Siward's Overview of Malaria


Welcome


Hello readers,
  sometime ago (end of 2006) i wanted to know about malaria,
  so i took some time (4 weeks at 70 hours/week) to find information about it,
  and another 3 weeks to organize that into a document.
My original goal was to get a solid basis to find numerical values of anti-malaria measures,
  and i have succeeded in compiling a basis of knowledge,
  but not in finding the numerical data.
The result would take you a day to read, and represents more than a month of literature-study,
  so it might be profitable for you to read,
  and that is why i have put it on the web.

Warning to the reader

I am not a medical doctor, and my knowledge about malaria is far from complete.
Therefore, for those of you who read this because
  they will be going to a country where malaria is endemic,
  please be aware that you NEED to get medical advice from a real doctor ;
Do not let your life depend on what you read here !

Version

This is version 1 , of 2008 march 25

Feedback, author and copyright

If you happen to know about anything that is marked 'unknown' here,
  or that is omitted, or described incorrectly,
  please let me know by sending an email to siward@wanadoo.nl .

This text was written in october/november 2006 and march 2008 by Siward de Groot.
This is a copyrighted text that you can use, modify, and distribute as you see fit,
  provided that
  * you do not change the authorname, and
  * if you distribute a modified version, you clearly mark it as modified.
 
 

Table of contents

1 - Overview of Malaria
1.1 - What it is
1.2 - What it looks like
1.3 - Cause
1.4 - Occurrence
1.5 - Who is at risk ?
1.6 - Protective measure
2 - Mosquitos
2.1 - Mosquito species
2.2 - Anopheles
2.3 - Mosquito lifecycle
2.4 - Mosquito behaviour
2.5 - Mosquito population
3 - Mosquito-bite prevention
3.1 - Removing potential breeding grounds from vicinity
3.2 - Removing potential feeding grounds
3.3 - Curing domestic animals (in asia)
3.4 - Staying indoors at night, and screening doors and windows
3.5 - Spraying insecticides in rooms
3.6 - Using insectice-treated bednets
3.7 - Sleeping in high places
3.8 - Effect of airconditioning
3.9 - Effect of moving air
3.10 - Cover skin with clothing in evening
3.11 - Wash yourself with soap
3.12 - Insect repellents for use on skin
4 - Red blood cells
4.1 - Function and occurrence
4.2 - Structure
4.3 - Creation
4.4 - Destruction
4.5 - Cell wall
4.6 - Immune system
4.7 - Duffy factor
4.8 - Blood proteins
5 - Plasmodium
5.1 - Classification
5.2 - Infective species
5.3 - Live stages of plasmodium
5.4 - Strains
5.5 - Origin of mating partner
5.6 - Times and numbers (of mosquito life stages)
5.7 - Effect of plasmodium on mosquito
5.8 - Response of human immune system to plasmodia
5.9 - Plasmodium's countermeasures against human immune system
5.10 - Resulting level of infected RBCs in blood
5.11 - Fraction of infected RBCs that infect a mosquito.
6 - Immunity
6.1 - Recapitulation
6.2 - Hereditary malaria-specific immunity
6.3 - Mechanisms of acquired immunity against malaria
6.4 - Multiplicity of infection
6.5 - Effects of acquired immunity in low-transmission areas
6.6 - Effects of acquired immunity in high-transmission areas
7 - Malaria disease
7.1 - Infection
7.2 - Uncomplicated malaria
7.3 - Chronic malaria
7.4 - Complicated malaria
7.5 - Severe malaria
7.6 - Classification of victims
7.7 - Diagnosis
7.8 - Treatment
7.9 - Relapses
8 - Anti-malaria medicines
8.1 - Classification of medicines
8.2 - Vaccines
8.3 - Natural Drugs and their derivatives
8.4 - Quinine
8.5 - Derivatives of quinine
8.6 - Primaquine
8.7 - Artemisinin
8.8 - Derivatives of artemisinin
8.9 - Anti-protozoans
8.10 - Anti-biotics
8.11 - Medicines that are combinations of drugs
8.12 - Curative therapies
8.13 - Special therapies
8.14 - Resistance against medicines
8.15 - Herbal medicines
8.16 - Future medicines
8.17 - Medicine policies
9 - People
9.1 - Illustration
10 - Epidemic
10.1 - Some theory on computing prevalence of malaria
10.2 - Limitations of this model
10.3 - Relevance of this model
10.4 - Localizedness of malaria
10.5 - Occurrence
11 - Anti-malaria measures
11.1 - Measures to reduce daily survival chance of mossies
11.2 - Measures to reduce mosquito population.
11.3 - Measures to reduce contact between mossies and people
11.4 - Measures to reduce fraction of people that are infectious
12 - Economic
12.1 - Total cost of malaria
12.2 - Direct costs
12.3 - Indirect costs
12.4 - Total funding of anti-malaria effort
12.5 - Cost of medication
13 - Politic
14 - History
15 - Malaria in Ghana

 
 

1 - Overview of Malaria

This presents a short overview,
  informational for travelers to areas where malaria is endemic,
  and also usable as introduction for more detailed descriptions given furtheron.

 

1.1 - What it is

Malaria is a life-threatening disease that is common in most developing countries.
It can cause death within 48 hours of first symptoms.
Malaria affects 300-500 million people, and kills 1-2 million people per year.
Over 90% of all cases of life-threatening malaria occur in African children.
Obviously it causes much grief ; It also causes a lot of economic costs.

Malaria is caused by a protozoan (slightly larger than a bacterium)
  of genus 'Plasmodium'.
  (In rest of this text, 'Plasmodium' will be abbreviated as 'P.'.)
There are 4 species of plasmodia that infect humans,
  of which P.falciparum is most dangerous, being cause of nearly all deaths.
  P.falciparum occurs mainly in Africa.
Malaria is transmitted from one person to next by a small mosquito, of genus Anopheles.
  (In rest of this text, 'Anopheles' will be abbreviated to 'A.'.)
  Anopheles are active from dusk till dawn, and often bite when you are sleeping.
  There are several species of Anopheles, each with their own characteristic behaviours ;
  In Africa, dominant one is A.gambiae, which prefers to rest indoors.

There does not yet exist vaccination against malaria.
There is effective preventive medication.
Malaria is curable if diagnosed and treated promptly and correctly.
If not treated promptly enough, patient dies, even in a modern hospital.

To prevent malaria :
* take your anti-malarials regularly, as prescribed.
* minimize chance of getting infected, by protecting from mosquito bites,
  for which the usual measures are :
  screening doors and windows,
  sleeping under a bednet,
  spraying sleeping room with insecticides,
  wearing long pants and sleeves during evening, and
  applying mosquito-repellent to exposed skin when outdoors.
* if malaria has developed in your body :
  visit nearest medical facility as soon as possible for emergency treatment.
* if you go to a place from where a well-equipped hospital can not be reached within 24 hours
  (taking into account that you would not be in good shape for travelling),
  take emergency medicines with you.

In most cases, patient is too poor to afford any of these protective measures.
Nevertheless, malaria does not eradicate the indigenous population of endemic areas
  because they develop resistance to it after being exposed to it for many years.
  (more precisely: children develop resistance or die.)
 

1.2 - What it looks like

First stages of malaria can look a lot like a severe case of flu :
  cold shivers, fever, headache, vomiting, general ill feeling, muscle- or joint-aches.
  Not all of these symptoms need to occur.
Malaria can (sometimes) kill within 48 hours of first symptoms.
Additionally, anti-malaria medicines take circa 12 hours to reach full effect.
You should not count on hospitals being open at night, in a developing country.
Medical attention should be sought immediately when you have any symptoms that could be malaria.

Time from infection to first symptoms differs per species of parasite ;
  for P.falciparum it is 10-14 days, for P.malariae it is circa 30 days.

Population of areas where malaria is endemic develop a limited resistance to malaria
  (or die before they have developed such resistance),
  to extent that they usually don't die from it ;
They do experience malaria 'attacks' circa once per year, which make them very ill.
For them too, anti-malarial medicines are helpfull, in as far as they can afford them.
 

1.3 - Cause

Malaria is caused by a small unicellular parasite, a 'protozoan' called 'plasmodium',
  that multiplies in human body, feeding on red blood cells ;
  In severe malaria, victims hardly have any red blood cells left.
There are 4 subspecies of plasmodium that can cause malaria in humans :
  P.falciparum, P.vivax, P.ovale, and P.malariae.
Almost all of the estimated more than 1 million deaths per year due to malaria
  are attributable to P.falciparum.

Function of red blood cells in human body is (mainly)
  transport of oxygen from lungs to rest of body,
  so if red blood cells are destroyed, that is bad enough,
  but in severe malaria, caused by P.falciparum,
  they also stick to eachother and to walls of bloodvessels,
  leading to blocked bloodsupply in brain, heart, lungs, and kidney,
  which is often fatal.

Malaria is transmitted from one person to next by bites of a mosquito, of genus 'Anopheles' ;
  when mosquito sucks blood from an infected person, parasites come along with blood,
  and a specialized form of parasite can survive mosquito's stomach,
  and develop inside mosquito.
When infected mosquito is hungry again, it bites next human,
  and before it starts sucking blood, it injects some 'saliva' into human,
  which contains painkillers (so victim, who is usually sleeping, will not notice mosquito)
  and anti-coagulants (for easy sucking),
  and, in infected mosquitos, it also contains plasmodium parasites.
 

1.4 - Occurrence

Anopheles mosquitos breed on water, so they don't live in deserts,
  although some specialized anopheles species can survive long dry spells.

Anopheles mosquitos live only shortly, just a few weeks ;
Whether this is long enough for plasmodium parasite to
  develop inside mosquito into a form that can infect humans,
  strongly depends on temperature :
  below 20 oC no transmission of malaria is possible ;
  below 25 oC P.falciparum can not be transmitted, but some other plasmodia can.
Therefore malaria as an epidemic does not occur in colder areas,
  (including places at high altitude inside regions where malaria is endemic).

Malaria used to occur in southern Europe and in south of USA, but it has been eradicated there.
In Europe it was eradicated mainly by draining of swamps and other sites of stagnant water,
  thus destroying mosquitos' breeding grounds.
In southern USA, it's eradication was also to a large extent due to
  screening and spraying with DDT, and treatment of infected patients with quinine ;
  Mosquitos that can transmit malaria still exist there, but plasmodia have all been killed.
  Therefore USA continues to run risk of new epidemics from travellers that get malaria abroad.
Between 1955-1969 there was a large effort to rid entire world of malaria,
  which was successfull in areas where re-infection rate was moderate to low,
  but failed when mosquitos developed resistance to DDT,
  as effective insecticides became more expensive,
  and donor-countries were less willing to pay for them.
Since that time, much more has been discovered about malaria,
  resulting in improved methods for killing mosquitos and new medicines against plasmodium.

Currently malaria is endemic
  in Americas from middle-america to northern brazil,
  in Africa from tropic of cancer to tropic of capricorn,
  in Arabia in Iraq and on coasts of Arabic peninsula,
  in Asia from Aghanistan to PapuaNewGuinea plus some areas in China.
Severity of malaria in these areas differs a lot ;
  Intensity of malaria is very dependent on infection rate, and thus on mosquito population,
    and different mosquito species, adapted to different climates,
    have different activity levels, and different habits.
  Mosquito that most effectively transmits malaria is A.gambiae, which is common in africa ;
    In most other places, other, less effective, mosquitos prevail.
  Most deadly plasmodium species, P.falciparum, is main cause of disease in Africa ;
    on other continents, less deadly P.vivax is main cause.
  In africa, there are two places where malaria is especially common, namely Ghana and Sudan,
    and in Sudan it is 3 times worse than in Ghana.
Places where malaria occurs, and intensity of risk there, also vary a lot inside countries ;
  Along coast of Ghana, roughly between ivory coast and Accra,
    climate is not so suitable for transmission,
    while climate of rest of country is suitable for that.
  In sudan, there are large swamp areas in south, which form ideal breeding grounds.
Mosquitos are also much more found in rural areas than in cities,
  because in cities their risk of getting killed is higher,
  and there is less food for them
  (mosquitos get their energy from sugars from plants,
   and only females mosquitos bite,
   to suck blood to gain amino-acids for their eggs to develop).
In all areas mentioned above as relatively safe,
  they still occur often enough that it is imperative for travellers to protect themselves.
 

1.5 - Who is at risk ?

Population of endemic areas generally has a limited form of immunity against malaria,
  so they would have a malaria attack about once a year, but would not die from it ;
  For them, too, protection would be beneficial, but most of them can not afford it.
Travelers to endemic areas do not have any immunity, so they must protect themselves.
People that emigrated from an endemic area, lose their immunity after circa half a year.
Women from malaria-endemic areas that have their first or second pregnancy
  run as much risk as people without immunity,
  because there is a specialized form of P.falciparum that infects placenta,
  and immunity to that form develops only after getting infected.
Infection during pregnancy
 increases risk of low birthweight and premature delivery,
 and there is sometimes transmission of malaria from mother to child.
Young children in endemic areas, from a few months to 5 years old,
  have not developed immunity yet ;
  Protecting them is beneficial, because
  their chance to survive and become immune depends on rate at which they are infected.
 

1.6 - Protective measure

Most important protective measures are :
* Wear clothing that covers skin as much as possible, from dusk till dawn,
* Sleep under an insecticide-treated bednet,
* Remove stagnant water from around house (even small amounts, like in a cup filled by rain),
* Put screens on doors and windows,
* Spray walls and roof of rooms with insecticide, or burn a mosquito coil or citronella candle,
* Apply insect-repellent to all exposed parts of skin when outdoors,
* Take preventive medication regularly, as prescribed by your tropical healthcare specialist.
* Whenever you have symptoms that could be malaria,
    visit a sufficiently equipped medical facility immediately ;
  If this is not guaranteed to be possible within 36 hours,
    make sure to carry emergency medicine for treatment
    (which is much stronger than preventive medicine).
* Do not bring limburger cheese with you, as that kind of smell attracts mosquitos.
* Wash your socks.

It is sometimes claimed that garlic or other herbal medication can be used against malaria,
  and it is true that some of these have some anti-malarial effect,
  but they are not effective enough to shield you from infection.
Exceptions to this are bark of cinchona tree and leaves of Artemisia annua plant,
  but these also contain substances that are not beneficial to you.
You can get medicines that contain extracts of plants mentioned above,
  which contain effective compounds in known quantities,
  so can be accurately dosed, to minimize unpleasant side-effects.

Be aware that taking preventive medication does not mean that you can not get malaria,
  and does not mean that you do not need to take other protective measures.
Effectiveness of preventive medication is usually in the 90 % - 99 % range,
  and if for example it is 95 %, then this means that
  the medicines take care of 19 out of 20 infectious bites that you get.
  In the most endemic areas,
  the infectious biting rate can be as high as 1.6 per person per night,
  so, on average, using the medicines, you would be infected after 12 nights.
Protecting yourself from getting bitten thus remains necessary.
Even the best protection only reduces the chance that you get malaria,
  which means that you might be unlucky,
  so you must always have access to emergency treatment on short notice.

