15 Malaria

Baz Nadjm, Tom Doherty 03/09/18

15.1 Introduction

The problem talking about malaria, is that its a v different disease in different places in the world.

15.1.1 What is malaria?

  • Parasite (Protozoa)
  • Infectious Disease
  • Vector Borne
  • Febrile Disease
  • Global Health Problem (Tropical)
  • Preventable

Biomedical Defn “Disease caused by protozoan parasites of the plasmodium genus, usually spread by female anopheles mosquito”

Ancient disease, all vertebrates can be affected be a malaria species

It’s a disease that can cause 10bn dollars economic loss globally

It’s a shaper of the human genome, through selecting out people before the reach the age of reproduction, think of sickle cell!

15.1.2 Cases and Death

2017 world malaria report, over 200m episodes yearly, estimated 450000 deaths. 90% of these deaths in sub saharan africa.

These figures are about direct mortality, not indirect mortality. An example would be looking at intervention of insecticide bed nets, all cause mortality was doubly reduced when compared to just malaria mortality.

Smoking related diseases: 6million deaths yearly world wide Obesity: 3 million Pneumococcal: 3 million

Malaria is only 1/2 million in comparison!

But when you look at deaths of children under 5 in sub saharan africa, in 2010 it was the leading cause of death. Now it’s about the 4th

There is a bit of a levelling off when it comes to this decline in malaria cases

15.1.3 Geographical

A band across the tropics, some countries at the edge of this band are coming close to eliminating

The distribution of malaria is not homogenous across the continent. Don’t pretend it is.

15.1.3.1 Entomolgical Inoculation Rate

The entomological inoculation rate (EIR): A measure of the amount of transmission of malaria, across the area you happen to be in. You used to capture mosquitoes, volunteers would sit overnight and catch mosquitoes that landed on them. These mosquitoes would be tested for what proportion had malaria parasites.

In coastal gambia, the EIR is 0.1 (infective bites/person/year), in farafenni (three hours inland) the EIR is 1, if you kept going to basse (6 hours inland), the EIR is 10

0.1 means you’d need to be there for 10 years before getting bitten by an infected mosquito

Moshi the EIR is 0-10 Coastal Tanzania, the EIR is 350! You’re effectively getting bitten every night by an infected mosquito.

There is not a western equivalent of a disease that varies this much and is so clinically significant

15.1.4 Hot Spots and Hot Pops

There are hotspots within countries, there are hotspots within towns!

Hot Pops are populations with increased prevalence (forestry workers in cambodia, miners, truck drivers). They’re often linked to population, and so often adult males.

15.1.5 Falciparum prevalence

It is impossible to be too afrocentric when talking about falciparum. 95% of cases occur in SSA. Similar to the deaths.

Vivax is asia, latin america, isn’t a major problem in SSA

Ovale is seen mainly in west africa (it’s confined to a relatively small part of west africa)

Malariae, least important, least common.

Knowlesi, first recognised about 12 years ago, only been reported in the jungles of borneo

15.1.6 Human Malaria

Falciparum - malignant tertian Vivax, Ovale - benign tertian Malariae - quartan

This terminology has come out of victorian, empire based medicine. These terms have stuck about despite the bening, malignant bit not being too useful Tertian fever means fever on day 1 and day 3 (so spike of fever every two days, despite tertian meaning three) Quartan fever means fever on day 1 and day 4 (so spike of fever every three days, despite tertian meaning four)

Remember that a roman numerical system starts on a 1 not on a 0

15.1.7 Life Cycle

This cycle involves humans and mosquitoes. It is asexual cycle in humans, sexual in mosquitoes.

Mosquito cycle is 10-20 days. As it gets colder, the mosquito cycle lasts longer, but mosquitos die faster. So cold temperatures can’t transmit malaria, as they die before parasites are ready.

