• Acute kidney injury = acute tubular necrosis.
• Severe jaundice = combination of haemolysis, hepatocyte injury, and cholestasis.

Question 30

Name three forms of malaria prevention.

Answer 30

• The RTS,S subunit vaccine is most advanced vaccine in development (pre-erythrocytic vaccine).
• Vector control - ITNs, etc.
• Chemoprofylaxis for travellers.

Question 31

Name all symptoms of Malaria.

Answer 31

• Anaemia
• Jaundice
• Hypoglycaemia
• Acidosis
• ARDS
• Organ injury (cytoadherence)
• Warm stage - Cold stage - Sweating stage