Medicines bought in developing countries are sometimes fake,
  containing no effective ingredients.
This occurs only in a minority of cases,
  but you should not let your life depend on it, if you don't need to.
Also be sure to check the expiry date of the medicines ;
  if the box does not mention any expiry date, then the medicines are certainly fake.

Be strict about your countermeasures.
Malaria can kill you.
 
 

2 - Mosquitos

Mosquitos are flying insects,
  that usually breed in stagnant water (eg swamps),
  bite humans or animals to feed on their blood,
  and in doing that can transmit diseases.

There are islands in pacific ocean that do not have any mosquitos,
  so it looks like there is nothing against eradicating all mosquitos from whole world
  (except that it would not be worth it's huge cost).
 

2.1 - Mosquito species

Malaria is mainly transmitted by mosquitos,
  and, conversely, mosquitos are mainly important because they transmit diseases.

There are about 3500 species of mosquitos, grouped into 41 genera.
Malaria is transmitted only by mosquitos of genus 'anopheles'.

Of this genus, there are 460 species described
  (meaning that more species could still be discovered).
Not all of these are 'vectors' of malaria
  ('vector' means that they are capable of transmitting a disease).
Currently only 68 species of anopheles are known vectors of human malaria, because
  some anopheles do not feed on humans,
  some are not susceptible to human malaria parasites,
  some have a life-span too short to allow the parasite to mature inside it.
 

2.2 - Anopheles

Anopheles mosquitos are 8 -13 mm long (looked smaller in a picture i saw),
  with a body circa 1 millimeter thick,
  and mostly whitish-translucent
  (when they have sucked blood, they are red).

Like all mosquitos, adult anophelines have slender bodies
  with 3 sections: head, thorax and abdomen.
Head contains
  two eyes,
  one proboscis (snout) : elongate, forward-projecting, used for feeding,
  two many-segmented antennae, for smelling ;
    these antennae are important for detecting host odors
    as well as odors of breeding sites where females lay eggs.
    ('Malaria' is derived from 'mala aria' which means 'bad air').
  two sensory palps.
Thorax has usual internal organs,
  and serves as attachment for three pairs of legs and one pair of wings.
Abdomen is for food digestion and egg development ;
  it expands considerably during a blood meal, and shrinks during egg-laying.

Anopheles mosquitos can be distinguished from other mosquitos
  by the palps, which are as long as the proboscis, and
  by the presence of discrete blocks of black and white scales on the wings.
Adult Anopheles can also be identified by their typical resting position :
  males and females rest with their abdomens sticking up in the air
  rather than parallel to the surface on which they are resting.

Anopheles species differ in
  * whether they prefer blood from humans or from animals
  * whether they prefer to live near human settlements (anthropophilic) or not
  * whether they prefer to bite indoors or outdoors
  * whether they prefer to rest inside house after having bitten, or prefer resting outside
  * how long they live
  * what climate they are best adapted to
  * their feeding and mating patterns
  * their sensitivity to insecticides

Table (very incomplete) :
SpeciesLocationAnthropophilicBiteRestBitetimeRemarks
A.gambiaeAfricayesindoorindoorlatenightprefers biting ankles and feet (related to feet smell?)
A.arabiensisAfricanooutdoor??seems to like rivers.
A.funestusAfrica?outdoor??can survive dry spells.
A.QuadrimaculatusSouthUSA????
A.freeborniSouthUSA????
???Mexico????
A.albimanusCentral+SouthAmerica?outdoor??
???Papua New-Guinea????

Anopheles species in asia are zoophilic
  ie they primarily prey on some species of animal, cows being well known,
  and humans are second choice.
Anopheles species in africa primarily prey on humans.

When a disease is spread by an animal that is itself not cause of that disease,
  that animal is referred to as 'vector' of that disease.
The best vectors
  are abundant and long-lived,
  prefer to feed on humans, and
  usually prefer to live in close proximity to human habitation.
Anopheles gambiae has all these characteristics and is, consequently, the best vector.
This is an important factor of high malaria prevalence in Africa.

Mosquitos do not specialize in type of plasmodium they transmit.
Mosquitos generally don't seem to become ill from plasmodia in their bodies
  as plasmodia can develop inside mosquito, but can not repeatedly multiply there.
They are adversely affected by plasmodium, however,
  because an infectious mosquito usually needs multiple bites to get a full blood meal,
  while a non-infectious one can ingest a full meal with one bite ;
This might be caused by human immune-system detecting injected plasmodia,
  and human body reacting to it.

'Species' are usually understood to be
  groups of similar animals that can reproduce among themselves,
  and if two individuals can reproduce together, then they are from same species.
For A.gambiae this is not quite so.
Literature has it that it forms a 'species-complex',
  of which A.arabiensis and A.funestus are also part.
What exactly this means in practice, i don't know.
 

2.3 - Mosquito lifecycle

Like all mosquitos, anopheles have four stages of life : egg, larva, pupa, and adult.
 

2.3.1 - Adult

Adult anopheles are flying insects.
They are crepuscular (active at dawn or dusk) or nocturnal (active at night).

FOOD

Anopheles feed on nectar,
  from flowers, extra-floral nectaries, leave-edges (of cassava plant for example),
  and other sources of sugar (eg maize pollen, honeydew produced by mealybug),
  from which they derive their energy,
  but females also need blood, as source of proteins for development of eggs ;
As human blood is unusual in composition by having very few of one type of amino-acid,
  a blood-meal can not be completely converted to offspring of mosquito,
  and fraction of blood that can not be used for synthesis is available as source of energy.
Females can do completely without sugar (although they feed on nectar if given chance),
  provided that they can eat blood at least every 3 days,
  but males, being physically incapable of biting animals, absolutely need a sugar-food.

MALES

Males live for circa 1 week (circa half as long as a female), and die,
  and consequently mosquito populations consist of twice as many females as males.
Males spend their whole life on feeding from sugar-food sources and on swarming.

MATING

In most Anopheles species, mating is usually done at dusk ;
  males form swarms then, into which a female flies to get fertilized.
These swarms often occur at places where a female can lay eggs or feed on sugar.
These swarms occur mainly at dusk, and last for 1-2 hours ;
  at dawn there is similar (but much less pronounced) swarming behaviour.
This might be caused by need for some light,
  for female to find swarm, or when inside swarm, to interact with a male.

One female gets fertilized by multiple males, and stores their sperm in her body ;
  it is used later, after she has fed on blood, and eggs are being developed.
This way survival of small number of mosquitos still represents a relatively large genepool,
  and female does not have to do a mating flight with weight of eggs in her body.

It is likely that females are attracted to swarms of males,
  and, when in a swarm, by individual males,
  which might be by some smelly substance males secrete
(It was found that when males can not feed on sugar,
  their chances of successfull mating are much smaller,
  unless they are in a very small cage (where male would be hard to miss)).

It is not impossible that males convert part of sugars they eat,
  and transfer this to female when they mate.

BITING

After female is fertilized (typically at dusk), she starts seeking a human to bite.
For A.gambiae it has been found that peak biting time is
  from a few hours after swarming time, to end of night
  (but biting is not unusual from right after fertilization to early morning).
This would increase chance that victim is asleep, and thus chance for mosquito to survive biting.
So other species likely behave similarly.
During time between getting fertilized and peak biting time,
  they probably sit down somewhere.
Those species that like to be indoors, can settle down on a wall in a house,
  waiting untill late at night before they bite ;
Female is guided to victims by scents in air,
  for which she needs to discern direction scent comes from,
  which is probably why antennae are placed as far apart as possible.
A house that has little human smell would give a smaller chance of getting bitten.
A house that is upwind from a mating/sugarfeeding location
  would give a larger chance of getting bitten.

When female finds a victim, and it looks safe and acceptable enough, she bites it.

First thing a mosquito does when it bites, is inject some saliva into victim ;
  this 'saliva' contains pain-killers, so victim won't notice being bitten,
  and anti-coagulants, for easy sucking,
  and, if mosquito is infected, also contains malaria parasites.

An uninterrupted blood-meal usually takes 2-3 minutes.
Quantity of blood ingested at a single feed can be up to 25 mm3 ;
  this amount exceeds normal body weight and size of mosquito.

RESTING

After having sucked blood,
  they find a place to rest, to digest food and let eggs develop ;
This process depends on temperature : it usually takes 2-3 days in tropical conditions.
Some species prefer to rest inside house, while others prefer outdoors.
During that time, place previously taken by blood (being digested)
  is becoming used by eggs (that are developing) ;
  total size of eggs is however smaller than that of blood ingested
  (to extent that a female that failed to find a place to lay eggs
   can bite a second time, and develop a second batch of eggs, before laying them ;
   second batch is circa half size of a normal batch in that case).

EGG LAYING

When eggs are ripe, mossie starts seeking for stagnant water, to use as a breeding place,
  for which she prefers clean water over polluted water as found in gutters.
It is likely that she flies downwind, to find same breeding area she herself emerged from,
  which would be near local swarm and sugar-feeding locations.

After mossie has laid eggs,
  she goes looking for males for mating or sugar for eating,
  whichever she encounters first.
Females are known to be attracted to smells like sweet flowers
  and at this stage in their life are often attracted more to sweet smells than to host-smells
  (which are smells that guide them to a human victim).
 

2.3.2 - Gonadotrophic Cycle

Female anopheles repeat this mating/biting/resting/egglaying cycle for rest of their lives.

This cycle is called 'gonadotrophic cycle'.
It's duration varies with temperature and per species.
In A.gambiae, cycle takes 48 hours when average day-night temperature is 23 oC .
In malaria models, gonadotrophic cycle is measured in degree-days,
  and i did not find a definition of that in what i read.
In A.gambiae living at a temperature near 25 oC,
  speed of it's metabolism is roughly proportional to ambient temperature minus 14 oC.
So if i define 'degree-days' like that, then A.gambiae needs 18 degree-days for egg-maturation.
  (and thus if temperature is 20 oC they would need 3 days for it).
Female anopheles feed on blood every 2 - 3 days,
  starting 2 - 3 days after they emerge from pupa
  (in which time they feed on blood 2 or 3 times, to fully mature).

Adult female mosquitos live for upto 4 weeks on average in a laboratory,
  1-2 weeks on average in nature.
They can withstand temperatures up to 40 oC ; 42 oC kills them fast.

Models of mosquito population size often assume a constant chance of surviving to next day,
  which is often in order of magnitude of 75 % .
Their chances of survival are said to be mainly determined by
  temperature, humidity, rainfall, and getting killed when feeding on blood.
 

2.3.3 - Egg

Egglaying is called 'oviposition' in Latin.
Adult female mosquitos lay 50-200 eggs per oviposition ; 100 is a typical value.
Eggs are laid on surface of water, as individual eggs (not as a group),
  where they float, because they have floaters on either side
  (which is unique ; other insect's eggs have only one floater).
Eggs, when fully developed, are circa 0.6 mm long and 0.2 mm in diameter ;
  they are dark brown to black when they are near hatching.
Eggs are not resistant to drying.
Eggs hatch within 2-3 days,
  although hatching may take up to 2-3 weeks in "colder climates".
Out of these eggs, larvae emerge.
 

2.3.4 - Larvae

Larvae are oxygen-breathing filter-feeders.
They live on surface of water,
  feeding on algae, bacteria, and other micro-organisms that live in surface-layer.
They are motile,
  swimming
  either by jerky movements of entire body, moving with an S-shaped motion,
  or through propulsion with the mouth brushes.
They dive underwater when disturbed, but need to surface frequently to breathe.

Larvae have
  a well-developed head, with mouth brushes (primarily used for feeding, but also for propulsion),
  a large thorax, and
  a segmented abdomen, with spiracles on 8th abdominal segment, through which they breathe.
They have no legs.
In contrast to other mosquitos, Anopheles larvae lack a respiratory siphon
  and for this reason position themselves so that their body is parallel to surface of water.
  Could this be why they need stagnant water ?
  Could this be why they need two floaters, to not drown as soon as they emerge from egg ?

Larvae have a natural enemy in 'mosquito fish' (Gambusia affinis),
  but this only applies to those that live in larger bodies of water that have that fish.

Larvae develop through 4 stages (called 'instars') ;
  At the end of each instar, larvae molt, shedding their exoskeleton, or skin,
  to allow for further growth.
After this sequnece of instars, they metamorphose into pupae.

Amount of food available to larvae is important,
  as it determines energy-reserves of mosquito they will develop into,
  which determines it's reproductive success,
  and it's survival chances immediately after birth.
 

2.3.5 - Pupa

Anopheles pupa does not have separate head and thorax,
  but it has a combination, called cephalothorax,
  which floats on top.
Abdomen has a curved shape and floats underneath cephalothorax.
Thus pupa is comma shaped when viewed from side.

Pupae are oxygen-breathing, and must come to surface frequently to breathe.
They breathe through a pair of respiratory trumpets on the cephalothorax.
After a few days as a pupa,
  dorsal surface of cephalothorax splits, and young adult mosquito emerges.
 

2.3.6 - From Egg to Adult

Time from laying egg to mosquito emerging from pupa depends on species and ambient temperature.
It is usually 10-14 days in tropical conditions, but some mosquitos do it in 5 days.

When water in which eggs were laid dries up before fly emerges from pupa, they die ;
  nor eggs nor larvae nor pupa can stand drought
In some species of anopheles, adult can survive dry spells, by sleeping through it ;
  this is called 'aestivation' ;
I read about one example of this, which concerned A.arabiensis
  living in roof of a cow-shed, from where it emerged periodically to feed on blood.
Rainfall is also dangerous for eggs (and larvae and pupae),
  as they might get washed away to a place that would dry up.
 

2.3.7 - Adult

Adult mosquitos start mating circa 2- 3 days after having emerged from pupa.
Females start seeking a human to bite after being fertilized.
First batch of eggs may require 2 to 3 bloodmeals to mature,
  because fly itself still has to mature.
After first egg-laying, they start mating/blood-sucking/egg-laying cycle,
  in which they mate once and suck blood once and lay eggs once per cycle,
  as described above.

Adults have natural enemies in spiders.
When they fly, they can get caught in a web.
This may be one factor that makes males live shorter than females, as males fly every day.
 

2.4 - Mosquito behaviour


 

2.4.1 - Activity Time

Most adult Anopheles are crepuscular or nocturnal in their activities.
Thus, blood-feeding and oviposition (laying eggs) normally occur
  in the evening, at night or in the early morning, before sunrise.

Anopheles mosquitos prefer to bite when it is dark,
  probably mainly because they would have better chance of surviving blood-sucking time,
  but maybe also because they have infra-red sight,
  which would be more usefull for finding exposed skin in absence of places heated by sunlight.
 

2.4.2 - Attraction Factors

Anopheles are attracted by human temperature, CO2, odour, and others (research is ongoing).
Mosquitos mainly find their way around by smell ;
  they are attracted by smells emitted by a bacterium (brevibacterium epidermis)
  that normally exists on human skin, especially skin of foot
    (and especially when it has not been washed),
  which has been proven to be similar to smell of limburger cheese.
Chemicals that constitute that smell include
  short-chain fatty acids and
  methane-thiol, responsible for the "cheesy odour".