INSERT THE MALARIA LIFE CYCLE DIAGRAM FROM INTRO LECTURE

Mosquito injects sporozoites (1 mosquito = 25-50 sporozoites) They almost instantaneously go straight into the liver (within minutes) They then breed and become merozoites (1 bite -> 40,000 merozoites come out) This takes 7 to 10 days for falciparum Merozoites almost instantly go into red blood cells and become a trophozoite (ring form for falciparum). This is what you see on a blood film. A trophozoite becomes a schizont. It’s largely the schizonts that are responsible for death, the mature form. This stage depends on the type of parasite system.

Sequestration is the binding of schizones to endothelial lining, only occurs with p falciparum

These schizonts go pop and become more merozoites (1 schizont = 16 merozoites)

Gametocytes are the sexual form of the parasites (male/female), within a red blood cell:

  • Gametocytes will reproduce with opposite gender gametocyte inside mosquito (mid gut)
  • Gametocytes cannot replicate asexually
  • Virtually none of any antimalarial drugs are active against gametocytes. So they may hang around within the blood, even after effective treatment. Can still be a source of new infections (primaquine has some affect in preventing this)
  • These gametocytes will be there for 4-6 weeks

Hypnozoites, these are the form living in the liver. Only occur in vivax and ovale.

15.1.8 Relapse/Recrudescence

Relapse, return of detectable fever, and asexual parasites, due to the rupture of hepatic hypnozoites.

Recrudescence, return of fever, and asexual parasitamia, without the involvement of hypnozoites

15.1.9 Parasite Biomass and resistance terminology

Biomass = The amount of parasites that you have within you at any one time

10% parasitaemia, this equal 10^12 parasites

On treatment if they drop to 0.0001% 10^7. THis is the limit of microscopy detection.

0.00001% = 10^6 parasites (PCR limit of detection). So still 1 million parasites!

The threshold for being febrile is the pyrogenic threshold, it depends on immunity, but if you aren’t immune, the threshold is close to the limit of microscopy detection.

Recrudescence is a failure of treatment, maybe due to drug resistance.

You can’t tell clinically recrudescence from new infection, in research settings you can look at genetics of parasite. 28 days is limit of recrudescence.

Drug resistance is not an all or nothing phenomenon.

R1 resistance, initially patient seems to be better, and slide negative, but then you get a recrudescence of infection. R2 resistance, initially patient seems to be better, but not slide negative, then recrudescence of infection R3 resistance, patient never seems to be better, blood film unchanged.

WHO doesn’t talk about R1 vs R2 vs R3. They talk about early treatment failure and late treatment failure.

This gets more complicated with people with some immunity. An immune person may finish off an infection themselves with an R2 infection.

Sulfadozine/Pyrimethamine (Fansidar) = SP

15.2 Clinical Features

Malaria can present as fever plus pretty much anything!

The classic cycles don’t really often occur. You often just have continuous fever with falciparum.

You can have cough/diarrhoea/coma or anything!

You shouldn’t get distracted by diarrhoea and think of gastroenteritis

Rash and lymphadenopathy are uncommon, but still possible!

15.2.1 Immunity to malaria, Prevelance

EIR : Level of Transmission <1 = very low < 10 = low 10-49 = moderate 50+ = high level of transmission

Another way is to study children and see how commonly they’ve got parasites. To see the parasite prevalence (proportion of population with parasites).

Hypoendemic < 10% Mesoendemic 11-50 Hyperendemic 50-75 Holoendemic >75

In hypoendemic areas you’ll see cases in all age groups In mesoendemic you’ll see kids and teenagers In hyper/holoendemic areas you’ll pretty much only see kids with malaria

Parasite prevalence is talking about people with parasites in their blood, this is not the same as them having clinical disease

15.2.1.1 High transmission area

Age < 6 Months multiple protective factors: Foetal haemoglobin makes red cells resistant to malaria Maternal antibodies protect against malaria Swaddled/more often in mos nets

6mo-5yrs will get repeatedly infected (many times in a year) Either they will get sick, possibly dying, or they well develop an immunity. They’ll stop getting severe disease but will continue to get infection and fever.