Mosquitos can be trapped by 'light-traps' (which is usefull for research) :
A lightbulb (switched on ofcourse)
  was placed near an insecticide-treated bednet under which a human was sleeping ;
Under lightbulb was an old tin can,
  and in top of can there was a piece of paper folded into shape of a cone,
  with narrow end of cone down, and having an opening just big enough to let a mosquito pass ;
Mosquitos would be attracted by lightbulb
  (probably by it's heat ; it also works if you use blacklight tubes ; these also become warm.
   attempts to kill mosquitos with ultraviolet radiation were not successfull.)
  they then bump into lightbulb, fall down into cone, and slide into can,
  from which it would be hard for them to escape.
It was found that putting crumbled-up inch-wide strips of paper in can
  reduced likeliness that they escaped, as they tended to hide among them ;
  (Other investigations found that they are hard to kill by insecticidal gases
    because they hide in narrow spaces where gas would mostly blow past.)
It was found that
  more mosquitos were collected when light-trap was placed at highest point of net
  than when it was placed at floor,
  suggesting that mosquitos go more by smell than by light.
It was also found that more mosquitos were caught if trap was near feat
  than when it was near head,
  suggesting that feet-smell is main attractive smell for mosquitos ;
  In other experiments, where mosquitos could freely choose where on a human they would land,
    it was found that more of them landed on ankles and feet than on other parts of body.
 

2.4.3 - Victim-Seeking

When mosquitos are looking for a human to bite, they follow smells,
  and if there were a crack in wall of a house, smell would emerge there,
  and mosquitos would enter house there.

It is likely that when looking for a human to prey on,
  they fly relatively low, probably mostly not higher than most houses,
  as that would give them best chance to detect smells of their preys ;
  There are indigenous people in southern Egypt that
  protect themselves by sleeping in towers that they build for that purpose.

Mosquitos do not usually fly long distances, apparently.
From a study undertaken in a valley in east-africa,
  where A.arabiensis had it's habitat near river in centre of valley,
  "occasionally" A.arabiensis were found in villages bordering valley,
  which were probably circa 7 km distant from river.
This still leaves open possibilities that they
  migrate over long distances over time, transferring from one habitat to next,
  or are blown by strong winds to far-away places.
One report says that 10 km is unusual, and 100 km has been observed but is extremely rare.

How fast moquitoes fly was not mentioned in what i read.
It does seem to be important, however, since, as mosquitos are guided by smell,
  they fly against wind,
  and must fly faster than wind, or they would never reach origin of smell.
Which would lead to conclusion that there is some maximum windspeed
  above which mosquitos do not like to fly.
As a rough guess, from mosquitos i saw in Netherlands, i think 10 km/hour is not unusual,
  which equals 2.7 m/s,
  and a wind with that speed is said to have a force of 2 to 3 beaufort,
  which are described as "light breeze" and "gentle breeze" respectively.
This would fit well with observations that mosquitos swarm for circa 1 hour,
  and are unusual to be found 10 km from their base.
One person claimed that mosquitos do not like air-currents caused by ceiling-fans.

Mosquitos do not like smoke.
It was found that women sitting unhealthily near inefficient indigenous cooking fires
  were less likely to get bitten by mosquitos.
 

2.5 - Mosquito population

There is some evidence that mosquitos occur in groups.
Especially for A.gambiae, which likes to stay near human settlements,
  it is probably true that most mosquitos stay near same settlement they were born near to.
For other anopheles species this may be less true.
Mosquitos usually fly less than 10 kilometers, 100 km being extremely unusual ;
  It may be that a strong wind could sweep mosquitos away over long distances.
It was found that in two villages (more than 10 miles apart)
  that each had malaria,
  strains of plasmodium in each village were genetically different,
  which means that mosquitos from one village did not reach other village.
So a mosquito population is not a continent-wide thing,
  but local to a village or town,
  especially for most effective vector A.gambiae.

I assume that female mosquitos, after being fertilized, and being guided by smell,
  fly against wind.
When they are ready to lay eggs,
  they could reach their old breeding ground by simply flying with wind,
  which would also be most efficient, as they are much heavier when filled with eggs.
As they are said to prefer clean water for breeding,
  it is probably not true that they are guided to their breeding grounds by smell,
  as is sometimes claimed.
 

2.5.1 - Population Size

When looking for info about malaria,
  i found no info about which factor constrains size of mosquito population,
  so what follows is just a guess.

A female anopheles lays circa 100 eggs,
  each egg has some chance to survive and develop into a mosquito,
  half of these mosquitos are female,
  these have some chance to become fertilized and feed on blood and live long enough to lay eggs.
If product of these factors is bigger than 1, then mosquito population size will increase.
If it is smaller, then population will decrease.
Increase or decrease is then exponentially,
  with a timeconstant of probably circa 15 days :
  12 days for eggs to develop,
  3 days for emerging mosquitos to die from exhausted energy reserves,
  or 3-4 days to feed, mate, bite and lay eggs.

Survival chances depend on
  environment, climate, and availability of food, blood and breeding sites.
Reproduction chances depend on survival and chance for a female to find a swarm,
  and for males in a swarm to have eaten enough sugar to successfully mate.

Environment and climate do not depend on mosquito population size,
  so if chances are good enough for one mosquito, they could multiply to infinite numbers.
In most parts of africa, climate is conducive for mosquitos all year round.

Chance to find a swarm would probably increase as swarms are larger, not decrease,
  so does not form an upper limit for population size.

As there are more mosquitos, they compete for victims to bite ;
  it was found in endemic areas that number of bites per person per night varies widely,
  so it is likely that this is not limiting factor,
  except possibly for those areas that showed highest biting rate.

Availability of breeding sites is a more uncertain factor.
Pupas are roughly as big as a mosquito,
  so 100,000 of them would fit on a square meter of water,
  but they also need food : micro-organismas from surface layer of water,
  and i have no idea how abundant these are.
It is said that mosquitos can breed in cups filled by rainwater,
  (in tropical conditions, where pollen could be blown into cup)
  so 20 cm2 would suffice for at least one pupa ;
  this provides a lower limit of 500 pupas per square meter.
This lower limit is probably nearer to truth than upper limit of 100,000 per m2 .

Studies in a highly endemic area in Kenya showed that
  rate of infectious bites was a bit less than one per person per night,
  and only a few percent of bites were infectious.
Total number of bites would thus be smaller than 50 per person per night,
  and thus for a village of 100 persons, there would be less than 5000 bites per night,
  which would be equivalent to a population of 12,500 adult female mosquitos.
Female mosquitos live circa 2 weeks on average,
  and it takes a similar amount of time for an egg to develop into a mosquito,
  so number of female eggs at any time roughly equals number of female mosquitos.
This mosquito population would need not more than 20 cm2 per mosquito for breeding,
  and half of eggs are female, so total number of eggs is circa 25000,
  so total needed size of breeding water is not more than 50 square meters
  (and might well be ten times less).
Mosquitos fly not more than a few miles per night,
  so these breeding grounds would need to occur in an area of a few square miles.
Thus if 1/100,000th of area was suitable as breeding ground, it would suffice,
  so i think in practice breeding grounds in rural settings can be considered to be abundant,
  and do not limit mosquito population size in most natural rural environments.

Thus i conclude that probably
  availability of sugar foods is limiting factor of population size in rural areas.
From this it follows that
  an average square meter of nature provides some sugar-food and breeding area,
  and number of mosquitos that that can support is limited by availability of sugar-food.

In a rural setting, like Accra, which has a surface area of a few square miles,
  and a human population of a few million people,
  there is a lot of roads and buildings and things like that,
  which do not support mosquito life,
  and there are also some nature-like patches that do support mosquito life.
There are additional non-nature-like breeding sites, like gutters.
There are probably hardly any non-nature-like sources of sugar available to mosquitos.
Thus in rural settings too,
  availability of sugar-food would be limiting factor of mosquito population size.

Dr. Gary found that (in semi-natural conditions with little risks and exertions)
  chance of successfull fertilization of a female
  in a swarm of sugar-deprived males was circa 1 % ,
  while in a swarm of sugar-fed males, it was 88 % .

The above line of reasoning does not prove that
  sugar-food-availability is the limiting factor on mosquito population size.
In a sufficiently sparsely inhabited part of countryside,
  the availability of humans for biting would be limiting factor.
How much would be considered "sufficiently sparse" i do not know ;
  it might be determined by
  comparing malaria prevalence among similar villages of different sizes in same area
  (about which i did not happen to find data).
 
 

2.5.2 - Consequences of Sugar-food as limiting factor

As number of mosquitos increases,
  they have to share food (eg nectar from flowers) with more mosquitos,
  so chance to get enough sugars to survive decreases,
  until product of all survival factors becomes 1 ;
  then mosquito population has reached it's final size.

If this conclusion is correct, then it would also seem likely that
  even for large cities like Accra,
  mosquitos would have their main feeding grounds outside city.
Consequently mosquito biting rate could be expected to be lower on side of city
  that is up-wind for usual direction of wind ;
  in case of Accra it would mean that you would get bitten less frequently on sea-side of city,
  because mosquitos, coming from down-wind,
  would find other victims to bite before reaching up-wind part of city.
From this it follows that average biting rate for a large city
  would be lower than average biting rate in rural areas.

Another consequence would be that
  malaria transmission would show increases in seasons when many flowers bloom
  (which would probably be in or after rainy season).

Sugar-food as limiting factor might also explain name 'malaria'.
It is well known that 'malaria' is derived from 'mala aria', which is italian for 'bad air'.
People infected with malaria do not give off any unusual smell.
Mosquitos prefer clean water over polluted water.
They do prefer stagnant water, which in swamps might be associated with smell of decay,
  so this is one possibility for origin of name.
Mosquitos are attracted by stinky-cheese-like smells
  given of by bacteria commonly found on human skin, especially on feet,
  but highest infection rates, and thus highest malaria risk,
    is not associated with concentrations of human population,
    where such smells would be most intense,
  but rather occur in rural settings.
If sugar-food is limiting factor of population size,
  then a fully developed mosquito population will use up all available sugar-food,
  and thus there will no longer be much sweet smell of flowers.
This is a possible reason for name 'malaria'.

Regulation of population size by available sugar-food is a saturated regulation.
Adults live much shorter in nature than in laboratory,
  because they produce so much offspring that their survival chances decrease.
Thus if survival chances decreased, due to some other cause,
  by same factor as average lifespan in lab divided by average lifespan due to competition,
  then mosquito population size would remain same.
This is important for estimating effects of anti-mosquito measures,
  as it means that these measures must reduce survival chances by circa 4/1.5 = 2.7
  before they would make any difference at all.
  
 

2.5.3 - Age distribution of Mosquitos

If there are 1 million mosquitos in an area (as limited by availability of sugar-food),
  it could mean that
  females live for 2 weeks on average,
  during which time they lay circa 450 eggs,
  and chance for an egg to develop into a mosquito is 1/225 .
It could also mean that
  females live for 1 week on average,
  during which time they lay circa 200 eggs,
  and chance for an egg to develop into a mosquito is 1/100 .

As will be mentioned in chapter about plasmodium,
  plasmodia need nearly two weeks to develop inside mosquito, before they can infect humans.
Consequently, in former case malaria would be transmitted,
  while in latter case nearly none of mosquitos live long enough to become infectious,
  so malaria would be much less of a burden, and much easier to combat.

If total amount of mosquitos is limited by availability of sugar-foods,
  and assuming this is distributed on a first-come first-serve basis,
  young and old mosquitos would have equal chances to it.
If that is correct, then
  increasing chance for eggs to develop into mosquitos
  would decrease average lifetime of mosquitos.
Conversely, if adult mosquito had a lower chance of survival,
  then there would be less competition for sugar-food,
  so that newborn mosquitos would have an increased chance to live to egg-laying age,
  which would increase overall chance for an egg to make it to that age.

It is generally assumed that this is not only factor that influences average mosquito lifetime.
Literature has it that their chances of survival depend on
  temperature, humidity, rainfall, and their ability to successfully obtain a blood meal.
It is also well-known that mosquitos have an irritating tendency to
  splat themselves on windscreen of your car,
  so their lifetime also depends on environment.
In areas where malaria is combatted, another factor is mosquito resistance to insecticides.
Temperature and rainfall also influence amount of flowers from which nectar can be gotten,
  and rainfall would influence distance to which pollen would be spread by wind,
  so these factors are interrelated.

Chance for a mosquito to survive to next day
  is usually considered to be independent of mosquito age.
And is usually found (actually inferred from other results)
  to be circa 70 - 85 % survival chance per day.
In one study in Tanzania it was found (indirectly) that
  estimates of daily survivorship of A.gambiae ranged from 0.77 to 0.84 .
However, if an area has daily survivorship 60 % or lower,
  then mosquitos don't live long enough to let plasmodium develop inside them,
  and consequently malaria is not transmitted,
  and consequently such areas are not studied,
  so it is entirely possible that values lower than 60 % do occur in nature.
 
 

3 - Mosquito-bite prevention


 

3.1 - Removing potential breeding grounds from vicinity

Most effective vectors prefer staying near human settlements.
Studies in africa showed that
  Infection level could vary significantly between villages,
    but not between houses in a village.
  Amount to which this is true depends on mosquito species,
    and was more true for more effective vectors.
That means that mosquitos are relatively local,
  and reducing local mosquito population can be effective.

For species that prefer to bite and rest outdoors,
  attacking them through their breeding grounds is most effective way.
For other species it is also effective,
  but screening, netting and spraying are easier and cheaper.

A method usable by individuals is :
  remove any stagnant water from vicinity, as far as possible, especially clean water.
  eg: remove empty cans, drain puddles.

This is not equally feasible for all locations ;
  fact that someone lives in rainforest increases malaria risk by factor 6 .
 

3.2 - Removing potential feeding grounds

This would require removing flowers from environment.
That would not be nice.
I have seen in Netherlands that
  after artificial fertilizers and weed-killers were introduced in 1960s,
  meadows that previously were filled with flowers, now only had grass,
So in developing countries this might be an unintended effect of modernizing agriculture.
Idea that this would reduce mosquito population is not substantiated by any research.
What has been found is that common food crops like cassava and rice provide sugar food
  via pollen, leaf-edges, and damaged leaves,
  so increased harvest might cause increased mosquito populations.

Related to this is idea that wearing sweet perfumes or aftershaves attract mosquitos.
 

3.3 - Curing domestic animals (in asia)

There are species of plasmodium that cause malaria in humans,
  and that are transported by mosquitos that prefer to blood-feed on animals,
  but bite humans too, if they happen to be available for that.
These occur mostly in Asia.
It has been found to be helpfull to sponge domestic animals (mainly cows)
  with insecticide every 4 - 6 weeks,
  thus ridding them of several diseases,
  which makes animals happier and stronger and more productive,
  and thus makes population willing to spend time and money on sponging.
It also reduces rate of malaria 'infection' (further unspecified,
  probably means average number of infective mosquito bites per person per night)
  by 90 % .
Thus it is more effective than indoor-spraying ;
  it is also 5 times cheaper.

In africa, there is a species of plasmodium that can infect monkeys and apes too,
  but it's effect on occurrence of malaria in humans is negligible.
 

3.4 - Staying indoors at night, and screening doors and windows

Keeping doors and windows closed would prevent mosquitos from entering your rooms ;
  even in not very well-constructed buildings it would help.
But weather is often too hot to make that desirable.
So thing to do is use screens on doors and windows,
  so that breeze can blow through them, yet mosquitos can not enter.

Main mosquito biting time is between dusk and dawn,
  and staying indoors during this time reduces chance to get bitten.

This measure is usually combined with spraying of rooms with insecticides.
In that case, it reduces incidence of malaria by a factor 5. (in a tropical country)

In year 1900, malaria was endemic in Italy,
  and some scientists studied effect of screening there.
Families in tightly screened homes, who stayed indoors from sunset to sunrise,
  had a chance of 5 % of getting ill from malaria.
Over same period, for their neighbours who did not use screening, chance was 86 % .
 

3.5 - Spraying insecticides in rooms

In a house that is screened,
  if any mosquitos managed to enter it, and are sitting somewhere waiting for a human victim,
  spraying with insecticide has a good chance of killing them.
In this case, since all other ways for mosquitos have been blocked,
  spraying adds an important amount of protection.

Usual practice is to spray walls and roof of rooms with pyrethroid insecticides.
Alternatives are burning mosquito-coils in room, or burning citronella candles.

I have no exact data about effectiveness of spraying.

Pyrethroid insecticides have very low mammalian toxicity
  but are highly toxic to insects
  and have a rapid knock-down effect, even at very low doses.
Pyrethroids have a high residual effect :
  they do not rapidly break down unless washed or exposed to sunlight.

There is also related practice of community-wide spraying with long-lasting insecticides ;
  It has recently been found that DDT can safely be used for this.
Difference with room-spraying is that
  community-wide spraying is more applicable to rooms that are not screened,
  and spraying includes all structures, including animal living quarters, barns, etc.
This kills, or at least reduces lifetime of mosquitos resting on wall or roof.
Mosquitos usually rest after they have bitten,
  which means that spraying non-screened rooms does not prevent infection.
If many people in a community do it,
  it reduces mosquito lifetime,
  and thus strongly reduces fraction of mosquitos that are infectious.
 

3.6 - Using insectice-treated bednets

When you are indoors in a screened room, risk is already lower,
  but main biting time is when you sleep,
  and you can easily reduce risk even further during that time by using a bednet.
This becomes especially important if you sleep in a room that is not closed off to mosquitos.

Usage of nets is usually combined with spraying room with insecticide,
  if only because you would not be in bed all evening.

These are nets of cotton or a synthetic yarn (polyester being most common),
  with a mesh so small that mosquito can not go through it,
  and soaked in a solution of insecticide (and dried after that).

A net of itself offers some protection,
  but when your foot is in contact with net,
  mosquito could land on net, and suck blood through maze,
  therefore these nets should always be treated with insecticide.
Inseticides recommended for use on nets include :
  'permethrin' : preferred, as it repels and kills ; US brandname "Permanone".
  'deltamethrin'.
All insecticides approved (in US) for use on bednets are pyrethroids
  (same type as used for spraying rooms).
Mosquito net should be tucked in very well, so that no tiny mosquito can get in.
They can be bought in most developing countries, if necessary,
  i heard they cost a few dollars at Makola market in Accra, Ghana.

Over time, insecticides used on net become inactive.
This happens faster if net is exposed to sunlight, or is washed.
Usual insecticides for bednets last for about half a year.
Thus they must be retreated with insecticide at intervals of 6-12 months.
Retreatment is done by simply dipping nets in a mixture of water and insecticide
  and allowing them to dry in a shady place.
Kits for retreating nets are available in most countries.
Need for frequent retreatments is a barrier to implementation of ITNs in endemic countries,
  since cost of insecticide and lack of understanding of its importance
  result in very low retreatment rates in most African countries.

There are now more modern insecticides available
  that last as long as net itself : 3- 5 years.
CDC is currently testing several of these products in Atlanta and Kenya.

Many nets need a point on ceiling to hang them from,
  which could be a problem when staying in cheap lodgings.
There are now also nets that have a frame like a tent.

A similar measure, used by some populations of endemic areas that don't have nets,
  is to apply insecticide to clothes worn while sleeping.
This has been reported to work surprisingly well ; reason for this is not yet known.
 

3.7 - Sleeping in high places

It was noted before that some people in southern Egypt use this as a defense measure.
Sleeping in high-rise buildings might have similar effect.
I found no data about altitude that mosquitos prefer to fly at.
 

3.8 - Effect of airconditioning

Yet another topic about which i have no data.
Insects are cold-blooded, and thus less active where it is cold,
  and their body chemistry will thus also be slower when it is cold,
  so that digesting a meal would take longer in a cold place,
  which would probably mean it would entail a bigger risk,
  so i would expect that mosquitos do not like cold places.
But who knows.

It might also perhaps be possible that humans emit less smells in colder environments.
 

3.9 - Effect of moving air

One source said that
  "mosquitos do not like moving air because they can not fly very well in it."
Whether this is true, i don't know.
 

3.10 - Cover skin with clothing in evening

Wear long-sleeved shirts, long pants, hats, socks.
Heat may prevent you from doing that at midday ;
  only doing it between dusk and dawn is still usefull,
  as this is mosquito's most active time.

A group of french paratroopers, after a mission in africa,
  were interviewed and medically examined ;
Their immunoglobulin levels revealed that
  35 % of them had been bitten by infected flies.
Questions of interview that most strongly correlated with infection
  were: "did you always sleep under a bednet ?"
  and "did you always wear long sleeves at night ?".
 

3.11 - Wash yourself with soap

Mosquitos are attracted by body smells and CO2.
There is not much you can do about exhaling CO2,
  but body-smells can be reduced with good personal hygiene.
Washing your socks is also a good idea.
 

3.12 - Insect repellents for use on skin

When outdoors :
Apply insect repellents to exposed skin (and clothing ?).
This will prevent mosquito bites for one to five hours,
  depending on
  person, mosquito species, number of mosquitos, and
  type and concentration of active ingredient of repellent.
Repellents are available as aerosol sprays, pump sprays, creamsticks, lotions, or foams.

N,N-Diethyl-m-toluamide (Deet)
  is very effective and widely used as a repellent
  but it should not be used indiscriminately
  as severe allergies can develop.
Repellents with high concentrations of Deet, 50% or more, should not be used on children.
Repellents with 5-10% Deet are equally effective as ones containing 90% or more,
  but they apparently do not last as long.
For how long these work, i don't know.

Avon Skin-So-Soft has been widely used as a mosquito "repellent" for a number of years
  (without being labeled as such).
Avon Products, Inc. has recently obtained EPA approval
  and is now marketing some of its Skin-So-Soft products for use as a mosquito repellent.

A new, not as widely tested, repellent is 'Picaridin' ; It lasts 1-4 hours.

Use repellent only outdoors.
Wash off thoroughly with water and soap after coming in.
Only apply repellents where skin is intact.
Avoid eyes and mouth when rubbing repellent on face. Do not spray on face. (poisonous!)
Do not apply to children's hands.
Do not let children younger than 10 years apply repellent themselves.
Do not use on children younger than 2 months.
 
 

4 - Red blood cells

Plasmodium parasite that causes malaria
  mainly lives and multiplies in human red blood cells (RBCs).
 

4.1 - Function and occurrence

Adult humans contain circa 5 liters of blood.
This is usually pumped around by heart,
  which normally beats circa 70 times per minute,
  and has a stroke volume of circa 70 milliliter,
  yielding circa 5 liters per minute.

Red blood cells, aka 'erythrocytes', make up about 1/4 of volume of human blood.
Their main function is to transport oxygen from lungs to body tissues.
Beside RBCs, blood also consists of
  white blood cells ('leukocytes'), that are part of immune system,
  some other (much less frequently occurring) cells of immune system,
  blood platelets, that cause blood to clot for healing wounds, and
  blood plasma, a clear yellowish fluid that contains many proteins and other substances.
Oxygen is used in tissues to generate energy by oxidizing sugars,
  yielding carbon-dioxide as waste product,
  which is transported to lungs by dissolving into blood plasma.

There is another mechanism by which oxygen is transported from lungs to tissues,
  namely by direct solution of oxygen into blood plasma ;
This is much less effective than via RBCs :
Under normal conditions (relative inactivity)
  plasma carries only 1.5 % of oxygen (and RBCs carry rest),
  and circa 25% of RBCs oxygen is actually used,
  so oxygen in plasma can deliver 6 % of normal need under normal circumstances.

Under abnormal circumstances,
  heartrate can be nearly thrice as high (which can be dangerous for untrained persons),
  and stroke volume of heart can be nearly 2 times as high,
  resulting in upto 30 liters per minute being pumped when doing extreme exercise ;
Body can, for a while, make do with only plasma for transporting oxygen,
  but increased heartrate and resulting high blood pressure needed for this
  are a severe stress, that trained athletes may be able to withstand for some time.
 

4.2 - Structure

RBCs are cells, so they mainly consist of
  a cell-wall (aka 'membrane'),
  fluid and dissolved substances inside that membrane,
  and structural proteins that give it it's shape.
RBCs are, when they are young, 'eukaryotic',
  which means that they have a nucleus that contains it's genetic information (DNA),
  and that nucleus is enveloped in a separate cell-wall inside cell-fluid.
When an RBC has matured, which is when it is released into bloodstream,
  it discards this nucleus (presumably to protect it from viruses).
  This is unusual, as RBCs of all other mammals do have nuclei
    (except for one species of salamander).
As it has no DNA, it can not synthesize proteins, and can thus not repair itself,
  and can not reproduce itself either.
As it can not synthesize anything, it also does not need energy,
  so organelles that normal cells have for this are also discarded upon maturation.
Thus RBCs are not really living cells.

RBCs are nearly completely filled with hemoglobin.
Hemoglobin consists of 4 identical subunits,
  each of which consists of an iron atom embedded in a porphyrin ring embedded in a protein.
Such iron in a porphyrin ring is called a 'heme' group.
Iron atom, due to way it is bound, can loosely bind, and easily release, oxygen.

RBCs passively flow with blood,
  and passively absorb oxygen where partial gas pressure of oxygen is relatively high,
  and passively release oxygen where partial pressure is low.

RBCs are shaped like a tire of a wheel that is completely wrapped up ;
  thus they are roughly disc-shaped, with a dimple in middle (on both sides).
They are 6 - 8 micrometer (um) in diameter, with a thickness of circa 1.5 um,
  and have a volume of circa 55 um3 .

25% of volume of blood is made up of RBCs,
  so there are circa 4.5 million RBCs per cubic millimeter of blood,
  so total amount of RBCs in an adult human is circa 2.2E13 .
  (people living at high altitudes have a bit more).

RBCs are normally flexible,
  and need to be flexible for being able to pass through narrowest of blood vessels,
  which are less than 8 um in diameteer ;
In such small bloodvessels (called 'capillaries') bloodcells flow in single file.
 

4.3 - Creation

Erythrocytes are continuously being produced in red bone marrow of large bones,
  (In embryo, liver is main site of red blood cell production)
  at which time they still have a nucleus, so they can divide and grow,
  and they also still have mitochondria, with which they synthesize hemoglobin.

Production can be stimulated by hormone erythropoietin (EPO)
  (well known from it's use as doping in sports).

Erythrocytes develop to maturity in about 7 days, and last a total of circa 120 days.
 

4.4 - Destruction

Main sites of destruction of RBCs are liver and spleen.
Liver specializes in absorbing nutrients from blood ;
  blood streams from bloodvessels surrounding stomach and gut to bloodvessels of liver.
Spleen specializes (among others) in defending against infection.

Spleen's blood vessels branch into many very narrow bloodvessels,
  that act as a physical sieve to RBCs.
As an RBC gets older, it can get infected or otherwise damaged,
  which makes it swell up to a sphere-like shape.
Then when it passes through spleen, it is filtered out.
Spleen also contains very many 'macrophage' cells (latin for 'big eater'),
  that eat damaged RBCs by completely enveloping it, and releasing destructive enzymes.

Most components of old RBCs are reused,
  but not heme groups, which are excreted by liver as bilirubin in bile.
If liver is damaged or overworked, as is frequently seen in malaria,
  level of bilirubin in blood increases,
  giving human skin a yellowish color that is typical for people who have malaria.
 

4.5 - Cell wall

Cell walls of RBCs, like walls of all animal cells,
  are composed of fatty acids, which have an electrically polarized acid 'head',
  and a relatively long non-polar carbohydrate 'body',
  so that head attracts water molecules, while body repels water molecules,
  resulting in a structure that has heads on both sides
    and bodys sandwiched in between them.

In this cell wall, there are proteins, which are much larger molecules,
  that often extend through on both sides of wall ;
Many of these proteins are chemically interconnected,
  forming a network inside cell, that is called endoplasmic reticulum,
  which gives strength and shape to cell.
There are also other proteins that have various other functions.
Among these other proteins are glyco-proteins,
  which consist of a series of sugars connected to a protein ;
Sugar part attracts water molecules, thus forming a slimy layer,
  which protects cell from being damaged.
 

4.6 - Immune system

These glycoproteins are important for immune response,
  because T-cells of immune system recognize glyco-proteins,
  and decide on that basis whether a cell should be destroyed or not.
If they decide on destruction,
  they remember which glycoprotein that cell carries,
  which results in creation of specialized macrophages
  that will eat any cell exhibiting those glycoproteins.
 

4.7 - Duffy factor

One of these glyco-proteins, which exist on cellwall of RBCs and on all other human cells,
  is called 'Duffy blood factor'.
These are important for plasmodium, as it abuses them to gain entry into RBC.
Nearly all west-africans have a genetic modification that causes them to
  express Duffy blood factor on all cells, except on red blood cells.
This gives west-africans near-perfect immunity from P.vivax,
  for which this is apparently only way it can enter an RBC ;
P.falciparum has found another entry, unfortunately.
 

4.8 - Blood proteins

Human blood is unusual, compared to that of nearly all other species,
  in that it lacks one amino-acid, 'iso-leucine'.
All proteins are built amino-acids,
  and there are circa 25 different amino-acids occuring in nature,
  and generally, for synthesizing a protein, all of these amino-acids are needed.
Thus lack of this amino-acid makes human blood much less suitable for parasites,
  because they are much less able to clone themselves from it's components.
 
 

5 - Plasmodium

Infectious parasites that cause malaria are protozoans of genus 'plasmodium'.
 

5.1 - Classification

Protozoans are small unicellular organisms that
  have circa 6 times as much genetic information as a bacterium,
  which makes them more versatile.
Protozoans are eukaryotes,
  which means that they have nucleus and organelles inside internal cell walls.

Among protozoans are many subgroups, called 'phyla',
  and these phyla are again divided into yet smaller groups called 'genera'.
Plasmodium is a genus of phylum 'apicomplexa'.

Apicomplexa are characterized by having
  a ring-shaped skeleton-like structure at one end
    (probably for providing support for proteins that bind to cell being attacked),
  and sacs full of chemicals with tubes leading through ring to cell-wall.
All species in phylum apicomplexa are parasites.