5yrs on. These kids may still get parasites, but will develop an immunity to fever. Later on they may get lower parasitaemia (from 30-40, to < 10). Later still they may get an actual immunity to parasites, a “sterile immunity”, but this is actually quite rare

In high transmission areas, as immunity kicks in, these children will get an anaemia, as parasitised cells don’t last as long. Slowly over time you’ll also get a splenomegaly. So a clinical setting you’ll see anaemia presentations

15.2.1.2 Low transmission area

The malaria prevalence in low transmission happens in later age groups, and to a lesser proportion.

In low transmission areas, where less people are immune, you see more severe disease, you’ll see cerebral malaria in older children

In very low transmission settings, you’ll get severe disease in adults, you’ll see multi organ failure.

This led to a real worry that controlling malaria would shift the burden of disease from anaemia, to cerebral malaria, with a higher mortality rate. But this didn’t really happen.

15.2.2 Loss of Immunity

The problem with immunity. Is that everyone talks about it and noone knows really what it is. You can’t really measure it. There’s no measure for this person being immune, and this person not being.

Someone who grows up in a high transmission area is v unlikely to get severe disease. But we can’t measure their likelihood of sickness.

We do know that lack of exposure results in reduction of immunity. This can take as little as 6 months! But the longer they’re away for, the more likely that they’ll lose immunity. This occurs from one high prevalence area to another high prevalence area (different strains of the same species)

Different strains go different places within the body. But pregnancy, parasites are likely to go to placenta (not that the parasites go into the placenta, just the red cells they infect get stuck in placenta). Women are more likely to get severe malaria during pregnancy, due to differing parasite strains expressiung receptors for placenta. You are more likely to get this in your first pregnancy.

HIV related immunosuppression may result in reduction in immunity. Not super likely though. But a pregnant women with HIV more likely to get sick from malaria, than a pregnant women without HIV.

15.2.2.1 Summary

In high prevalence areas, severe disease is seen in:

  • Children
  • Pregnant
  • People entering area (travellers, migrants, refugees)

In low transmission areas, anyone can!

15.2.3 Cases

15.2.3.1 Case One - Case in non immune adult:

Fever ten days post return Splenomegaly Low parasitaemia (0.8%)

IV quinine Splenic Rupture, emergency splenectomy, with a full recovery

15.2.3.2 Case Two - 3 yr old in tanzania

Presents with coma Parasitaemia

Distinguishing severe vs non severe. Clinical vs laboratory features. LOOK AT WHO 2015

Impaired consciousness would count as a clinical feature. Prostration is when a child that should be able to sit, cannot (a good reproducible sign).

Cerebral malaria is a GCS < 11 or a BCS <3, or prolonged convulsions in the presence of asexual parasitaemia. With no alternative cause.Alternative causes include hyper/hypoglycaemia, any metabolic cause, encephalitis/meningitis, sepsis of any cause, primary seizure disorder, intoxication/poisoning. You would often give a child some glucose to start with

Parasite count may or may not be useful, if you have an idea what that population average parasitaemia you could see if above. But really not useful for any individual

LOOK AT SLIDE OF DISTRIBUTION OF PRESENTATIONS

15.2.3.3 Blantyre Coma Scale

Motor 2 Localises to pain 1 Withraws to pain 0 No response

Verbal 2 Normal Cry 1 Abnormal Cry 0 No response

Eyes 1 Follows an object (generally Mum) 0 Closed/Starring

15.2.4 Presenting syndromes in malaria

  • Malaria with imparied consciousness (10%)
  • Malaria with severe resp distress (6%)

  • Malaria with anaemia (1%)

  • If you don’t have one of these syndromes, your mortality is <1%
  • If you have all three syndromes, in a specialist unit (no organ support), your mortality is around 35%
  • Acidosis plus gcs = 38%

  • Acidosis plus anaemia = 7%

This data is pre-artesunate - post artesunate is less!

15.2.5 Treatment

Indications for parenteral treatment: Severe malaria, Persistant vomiting, Parasitaemia >2%, WHO says 5%, Schizonts seen on peripheral film

Meaning of seeing schizonts, is they’re supposed to stick in peripheral tissues (brain, organs, etc). If they arent there, the suggestion is those binding sites are full! There is a hidden parasitaemia that you cannot see.