Plasmodia, when bumping into a red blood cell,
  quickly move ring-part of their body toward RBC,
  take a firm hold of it,
  and empty contents of their sacks of chemicals outside cell-wall,
  so that these contents, due to pressure, end up inside cell being attacked.
 

5.2 - Infective species

Plasmodium genus consists of more than 125 species,
  that produce malaria in mammals, birds, and reptiles.

Five of these affect humans:
  * plasmodium falciparum
     is main cause of malaria in africa.
     nearly all deaths due to malaria are caused by P.falciparum.
  * plasmodium vivax
     is main cause of malaria outside of africa.
     can remain dormant upto 2 years after infection (but this is rare).
  * plasmodium ovale
     not very common.
     can remain dormant upto 4 years after infection (but this is rare).
  * plasmodium malariae
     occurs in southeast asia.
  * plasmodium knowlesi
     occurs in south-east Asia.
     is mainly a disease of monkeys, but can infect humans.
     it's reproductive cycle takes only 24 hours.

'Dormant' here means that they remain inactive in liver for up to a couple of years,
  and thus can cause malaria long after a traveller has returned from an infected area.

Species that cause malaria in animals are not dangerous to humans,
  with exception of a subspecies of plasmodium ovale
  that can infect monkeys and apes.
This subspecies is much less dangerous to humans than other plasmodia.
According to CDC's website,
  extent to which monkeys and apes constitute a reservoir for malaria is also negligible.

P.malariae is unusual in that it's reproductive cycle takes 72 hours
  (as opposed to 48 hours for most other plasmodia).
Malaria caused by P.malariae is relatively benign (often chronic but seldom lethal).

P.knowlesi is unusual in that it's reproductive cycle only takes 24 hours
Red blood cells infected with P.knowlesi look a lot like those infected with P.malariae,
  so it is advised that in areas where P.knowlesi occurs (southeast asia),
  patients who are diagnosed as being infected with P.malariae
  should be treated as if they are infected with P.knowlesi,
  which means they get the same intensive medication as is used for P.falciparum.

Rest of this text deals nearly exclusively with P.falciparum and P.vivax,
  because these cause nearly whole disease burden,
  and nearly all research data is about these too.
 

5.3 - Live stages of plasmodium

There are 3 main live-stages of plasmodium :
 

5.3.1 - Sporozoites

These are present in mosquito saliva,
  from which they enter human bloodstream when mosquito bites,
  are then carried through body by blood,
  and when they reach liver, they enter hepatocyte cells there ('hepato cyte' = 'liver cell').
In liver cells they multiply a-sexually, and their offspring are merozoites.

In some species, sporozoites can remain dormant in livercells.
These are called 'hypnozoites', and are usually not considered to be a separate life-stage.
 

5.3.2 - Merozoites

These are form that infects red blood cells.
They are result of
  either a-sexual reproduction of sporozoites in liver cells
  or a-sexual reproduction of merozoites in red blood cells .
When a merozoite has entered an RBC, it multiplies there,
  and when multiplication is complete, it destroys remains of RBC,
  and then young merozoites are in bloodstream ;
Each of them bumps into an RBC, clings to it like an octopus,
  and injects chemicals into it, that cause RBC to go soft,
  after which merozoite pulls RBC around itself.
Merozoite is then inside RBC, yet it is not in RBC's endoplasma (cell fluid),
  rather it is inside a vacuole (hollow space) inside RBC,
  and wall of vacuole was previously part of outside-wall of RBC.
This protects plasmodium from immune system.
Once inside RBC, plasmodium eats amino-acids that form protein-part of hemoglobin.
It uses these amino-acids to duplicate itself, repeatedly,
  after which RBC bursts and young merozoites find themselves in bloodstream.
This cycle repeats itself until human host dies
  (or receives medicinal treatment, or has a very effective immune system).
  
Some of merozoites do not duplicate themselves ;
Instead, they discard half their genetic material, and develop into gametocytes.
  (thus there is never more than one gametocyte in an invaded RBC).
It is not yet known what determines whether a merozoite will become a gametocyte.
 

5.3.3 - Gametocytes

These are either male or female.
They can not infect RBCs.
Their purpose is to remain in bloodstream until some mosquito sucks them up.
Once inside mosquito's gut, RBC they live in is discarded,
  and they develop flagella, so they can move around ;
When they encounter a gamete of opposite sex, they merge,
  small gametes ('males') being absorbed into large gametes ('females') ;
  result of merger is called 'ookinete' (latin for 'dynamic egg').
These move to skin of mosquito's gut, and invade a cell there,
  thus forming an 'oocyst' (latin for 'egg container').
Inside this oocyst, they multiply sexually, and their offspring are sporozoites.
 

5.3.4 - Sporozoites

When sporozoites are ripe, they break out of mosquito-gut-skin-cell
  on side of mosquito's bloodstream.
They are then carried through mosquito's body by bloodstream,
  which they leave when they reach mosquito's salivary glands.
They stay there, waiting to be injected into next human victim.
 

5.4 - Strains

A Plasmodium inside human body multiplies there, but does not reproduce sexually,
  so it's offspring all have same genetic composistion.
Thus, unlike in humans,
  a different genetic composition is not same as a different individual.
A genetic composition of plasmodium is called a plasmodium 'strain'.
 

5.5 - Origin of mating partner ; Can plasmodia reproduce sexually inside humans ?

An interesting question is : "Where does that opposite sex gamete come from ?".
For sexual reproduction to have desired effect of increasing genetic variation,
  there should be, inside mosquito gut,
  an opposite-sex gamete from another plasmodium strain.
But if that other strain had to come from another bite into another infected human,
  it would mean that gamete from first bite would have to wait inside mosquito gut
  until mosquito had digested all it's food and became hungry again.
However, from what i read, it seems that,
  while gametes are optimized for surviving mosquito's gut,
  their chances of survival are not really all that good.
And also, in many areas mosquitos barely live long enough to allow oocysts time to develop,
  so waiting for a few extra days would be a bad idea in itself.
So most likely answer seems to be that
  infected humans are generally infected with multiple plasmodia strains,
  so that these can combine sexually in mosquito, forming many new strains,
  and an infection by a mosquito would then also transmit multiple strains to victim.

I have (after some more reading) found that,
  in an area of low infection-rate in french guyana,
  plasmodium population was said to be 'clonal'
  from which it follows that male and female gametocytes of same strain can mate,
  yielding a near-identical copy of their parents.

In areas of high transmission,
  humans are usually infected by more than one strain simultaneously ;
A study in Papua New Guinea reported 6.6 different strains on average per infectious bite.
An other study in PapuaNG found people infected with
  all 4 species of plasmodia that are infectious to humans :
  P.falciparum, P.vivax, P.ovale, and P.malariae.

So it seems that mosquitos are only needed for transmitting disease,
  and would not be necessary for sexual reproduction,
  as it would suffice for gametocytes to mate inside infected human.
For now, all that can be said about it is that
  sexual reproduction of plasmodia inside humans has never been observed.
Perhaps once an RBC is infected (ie merozoite has pulled it around itself),
  it can not subsequently be also infected by an other merozoite.
 

5.6 - Times and numbers (of mosquito life stages)


 

5.6.1 - Sporozoites

Saliva injected by mosquito when it bites can contain plasmodium sporozoites.
Salivary glands of infected mosquitos can contain 10,000 to 200,000 sporozoites,
  but only few sporozoites are actually found in each drop of saliva injected.
Typically, an infective bite contains between 5-200 sporozoites.

They are injected into blood, traveling from place of infection to liver.
They probably infect liver as soon as they reach it with blood flow,
  which would be in less than 1 minute.
Each sporozoite penetrates cell-walls of liver cells, settling down in one them.

Infecting liver cells is done in an unusual fashion (unusual for sporozoites) :
Normal sporozoites trick a cell to encapsulate it in a vacuole,
  plasmodium sporozoites, however,
  traverses multiple cells rapidly, like a bullet, rupturing cell-walls,
  before settling down in one of them.
One it setteles down in is thus in a deeper layer,
  so that substance on outside of it's cell-wall is same as it has on inside,
  and therefore cell-wall is easily repaired.

Once settled, nucleus of sporozoite divides many times
  and cytoplasmic mass grows substantially (probably feeding on contents of liver cell).
Number of nuclear divisions, and duration of this 'schizogony'
  varies between plasmodium species ;
  in P. falciparum it reaches a diameter of 60 Ám
  and contains 20,000 - 40,000 nuclei .
After nuclear divisions are completed,
  cytoplasm segments are formed, resulting in individual merozoites.

This process takes a few days ; how many days depends on species :
  P.falciparum is fastest with a minimum of 5.5 days.

When merozoites are thus completely formed, they break out of liver cell, into bloodstream.
One falciparum sporozoite thus produces circa 30.000 merozoites.
One infectious bite (with 100 sporozoites) would thus produce 3 million merozoites.
 

5.6.2 - Merozoites

From a (not very detailed) picture, i estimate diameter of merozoites to be circa 1 um .

In bloodstream, they attach to an RBC relatively fast,
  but it takes them about 30 minutes before they are completely enveloped by it.
Human body has circa 2E13 red blood cells,
  so at this stage, infection does not yet cause clinical symptoms.

Once inside red blood cells, merozoites eat protein-part of haemoglobin,
  break them down into amino-acids, and use these to multiply themselves.
Where they derive their energy from during that time was not mentioned in anything i read.
  maybe from proteins ?
Inside RBCs they multiply by a factor 8 - 20, depending on species,
  P.falciparum multiplies 16- to 18-fold.
  P.vivax multiplies 6- to 8-fold.
This repeated division process takes a few days :
  2 days for most Plasmodium species,
  3 days for P.malariae.
After division is complete, young merozoites are ready for entering blood.
At this time a group of merozoites is
  inside a sac inside vacuole wall formed from host RBC's cellwall.
They release enzymes that rupture host RBC.
Remaining contents and fragments of cell wall of host RBC are thus dumped in blood,
  which is not healthy, as large fragments of cell wall may clog narrow blood vessels,
  and heme groups (iron in porphyrin, remnants of hemoglobin)
  are allegedly "poisonous" to human body.
Fragments of cell-walls are a major cause of fever,
  because inside of cell-wall is not meant to be exposed to blood,
  and human immune-system treats it as wall of some unknown kind of infectious cell.
After a short while, probably when remnants of destroyed RBC have become dilute enough,
  protective sac is also discarded, and individual merozoites are in blood,
  attaching to first RBC they bump into.
This makes me wonder how they avoid all attaching to same RBC.

As merozoites are circa 1/8th of diameter of RBCs,
  this means that at this stage, RBCs infected by P.falciparum can not be flat,
  but must be globe-shaped to contain this many plasmodia.
With P.vivax, which multiplies by a smaller factor,
  loss of shape would not be as necessary.
From a picture (of P.falciparum) :
  before an RBC ruptures, it seems completely filled with plasmodia.

Merozoites produced in RBCs are same as merozoites produced in liver cells,
  so these young merozoites invade new RBCs, and multiply there,
  and this cycle continues, leading to an exponentially growing number of infected RBCs.
About 30 minutes later, each surviving merozoite has infected another red blood cell,
  where it again multiplies, etcetera. ad infinitum.
Time between infecting a red blood cell and breaking out of it is
  48 hours for vivax and ovale,
  72 hours for malariae, and
  fluctuates around 48 hours for falciparum.
 

5.6.3 - Gametocytes

Some of merozoites' offspring formed in red blood cells, are gametocytes.
A Gametocyte is circa as big as an RBC, and banana-shaped.
I know very little about them.
How many of them there are, and what their chances are to be ingested by a mosquito
  are discussed in paragraphs furtheron.

Some merozoites, after infecting an RBC, develop into gametocytes.
Some gametocytes are taken up by mosquitos feeding on blood of human host.
 

5.6.4 - Development inside Mosquito

When mosquito ingests blood from an infected human,
  it ingests infected RBCs, merozoites and gametocytes with it.
I presume merozoites or unripe gametocytes (in an infected RBC)
  find themselves in an environment that they can not handle, and die.
Gametocytes, however, are made for this environment, and survive it.

Gametocytes mate in mosquito gut.
Each male/female mating result bores through wall of gut,
  and become encapsulated in a cyst called 'oocyst'.
Inside that cyst, cell divides repeatedly
  (i don't know whether this is done by repeated division into independent cells,
   or by multiple division of nucleus followed by formation of cellwalls,
   like sporozoites do),
  ultimately forming circa 1000 sporozoites, which are then released from sporocyst.
This takes 5 - 7 days for plasmodium falciparum (depends on temperature ?).

Sporozoites then travel to salivary glands (via mosquito's blood stream ?).
How long they can remain alive there is not known,
  but is probably not very important,
  as new gametocytes would be taken up at every bloodmeal,
  so if they survived 3 days it would already be enough for continuous infectivity.

Time from ingestion of gametocytes to sporozoites present in saliva depends on temperature ;
  one source says 10 - 18 days,
  CDC's site says 9 - 21 days @ 25 oC, (for P.falciparum)
Models of transmission rate use 'degree-days'
  and assuming plasmodium's metabolims is speeded up by temperature
    just like anopheles's metabolism is,
  ie assuming 14 oC as temperature of no activity,
  development would take 100 - 232 degreedays.
Furthermore, it is reported that
  development of gametocytes into sporozoites needs a minimum temperature,
  which depends on plasmodium species :
  15 oC for P.vivax, and
  20 oC for P.falciparum.
This helps explain that falciparum, while being much more active and versatile,
  is not dominant plasmodium species in many areas.
 

5.6.5 - Maturation time inside mosquito Restrains Survivability of plasmodia

Gametocytes need days to develop into infectious sporozoites,
  and Anopheles do not live very long ;
As a result, only part of Anopheles are infectious,
  even if they already have oocysts in their stomach-wall.

For a numeric example, see section 'Epidemic'.
 

5.7 - Effect of plasmodium on mosquito

Apparently a mosquito does not get ill from plasmodia it carries.
This is probably because Plasmodia do not keep multiplying inside mosquito.

Having plasmodia in it's salivary glands causes blood-meals to be taken in multiple bites,
  presumably because human detects plasmodia being injected.
Mosquito does reduce number of plasmodia that enter with bite ;
  there are several 10,000 in salivary glands, but only circa 100 are injected with saliva.
Infected mosquitos' immune system responds to presence of plasmodia in mosquito blood
  by producing nitrogen-monoxide, which is poisonous to many micro-organisms.
None of investigations i read about found that
  presence of plasmodia significantly shortened mosquito lifetime.
 

5.8 - Response of human immune system to plasmodia

When a human is bitten, sporozoites are injected, and travel to liver, where they settle.

Time to mature in liver cells usually lies between 7 and 30 days, depending on species,
  shorter periods being more usual with P.falciparum,
  and longer ones with P.malariae.
Other reports say incubation period for falciparum is 5.5 or 6 days.
For vivax and ovale it is probably 10-14 days.

During this time, in an individual without immunity,
  immune-system is not aware that anything is wrong.
In immune people in endemic areas, detection of sporozoites may have led to some preparations,
  but i know practically nothing about this.

When merozoites break out of liver cells, and invade RBCs,
  and destroy them, and dump remnants in blood, their effect becomes noticed by immune-system.
As number of RBCs that burst increases, immune system starts reacting.

Number of plasmodium sporozoites per infectious bite is reported to be
  by one source : between 1 and 100 ,
  by another : between 5 and 200 .

If a human is infected by 1 falciparum sporozoite :
dayeventnumber of merozoites
0infection by 1 sporozoite0
6break out of liver cell 3.0E4
8has multiplied in RBCs 5.4E5
10has multiplied in RBCs 1.0E7
12has multiplied in RBCs 1.8E8
14has multiplied in RBCs 3.2E9
16has multiplied in RBCs 5.7E10
18has multiplied in RBCs 1.0E12
20has multiplied in RBCs 1.8E13

A human only has 2E13 RBCs, so by this time (s)he would be dead.

Some people do die from their first infection.
  If they were infected by 1 sporozoite , this would happen 20 days after getting infected.
  If they were infected by 10 sporozoites, this would happen 18 days after getting infected.
  If they were infected by 180 sporozoites, this would happen 16 days after getting infected.
In most cases, human immune system prevents this.
 

5.8.1 - Incubation Time

First reaction of immune system is fever.
Cells of immune system (free floating in blood)
  detect fragments of RBC cell-walls and heme-groups in blood,
  which they consider to be material foreign to human body,
  so they release chemicals (called cytokines) that produce fever.
Amount of fever produced depends on amount of cytokines released,
  which depends on amount of destructed RBCs ;
Fever starts having an effect when
  it produces a significant increase in temperature and heartbeat.
When this happens, it is apparent from outside of human, as a clinical symptom.

It is reported that time between infection and first clinical symptoms (called incubation time)
  is between 10 and 14 days for P.falciparum.
As shown above, this would depend on number of sporozoites in infectious bite.
There may however be more than one infectious bite
  in first night that human is exposed to mosquitos ;
In an area where malaria-transmission is extremely intense,
  it was reported that natives get up to 60 bites per night
  (usually only a fraction of these are infectious),
  so it is quite possible to get more than 180 sporozoites in one night.

Entire range of incubation times can be explained by number of sporozoites.
Thus maximum incubation time (14 days)
  would apply for infection with few sporozoites (between 1 and 15),
  which means that fever becomes apparent when there are circa 1E10 merozoites,
  ie 0.1 % of RBCs is infected, and 0.01 % of RBCs have recently burst.

It has been found in practice that generally at first fever
  fraction of infected RBCs is circa 1 % .
It could be that figures given above only apply to
  people that have absolutely no immunity against malaria.

If numbers given above are usable,
  then incubation time for other plasmodium species would be considerably longer,
  as their multiplication factor in RBCs is lower (typically 12 for P.vivax).
 

5.8.2 - A note about fever

Fever means that temperature set-point of body is raised.
This first causes a feeling of chillyness,
  as body registers that it's temperature is lower than setpoint.
In response to that, body heats up, until it's temperature reaches new setpoint.
As temperature rises, heart-rate rises with it,
  at a rate of 10 extra beats per minute for every degree centigrade rise in temperature.

Presumably intended effects of this are that
  increased heat makes life difficult for cells of human body
    (infecting organisms are not bound to human temperatures), and
  increased heartbeat makes blood flow through spleen more often,
    where there are a lot of immune-system cells.
Raised temperatures will hasten destruction of all red blood cells
  but old or diseased ones, who are less strong, would die first.

Amount of fever produced depends on amount of cytokines released,
  and so is proportional to amount of infected RBCs in blood.
I read that, with malaria, first noticeable fever occurs when
  circa 1 % of RBCs has been infected.
Malaria tends to produce repetitive fevers, every 2 or 3 days.
Thus it is practically certain that in falciparum malaria,
  fever after first noticable one will be at least 18 times as severe as first one.
Many deaths occur at time of second fever.

Fever is effective in killing infected RBCs,
  as is demonstrated by ability of young malaria-infected children to survive.
Young children between 2-months-old and 2-years-old do not have immunity against malaria,
  and falciparum can avoid most of body's other defenses,
  so fever is only mechanism that reduces number of infected RBCs.
This means that a malaria fever 'attack' kills at least 17/18th of all infected RBCs,
  thus limiting ultimate fraction of RBCs that is infected.
As number of infected RBCs gets lower,
  fever subsides, and a smaller fraction of infected RBCs get killed,
  so effect of fever is to limit infection, but not to eradicate it.
 

5.8.3 - Activation of Spleen

RBCs are normally destroyed in spleen (when they have become old),
  and spleen is organ that takes care of recycling their components.
I did not come across any data about this in my 2-week search of malaria data,
  but i assume that
  increased occurence of RBC cell-wall fragments in blood (flowing through spleen)
  increases spleen's activity, to clear these from blood.
Also, it may be that cytokines increase spleen activity,
  as fever is reaction to infection of blood,
  and spleen is important for clearing blood of infected RBCs.
More directly, when merozoites in RBC are nearly ripe,
  their combined volume is so large that it makes RBC swell up to a globe shape,
  which causes it to no longer be able to
    pass through physical filter constituded by spleen blood-vessels,
  so spleen starts destroying that RBC,
  which would obviously increase activity of spleen if it happened a lot.
As fever comes with increased heart rate, blood flow through spleen increases with it,
  which would make it catch more diseased RBCs.
It is known that in acute malaria, spleen is often enlarged,
  to a volume that is up to 4 times it's normal volume.
Spleen is located in lower portion of rib cage,
  and an enlarged spleen can easily be felt.
This causes an increased risk of rupture of spleen,
  so if malaria has been cured by medicines but spleen is still enlarged,
  additional bedrest is advisable.
One report had it that it took 4 days for spleen to return to a normal volume again.

In animals (eg dogs and horses) spleen acts as a reservoir of red blood cells,
  which are dumped into bloodstream at times of stress,
  yielding a higher oxygen transport capacity.
In humans this is much less pronounced.
 

5.8.4 - Role of Liver

Heme groups (iron in porphyrin rings) that form centre of hemoglobin
  are not recycled when an RBC is destroyed.
(Therefore humans need small amounts of iron in their diet).
Instead they are somehow collected by liver,
  which excretes them (as 'bilirubin') in bile into stomach.
Further than that, liver does not seem to do anything.
Liver can be severely affected by malaria, but it may be that
  this is just caused by sporozoite infection and clogging of blood vessels.
 

5.8.5 - Production of Antibodies

Cells of immune system that release cytokines when they encounter foreign cells
  also do something else :
  they remember (part of) chemical composition of infecting cell's cell wall.
Animal cells are all roughly built same way,
  but which exact proteins they have in their cell-walls differs per species and per body-tissue.
A common type of proteins of cell-wall are glyco-proteins ;
  These consist of a protein stem with sugar molecule(s) at end of it ;
Probable reason for having them is that sugar group relatively strongly attracts water,
  so a cell with a lot of glyco-proteins gets a slimy layer of weakly-bound water around it.
Which exact protein part and which exact sugar part are used for this
  does not make much of a difference, and varies per type of cell.
Immune-system cells, when encountering an other cell,
  check composition of it's glyco-proteins
  by matching it against shapes and electric charges of proteins on their own cell wall ;
If they match like normal human glyco-proteins, immune-sysem cell does nothing.
If they match some other pattern, they are recognized as foreign,
  upon which immune-cell releases cytokines, and remembers patterns it detected ;
It then no longer checks any further cells,
  but stays like this until it reaches an area where macrophages are produced
    (macrophages are big cells that can eat other cells by completely ingesting them),
  such as spleen.
There it causes production of a new generation of macrophages
  that only eat cells whose glyco-proteins match like those of detected foreign cell.

Result is that body can selectively attack these cells,
  so that this attack does not attack cells of body,
  and therefore this attack can be much more intense and effective.
Disadvantage is that it takes time to form new generation of macrophages ;
  3 days is apparently a typical time for that.

For most infections, usually caused by bacteria,
  this suffices to completely eradicate them from body,
  so that you would experience a bit of fever, and a few days later you would be better again.
Plasmodium, a protozoan that is 6 times more complex than a bacterium,
  has found a way around this immune mechanism,
  so that you would experience a bit of fever, and a few days later you could be dead.
This is reason that first symptoms of malaria look a lot like common flu.

When infection has been eradicated, these macrophage antibodies would no longer be needed.
Body keeps them around for a while (i don't know exactly how long)
  because it is more likely that next infection would be by same species of infecting cell
  than with a random other one.
As long as antibodies specific against this infector keep being usefull,
  they keep being produced.
A while after they are no longer active because there is nothing for them to do,
  they are no longer produced.
At that time, body does not completely forget about infectors they were targeted at,
  as it retains capability to start producing such macrophages rapidly,
  ie: it would take a lot less than 3 days (i don't know how long)
  to have production up to maximum level.
Over longer periods of time (can be many years),
  when this rapid-production capability has not been used,
  then body no longer uses resources for it, and forgets it.
Thus immunity against an infecting species is high after an infection,
  and gradually becomes less over time.
 

5.9 - Plasmodium's countermeasures against human immune system

Each of body's defenses mentioned above
  would cause RBC to be disassembled, which merozoites would not survive.
What Falciparum, does to avoid this has already largely been found out ;
  there is less knowledge about what other plasmodium species do against it.

Known avoidance mechansims are :
 

1) Enveloping itself (against anti-bodies) :

As long as a merozoite is enveloped by an RBC,
  merozoite cell-wall is not exposed to blood, so antibodies can not harm it.
When merozoites have eaten all of hemoglobin of RBC they have infected,
  they have no other choice than leaving it and entering bloodstream to find an other one ;
  during that time they are vulnerable.
This causes a factor (48hours/30minutes =) 96 reduction in effectiveness of immune response.
 

2) Synchronization (against fever) :

A merozoite that is attached to a healthy RBC, is relatively safe from fever,
  as that RBC has a good chance of surviving fever.
Likewise, a merozoite that has just enveloped itself in an RBC is relatively safe from fever,
  as it has not yet damaged that RBC very much, so that RBC is nearly as good as a healthy one.
Main fever triggers when merozoites leave an RBC, dumping toxic waste into bloodstream.
If merozoites left RBCs randomly, there would continually be a fever,
  causing many merozoites that were nearly ready to leave their used-up RBCs to die.
Instead, and maybe even caused by fever itself,
  all merozoites tend to leave their RBCs at same time,
  and thus infect next RBC at same time,
  so they all have same time between infecting and RBC and leaving it again.
There is ofcourse some spread-out in this time between individual infected RBCs ;
To which extent this manifests itself would depend on
  amount of stress that fever posed to merozoite population,
  as merozoites that are more out of sync are more affected by fever.
P.falciparum shows least synchronicity, as it has more avoidance mechanisms than other species,
  and rest of plasmodia show very clear 2-day or 3-day (for P.malariae)
  periods between fevers.
So at time merozoites emerge, and attach to next RBC, fever has not started yet,
  and by the time they emerge from these RBCs again, fever has subsided.
 

3) Synchronization with mosquitos (against all human defenses) :

Fact that these periods are whole numbers of days is not a coincidence.
It has been found that plasmodia has some (yet unknown) way of
  synchronizing itself with it's human host,
  such that emerging from RBCs occurs much more frequently at night than in daytime.
This activity was measured in a patient that was
  awake at night in a room with lights on, and sleeping in daytime in a darkened room,
  which revealed that plasmodia became active when that person experienced 'evening',
  ie when it was really mid-morning.
This is thought to serve purpose of
  maximizing chance for gametocytes to be sucked up by mosquitos,
  as mosquitos are mainly active when it is dark.
 

4) Stickyness (against destruction in spleen) :

This is a mechanism that only P.falciparum has.
It's merozoites inject proteins into host RBC, which then become part of host RBC's cell wall.
These proteins make RBC stick to other RBCs and to walls of blood vessels.
Then this RBC no longer flows with blood, so does not pass through spleen.

(It makes me wonder whether P.falciparum injects duffy-like proteins into RBC
  to subsequently use them to enter cell.)

These sticky RBCs can form clumps that block small blood vessels,
  which is main cause of death of falciparum infections,
  because result is that many small vessels of brain, lungs, kidney, and heart become blocked,
  leading to loss of function of these organs, which often causes death.
Infected RBCs in blocked blood vessels are relatively isolated from immune-system,
  but their neighbourhood doesn't receive oxygen anymore ;
  resulting chances of merozoites to survive i don't know.

Majority of infected RBCs, these that are not part of a clump that completely blocks bloodflow,
  are still exposed to cells of immune-system in blood flowing past them.
Due to these infected RBCs now having sticky substances on their outside,
  immune system can recognize that they are different.

Recent research in india found that stickiness only results if there is fever
They also identified surface-protein that causes it. (called PfEMP-1).
This may explain why malaria patients often deteriorate significantly at fever stage.
This discovery has also caused interest in
  use of anti-fever medicines against acute falciparum malaria.
 

5) Release of immuno-suppressants (against immune-system) :

Falciparum releases chemicals into blood that are
  same as human body uses to down-regulate activity of it's immune system.
This reduces acitvity of immune-system, but does not stop it.

I have no info about details of this, so i will mention some general features.
Usually, when body regulates some function,
  it does this by changing production levels of two hormones,
  one that inhibits that function, and one that activates that function.
  Resulting level of that function is then determined by ratio of these hormones.
Such regulations are usually adaptive, meaning that
  body monitors effect of regulation,
  and adjusts production of hormones until desired effect is reached.
Body's adaptive regulations are usually of proportional type,
  without integrating or differentiating component,
  and loop-gain is usually at least a few dozen,
  so that in final situation deviation from intended is a few percent at most.
All adaptive regulations have some slowness,
  caused by need to first measure and then adjust, both of which take time.

Thus release of immuno-suppressants by plasmodia
  would cause an initial reduction in immune-system activity,
  that would be detected by body,
  which would change it's own hormone-output to compensate for it.
That compensation would be effective,
  but would take some time to be established,
  during which time attack on plasmodium is less intense.
Advantage for plasmodium is apparently big enough to make releasing suppressant worthwhile.

I guess it also has another important consequence.
It was observed that a large part of mortality of falciparum malaria occurs
  at time of peak fever (ie most active immune-response).
  This is no doubt connected to fever causing stickyness.
However, this mortality occurs much less often in cases where a victim is infected with
  both P.falciparum and P.vivax (as found in Vanuatu), or
  both P.falciparum and P.malariae.
So it might be that mortality is partly caused by an overshoot in immune-system regulation :
  when body succeeds in ridding itself of falciparum,
  this causes a drastic reduction in release of immuno-suppressants by falciparum,
  which would cause a drastic increase in activity of immune-system
  beyond level that body's regulation deems optimal for acute infection.
If there is also a vivax infection, then vivax would continue to emit immuno-suppressants,
  and overshoot would not happen.
But this is just a guess.
 

6) Clonal variation (against immune-system macrophages) :

Sooner or later an infected RBC bumps into a cell of immune system known as 'T' cell ;
'T' cells recognise that RBC as diseased,
  and remember which glycoproteins they have on outside,
  and pass this on, to cause creation of macrophages that eat cells that have this glycoprotein.
It takes a while (a couple of days) for those macrophages to mature,
  and in meantime RBC whose glycoproteins were detected has already been used up,
  and merozoites have infected next RBC.

Result of a-sexual multiplication of a merozoite inside RBCs are young merozoites,
  but they are not quite clones of their parent (at least not in P.falciparum),
  because falciparum has a variable portion in it's genes,
  so that offspring has same genes, but which portion of it will be used is somewhat random.
This variable gene determines which glycoprotein will be put on outside of cell.
One study found that 2% of merozoites had different glycoproteins than their parent.
Importance of this is that
  when human immune system has made antibodies to glycoproteins of infecting plasmodium,
  which are therefore also effective against their cloned offspring,
  2% of young merozoites would survive
  (unless body would also have antibodies against that other glycoprotein ofcourse).
This explains why in endemic areas
  children are subjected to repeated attack of malaria for first few years
  and then become immune to further infection,
  when they have developed immunity to all different surface proteins of local malaria strains.
 

5.10 - Resulting level of infected RBCs in blood

In areas where malaria is endemic, nearly all people are immune to it.
Their immunity kills plasmodia as soon as they emerge from livercells,
  but does not protect them from sporozoites,
  so livercells continue to be infected as long as infected mosquitos continue to bite humans.
In highly endemic areas, people receive up to 60 infectious bite per night on average.
Result is that they are infected with malaria (which causes their immunity to remain active),
  but do not show clinical symptoms like fever etc.

Sometimes they are infected with a strain of malaria that
  presents surface proteins against which they do not yet have immunity,
  they experience a malaria 'attack',
  which gives them bad fever and makes them unfit for work for a week or so,
  until their immune-system learns to handle new membrane-surface-protein.
Patients suffering a malaria attack, and being treated in a hospital, have fever,
  and in patients with fever, level of infected RBCs is in order of magnitude of 1 % .
That seems to imply that level of infection that body already can and does handle
  would be a few powers of 18 less (at least 1, at most 3, i guess),
  so normal level of infected RBCs would be around order of magnitude of 2 per million.
It is just a rough guess, but i need it for next paragraph.
 

5.11 - Fraction of infected RBCs that infect a mosquito.

A single byte can contain upto 25 cubic millimetres = 2.5E-5 liter,
  and a human has 5 liters of blood,
  so a bite ingests upto 5E-6 of total blood.
If level of infected RBCs is 2E-6 , as guessed above,
  and blood contains 2E13 RBCs,
  then total number of infected RBCs is 4E7 .
If a bite ingests 5E-6 of that, then it contains 200 infected RBCs.

For mosquito to then become infected, it would need to ingest a male and a female gametocyte,
  so on average it would need to ingest 4 gametocytes.

I don't know how long a mature gametocyte can remain alive in an RBC in bloodstream,
  nor how it's chances are of not being destroyed when it passes spleen.
It can be assumed that they live in blood shorter than 8 hours,
  because otherwise synchronization with host's day/night rhythm would not be so precise,
  and it takes them 2 days to develop inside RBC,
  which would already decrease availability to mosquito by factor 6 ,

Blood smears of malaria-patients "occasionally" show gametocytes.
That might indicate that the number of gametocyte-RBCs per merozoite-RBC
  is in the order of magnitude of 1/100 .

It may be that
  infected cells transform into gametocytes when they are in peripheral areas of body,
  where temperature is a bit lower,
  where blood streams slower because blood-vessels are narrow,
  so gametocytes would live a longer while before having to risk passing through spleen
  and where chance of being ingested by a mosquito is much bigger.
It might even be that they stick to blood-vessel wall there,
  and release their stickyness when they detect anestetics injected by anopheles ;
  it sounds unlikely, but a lot of plasmodium's adaptations sound unlikely.
If they do not have such or a similar mechansim,
  it is hard to imagine how they could pass spleen without being destroyed,
  since they clearly do not have a normal RBC shape (but are rather banana-shaped).

In all, i do not know enough about it,
  best i can do is guess that
  fraction of infected RBCs that become gametocytes is in order of magnitude of 10% ,
  because less would not significantly increase chances of RBCs as a whole.
This would result in a number of ingested gametocytes that,
  for symptomless immune persons that are continually infected,
  would be barely large enough to make majority of bites infectious to mosquito.
 
 

6 - Immunity

Human body has a general defense mechanism against infections, called 'immune-system'.
When immune-system has learned (from previous infections) to defend against a disease,
  it has developed 'acquired immunity'.
Humans can, due to genes they got from their parents, be invulnerable to a disease ;
  this is called 'hereditary immunity'.
These are subject of this chapter.
 

6.1 - Recapitulation

A lot was already said in previous chapters
  about how immune-system affects RBCs and plasmodium,
  and i'll recapitulate these things here,
  without repeating all details, but adding a few new ones.
 

Immune-system guards against infections

Many cells of immune-system are floating in blood.
Immune-system cells detect substances that are not normally present in body,
  including deviations on infected cells,
  and causes production of cytokines and antibodies.

Cytokines cause fever.
I presume fever is a general mechanism for reducing lifetime of bodycells,
  thus decreasing infected fraction (at cost of needing to create more new ones).
I also presume that
  infected cells are usually less able to withstand elevated temperatures than sound ones.
If many infected RBCs are destroyed,
  much foreign matter is detected in blood, so many cytokines are released, and fever goes up.

Antibodies are specially grown cells
  that attack cells exhibiting some specific surface protein.
Which proteins to react to is determined when they are formed,
  from an impression of infector cells' proteins upon
  a cell of immune-system that specializes in this kind of typification.
Antibodies are large cells that envelope infectious cells into a vacuole,
  and then release digestive enzymes onto them.

Fever is a general-purpose response, that has unpleasant side-effects,
  as it is also very stressfull for healthy cells.
Antibodies are much more specific to infector than fever is,
  but take circa 3 days to develop.
So, normally response of immune-system consists first of fever,
  and a few days later specific immune-response starts,
  which is much stronger at combatting infection,
  because it does not need to be limited to avoid harm from side-effects as much.
Extent to which antibodies can reach infectors varies per disease,
  while heat of fever reaches all parts of body.
Both these immune-responses keep being active until body is rid of disease,
  but production of anti-bodies grows stronger over time ;
I presume this is because
  if an antibody is successfull, it gives rise to production of more antibodies of this type.

Human body has a finite capacity to generate anti-bodies.
If more than one infector-protein is detected,
  i presume anti-bodies to them are produced in proportion to number of them that are detected.
Body can regulate general activity of anti-body generation (presumably by hormones)
  so that it can throttle it down
  if anti-bodies being produced harm healthy parts of body,
  and when there is no infection.

In reality these functions of immune-system are performed by
  more different specialized types of cells.
 

Spleen guards against infected bloodcells

Blood is filtered through narrow vessels in spleen,
   so that RBCs that have lost their flexibility or have swollen up get stuck there.
When there is no infection, some fraction of sound RBCs are destroyed there,
  which limits RBC lifetime to circa 120 days.
Constituents of destroyed RBCs are collected from blood (presumably in liver)
  to be used for building new RBCs,
  and most of them are reused in (red) bone marrow of large bones for creating new RBCs.

This thus presents a mechanism of destruction of obstructing materials
  even if they are not detected as foreign to body.
Clearly, activity of this mechanism would need to be regulated,
  to keep it from attacking healthy cells.

Macrophages in spleen that destroy damaged RBCs
  can also function as part of general immune-system response to foreign materials.

Cells that remember surface-proteins of previous infections are probably located in spleen.
When a spleen was transplanted to an other human, immunity to malaria was transplanted with it.
 

6.2 - Hereditary malaria-specific immunity

Hereditary immunity affects
  * resilience of RBCs against being infected by merozoites,
  * destruction of merozoites inside RBCs by that RBC itself,
  * increasing likeliness of an infected RBC to be destroyed
There is no known immunity against sporozoites from mosquitos infecting liver cells ;
  continuous defenses of body (white blood cells) are relatively ineffective against this,
  and immune response is too slow to have any effect
    before sporozoites are already inside liver cells.

Known forms of hereditary immunity of RBCs are :
Cell ComponentAlterationGlobal Distribution
MembraneDuffy antigen nullAfrica
Melanesian ElliptocytosisMelanesia
Gerbich mutation PapuaNewGuinea, others???
HemoglobinHemoglobin SAfrica,Middle East,India
Hemoglobin C Africa
Hemoglobin E S.E. Asia
b-thalassemia Africa,Mediterra,India,SE Asia,Melanesia
a-thalassemia Africa,India,SE Asia
Red cell enzymesG6PD deficiencyAfrica, Mediterra, India, S.E. Asia

 

DUFFY FACTORS

Duffy factors are proteins that are normally present on outside of many human cells,
  including RBCs ;
P.vivax uses Duffy factor to grab hold of RBC and to invade it ;
  without Duffy factor on RBC, P.vivax can not invade RBC.
Practically all africans have genes that cause RBCs to not have Duffy factor
  (while their other cells still do) ;
Due to this, P.vivax is negligible as cause of malaria in africa
  (less than 1 % of clinical malaria cases in africa are caused by P.vivax),
  while P.falciparum, P.ovale and P.malariae continue to flourish there.

In all other parts of world, P.vivax is main cause of malaria, and P.falciparum is absent.
It may be that P.falciparum developed from P.vivax
  due to increasing fraction of humans that lacked Duffy factor.
Falciparum is more agressive than vivax in many respects,
  but in one respect it is inferior :
  it needs 25 oC for transmission, whereas vivax needs only 20 oC ;
  This is a main reason for absence of falciparum from most other places on earth.
However, there are areas outside of africa that would support transmission of falciparum,
  and absence of falciparum from these areas suggests that
  development of falciparum happened relatively recently.
 

MELANESIAN ELLIPTOCYTOSIS

Many humans in melanesia have RBCs that are different from ordinary ones,
  in that they are elliptical in shape,
  and that they can not be infected by P.falsiparum, P.vivax, and P.malariae
    (i don't know about P.ovale),
  they also withstand attacks by P.knowlesi, which causes malaria in apes.
 

GERBICH MUTATION

P.falciparum can use same attachment as P.vivax,
  but if that is not present, it has (at least two) alternatives.
Gerbich mutation is a mutation of humans that causes them to
  produce red blood cells on which's surface there is a change in certain sialoglycoproteins ;
  this change gives improved immunity from P.falciparum infections,
  against some variants of P.falciparum, but not against all of them,
  so it is thought that this is one of attachments for falciparum infections.
This glycoprotein is currently subject of further research.
 

HEMOGLOBINS C, S, and E, and THALASSEMIAS

All of these are deviations of red blood cells that cause them to
  contain more oxidizing substances,
  such as hydrogen peroxide, and oxygen radicals,
  which are very damaging to plasmodium, as soon as it tries to feed on hemoglobins of RBC.
For persons that do not have malaria, this is a disadvantage,
  because they also shorten life of RBC itself ;
  therefore these are usually considered to be a disease.
Hemoglobin S provides more effective destruction of infected RBCs when malaria strikes,
  gene that causes it thus is beneficial ;
  However, a child of parents both of whom have this gene, develops sickle cell disease,
    which is even more deadly than malaria.
At least some of these deviating RBCs
  also change to a different shape when oxygen tension is very low,
  as is case when they are infected and their hemoglobin is eaten by parasite,
  thus leading to increased rate of destruction by rest of body if they are infected.
 

G6PD DEFICIENCY

Humans whose genes do not support synthesis of Glucose-6-Phosphate-Dehydrogenase
  have RBCs that can easily be damaged by oxidative substances,
  thus causing severe illness when they eat some specific foodstuffs.
This is normally considered to be a disease.

When P.falciparum infects an RBC of such a person,
  it finds there an insufficient amount of some substances it needs from its prey,
  and dies.

Anti-malarial medicine "primaquine",
  that is only medicine that is active against liver-stage of plasmodium,
  can cause death in G6PD deficient people.
 

6.3 - Mechanisms of acquired immunity against malaria

Most of this was already discussed previously :

* initially, in non-immune persons, there is no defense against infecting plasmodium,
  so infector multiplies, until it's garbage causes fever,
  which strongly increases number of infected RBCs that get killed,
  thus (in most cases) keeping infection from killing victim.

* during time of high parasiteamia and fever, immune-system learns to recognize infector,
  and to produce anti-bodies to it.

* immune-system remembers surface proteins of infectors,
    for immediate use against current infection,
    and for future use against re-infection.

* plasmodium can to some extent vary surface proteins that it puts on membrane of RBC
    (which i call 'PESP' for 'plasmodium-induced erythrocyte surface protein').

Details about pattern of variation of PESP by plasmodia are not yet known.
I think it can be assumed that various possible proteins occur at random, not sequentially.
One source said that 2 % of offspring of an infected RBC had a (specific) surface protein.
There are 50-100 proteins
  that can be synthesized by gene responsible for which surface-protein is expressed,
  and apparently chances of expression are not same for all proteins.
Chances for offspring to have same PESP as it's parent
  is expected to be considerably higher than chance of having an other variant,
  in order for variants to which body has no immunity to thrive.
As a complete gamble by me, i guess at 50 % having same PESP, 25 % having a variant PESP,
  and 25 % developing into gametocytes.
Average fraction of offspring for each variant PESP would be in order of magnitude of 0.5 % .

It takes time for human body to mature, and with it immune-system matures,
  and in children neither their body nor their immune-system are at their maximum strength yet.
Therefore children are more vulnerable to malaria.
Children under 6 months old are still protected by immune-cells from their mother's blood.
Children over 5 years old have developed a reasonably mature immune-system themselves.

Even a mature immune-system needs time to detect infectors and develop antibodies
  and remember which of them were successfull in getting rid of infection.
Developing a successfull anti-body takes a lot of time,
  because a lot of different non-human chemicals may be present
    (a living cell is quite complex),
  and immune-system simply tries anti-bodies to all of them
  until one (or more) of them are found to be effective in killing infectors.
It is for this reason that once an effective anti-body is found, it is remembered ;
  in subsequent infections those anti-bodies that were previously successfull are tried first.
After a successfull anti-body has been found, it must be produced on a large scale,
  taking priority over production of random other anti-bodies.
Time needed for macrophage to mature is circa 3 days,
  so minimum time to start seriously combatting a disease would be twice that much.
After production of anti-bodies has been ramped up,
  it also takes some time to actually kill infectors.

Number of macrophages produced against a specific PESP
  is probably proportional to number of those PESPs detected in blood
  and is increased when a macrophage makes a successfull kill of an RBC with that PESP.
For a macrophage to kill an infected RBC, it must encounter it.
Chance for a macrophage to encounter an infected RBC
  is proportional to amount of macrophages
  and is also proportional to amount of infected RBCs.
Therefore, in a situation where
  effect of increased macrophage production after successfull kill can be neglected,
  such as in an infection where a new PESP becomes dominant one every few days,
  rate at which infected RBCs of a PESP are cleared from blood
  is proportional to square of amount of infected RBCs with that PESP.

It is better for body to get rid of parasites by anti-bodies than by doing it with fever,
  so it can be assumed that
  when a fever does occur, body is producing anti-bodies at maximum rate,
  and conversely, number of infected RBCs is so large that
    they cause this many anti-bodies to be produced.
An anti-body can only attack cells having it's type of PESP,
  so total anti-body producing capacity is divided over occurring PESPs,
  thus reducing effectiveness of immune-response
  (by a factor in order of magnitude of 50).
This may be explanation why
  malaria attacks caused by P.falciparum last longer (up to 16?? hours)
  than malaria attacks caused by other plasmodia (6-10 hours).
(Recent research has it that P.vivax also has variable PESPs,
   but not as many as P.falciparum.)

Prevalence of parasiteamia in an area where transmission was low, but not zero
  (as detected by sensitive techniques such as PCR (polymerase chain reaction)),
  was 17 % in one study,
  from which it is clear that a large part of the population was completely free from malaria
  (but less than 83 %, because although this technique is much more sensitive than microscopy,
   it can not detect 1 merozoite in 5 liters of blood).
Apparently immune-system of adults in areas with low infection rates
  does succeed in ridding body of plasmodia ;
From prevalence of malaria in such populations, combined with biting rate of mosuitoes,
  it is estimated that adult humans, on average, rid themselves of plasmodia in circa 20 days.

After plasmodia have been rid from body, macrophages remain alive for some time,
  but allegedly not much longer than duration of infection.
After this time, they can still be produced very rapidly,
  because surface-protein to react to is being remembered.

If no further infection by an infector with that surface-protein occurs,
  memory of that surface-protein disappears after some time ;
In one mathematical model that i saw, it was assumed that
  chance that a surface-protein was remembered was halved every 100 days,
  so this might be a realistic value.

Immuno-chemistry of these cell-wall surface proteins is subject of a lot of ongoing research.
If you want to find out more, it may be helpfull to know that some names of these proteins are:
  circumsporozoite protein, merozoite surface proteins MSP2, MSP3, and Pfemp1 .
 

6.4 - Multiplicity of infection

Until here,
  i have looked at mechanisms of malaria as that of infection by one strain of plasmodium,
  except for section about mating of gametocytes in mosquito,
  where i considered that mating might only be successfull if
  plasmodia from more than one strain were ingested simultaneously.
In a study in Papua New Guinea it was found that on average
  an infectious bite contained 6.6 different strains.
This implies that immune-system has to spread it's efforts
  over a large number of different diseased cells, each expressing a different surface protein.

Being infected with multiple strains simultaneously also has a lighter side :
When infected by a single strain of P.falciparum,
  time of highest activity against that strain (ie when it is being ridded from body)
  is also time of greatest riks of death for human,
  possibly caused by decline of parasites causing decline of inhibition of immune-system,
  which causes an overly strong immune-response.
It was found that when a person is infected with both P.falciparum and P.vivax,
  and it's body gets rid of P.falciparum (with fever etc),
  then risk of dying is not unusually high,
  maybe because P.vivax maintains inhibitory effect on immune-system, so there is no overshoot.
 

6.5 - Effect of acquired immunity in low-transmission areas

In areas where rate of infection with malaria is low
  (ie where number of infectious bites per year is low),
  people seldom get malaria.
In such areas there are few strains of malaria, possibly only one.
One study found that
  of those people that did have plasmodia in their blood but did not show symptoms of malaria,
  11 % got rid of infection without developing symptoms,
  50 % developed symptoms within 30 days, and
  39 % still had symptomless malaria after 30 days.
This fits well with idea that
  malaria is gotten rid of in 20 days on average, in adults with full immunity.
People developing symptomatic malaria would be
  those who do not yet have enough immunity (ie children), and
  those whose immunity had decreased due to long times between infections.
The ones who continued to have symptomless malaria might be explained as
  developing immunity to the various surface proteins
  at the same rate as the infector was able to change to new surface proteins.

In a relatively hot area in Kenya,
  where malaria transmission is strongly seasonal, peaking at end of rainy season,
  presence of malaria has two components :
* Low level prevalence, as in areas with low biting frequency.
* Transmission from more highly endemic areas when transmission is high.
    resulting in new infections that are mainly strains to which population is not immune ;
Consequently people there typically develop symptoms when they are infected,
  and number of clinical malaria cases is roughly proportional to intensity of transmission.

In such areas, as everybody that gets infected also becomes ill (with fever etc)
  women are not significantly more vulnerable than rest of population.
While adults' immune system can often have memory of previous infections,
  children lack this, so infections last longer in children
  (one source assumed 100 days as duration of infection in children).
An other source mentions disease to possibly last multiple years,
  but what it bases that assumption on was totally unclear.

Children are also economically weakest, so often more malnourished than rest of population,
  and malnourishment is detrimental to body's ability to counteract infections.
 

6.6 - Effect of acquired immunity in high-transmission areas

In most-highly endemic areas of world, malaria transmission is so intense that
  unprotected adults receive on average slightly more than 1 infectious bite per night.
Rate of infectious bites per night is called 'effective inoculation rate' (EIR).
If 20 days is an average time for an adult to clear him/herself of a malaria infection,
  then it is clear that
  if EIR is larger than 1/20th, adults will continuously have malaria,
  and seldom be free from it.
Also, in such areas there are many different strains of malaria,
  because if a strain is present in some part of that area,
  it will easily spread throughout that area.

As duration of infection is longer in children,
  an area that is low-transmission for adults can still be high-transmission for children.
 

6.6.1 - Qualitative description

Thus each person is continuously infected with a lot of plasmodia,
  many of these have PESPs that human has antibodies against
    (because they were infected by them a short while ago too),
  others have PESPs that victim can rapidly produce antibodies against
    (because they were infected by them a longer while ago too),
  and some have PESPs that victim has no immunity against
    (because they never were infected by these yet, or it was a long time ago).

When a human is infected,
  all sporozoites will be attacked by antibodies against circumsporozoite protein,
  but due to short duration of travel to liver, this does not greatly reduce their number.
When they reach liver, sporozoites settle there, to mature into merozoites.
During maturation time, they are to some extent vulnerable to immune-system,
  but because they hide in deeper tissue layers, this is not very intense ;
However, it does mean that if they remain in liver longer, their numbers are reduced more,
  so it is best for them to not stay there longer than necessary,
  which may explain why
  plasmodium species that is best adapted to highly endemic areas, P.falciparum,
  does not develop dormant liver stages.
Multiplication in liver cells
  (by circa 30,000 in 6 days for P.falciparum, ie by a factor 5.57 per day)
  is higher than rate of multiplication in RBCs in non-immune individuals
  (by circa 18 in 2 days for P.falciparum, ie by a factor 4.24 per day)
  and much higher than rate of multiplication in RBCs in immune individuals
  (where plasmodia would be lucky to increase their numbers at all)
  so plasmodia do multiply in liver as long as they can,
  probably until liver cell they have invaded is completely filled.

Merozoites then break out of liver cells into blood,
  where their number per infectious bite
  (which is maximum number of merozoites of one strain per infectious bite)
  is circa 3 million,
  which is much less than number of merozoites in a continuously infected person
  (as will be described furtheron).

Merozoites with a PESP that immune-system is currently actively fighting
  thus add little to number of merozoites with that PESP, so their effect is negligible.

Merozoites with PESPs against which no antibodies are present in bloodstream
  get some time to multiply in RBCs.
While doing so, they are detected by immune-system, and anti-bodies against them are developed,
  but as immune-system is already engaged against merozoites with other PESPs,
  amount of resources used for dealing with this new, still low-density, infection,
  is relatively small.

Body is constantly being infected, so it constantly needs to recognize new infectors,
  so cells to detect infectors whose PESP is remembered are constantly released into bloodstream.
Consequently detection of infectors with PESPs that were seen before is rapid.
As merozoites of that strain increase their numbers,
  antibodies to them are produced in proportion,
  and rate of decline of number of merozoites of that strain
    increases proportional to square of number of merozoites of that strain,
  until rate of decline outweights rate of multiplication.
If there are no other infections to fight,
  or if this strain's numbers are much higher than those of other strains body is infected with,
  then high-level production of antibodies continues
  until no more merozoites of this strain are present,
  just like in case of a single infection in a low-transmission area.
Usually, in high-transmission areas, there are multiple infections,
  and those strains that have largest number of merozoites are downregulated strongest,
  leading to a situation where all infectious strains have comparable numbers of merozoites,
  although there will be some per-strain variation,
  due to variation in how effective an antibody is against it's PESP.

It has been found in practice that,
  when in a hyper-endemic area people get fever from malaria,
  then this is caused by them being infected by a new strain
  against which they had no immunity.
  (so: if they have fever, then they had no immunity against an infecting strain).
Conversely, if they are infected by a strain to which they have no immunity, they get fever.
This is really just like people that are seldom infected in low-transmission areas,
  only difference being that
  in high-transmission areas, immune-system needs to
  dedicate a relatively small part of it's maximum capacity
  to fighting other (allready recognized) strains.
Reason for fever is that body needs a lot of time for trying out all kinds of antibodies
  until it finds one that is effective against new strain,
  during which time new strain can multiply unhinderedly.

Fever does not occur for strains against which immunity exists ;
These are down-regulated individually in proportion to their relative density of merozoites.
As a group they are apparently also downregulated,
  quite possibly also in proportion to their combined density.
It is found that in highly endemic areas, people have a nearly constant level of parasiteamia.
It seems likely that immune-system has some basic level of activity,
  and that when density of parasites ('parasiteamia') is low,
  then immune-system would function at that level of activity,
  producing some number of antibodies per day,
  against each infector in proportion to it's density,
  thus stabilizing total density of infectors as well.
If parasiteamia can not sufficiently be reduced this way,
  then immune-system would need to increase it's activity ;
Site of immune-system memory, and a place where antibodies are produce is spleen,
  and it is known that spleen is often enlarged during a malaria attack,
  which probably represents an increase of it's activity
  (but in chronic malaria may result from parts of it being damaged,
   (probably because small bloodvessels of 'sieve' become clogged)
   so that other parts have to work harder).
A minority of people in highly endemic areas have enlarged spleens,
  and this suggests that
  at least some people some times need to ramp up activity of their immune-system,
  but normally basic level of activity suffices.
Thus it seems likely that there is no separate mechanism for regulating total parasiteamia.
 

6.6.2 - Multi-infection causes Sequential attacks

In one study it was found that
  people that are infected with multiple strains of plasmodia to which they have no immunity
  manifest sequential episodes of illness, from one strain after another.
It might be that not all strains have same speed of development,
  so strain that multiplies fastest causes fever,
  and it only needs to be a few days faster than others to
    have 10 times as much merozoites as other strains have.
Body produces fever, sufficient to reduce numbers of dominant strain,
  and therefore even more strongly reducing slower strains.
Fever continues until an antibody against dominant strain has been developed,
  (in meantime antibodies against some of other strains may have been found too),
  uses these to combat dominant strain,
  which results in many successfull killings of merozoites of that strain,
  and thus causes production of an even higher level of antibodies against that strain,
  which remain in blood for some time ;
  I expect they normally succeed in completely eliminating that strain.
Then second-fastest strain has become fastest.
It's numbers have been reduced by fever, so it needs some time to multiply,
  and then it becomes cause of next fever.
Etcetera, until all strains have been dealt with (or until a new infection occurs).
 

6.6.3 - Groupwise Vulnerability

In high-transmission areas, women that survive to child-bearing age have developed immunity.
When they get pregnant for first time, that is first time they develop a placenta,
  so it is first time they are susceptible to PESP variant that attaches to placenta,
  so this variant never had a place to thrive yet, so it didn't thrive,
  so these women never had fever from them, and never developed immunity to them.
Therefore, at first pregnancy they get a malaria attack.
Some also get it at second pregnancy ; after that they apparently have longlasting immunity.
This also shows that remembered immunity can last longer than
  2-3 years for young women (average weaning period in Africa), and
  5 years for older women (circa 4 children/woman between ages 20 and 40).

For children, most important difference is that
  infection rate is much higher, so burden of disease on children is much higher,
  so chance of being overburdened (and thus dying) is very much higher.
In africa, circa 5 % of children die before their 5th birthday.
20 % of these deaths are due to falciparum malaria.
  (but some more may be indirectly caused by malaria ; i don't know how many).

(Now i am editing this text for publication, and i reread the above paragraph,
   and i wonder if i didn't mean 'effective infection rate',
   ie: rate of infection with strains that they have no immunity against yet.
 If somebody knows whether rate at which children get bitten is higher than for adults,
   please let me know)

Immunity develops much more quickly in high-transmission areas.
It has been found that speed of development of immunity
  increases with total time being infected,
  but not with severity of infections.

For adults, it is found that their immune-system keeps improving with age,
  eg 60 year olds have clearly better immunity than 30 year olds.
 

6.6.4 - Levels of Parasitaemia found in practice

In malaria-patients in a hospital in a high-transmission area,
  number of infected RBCs was determined, and depended on severity of infection :
Symptoms Number of Plasmodia
non-severe malaria 2.3E11 - 3.5E11
severe malaria 1.3E12 - 2.3E12
death 1.9E12 - 6.3E12


Earlier i already mentioned that a (healthy) adult has circa 2.2e13 RBCs .
I assume that in paragraph above
  "patients that died" means that the blood sample was taken before they died,
  so that it is likely that they died because
  next multiplication of merozoites infected all RBCs.

2.5E11 parasites per adult is equivalent to 50,000 parasites per microliter.
All these people had at least fever, so level of parasiteamia in immune people would be less.
(These numbers are not really comparable, because apparently
  severe malaria is caused by different P.falciparum strains than non-severe malaria).

In an investigation about effect of vitamin A supplements on malaria
  in children between 0.5 and 5 years old in a high-transmission area in PapuaNG
  it was found that parasite levels were
  1300 parasites/microliter of blood for those receiving vitamin A supplements, and
  2039 parasites/microliter of blood for others.
Also number of children with spleen enlargement was found :
  64 % (with vitamin A) and 71 % (others).

In another study, it was found that
  level of parasiteamia that causes fever depends on age of victim.
They measured this level as number of trophozoites per leukocyte,
  where a 'trophozoite' is an infected RBC,
    but does not include last stage of infection, where merozoites are preparing to burst out,
  and 'leukocyte' is a white blood cell (ie an immune-system macrophage),
    of which there are fewer than red blood cells,
    and which are easily recognized (and counted) under a microscope.
Level of fever-threshold varied as
  2.45 trophozoites per leukocyte maximum, at age 1 year old
  0.5 trophozoites per leukocyte minimum, at age 60 years old.
When parasite density of a person crossed threshold level corresponding to his or her age,
  that person's risk of fever was multiplied by a factor 44
  (95% confidence interval = 13.6-144.8).
 
 

7 - Malaria disease

In this section, i look at malaria as a disease,
  causing manifestations ('symptoms')
  that are detectable on a macroscopic scale ('clinical symptoms').
This includes symptoms that are clear for everyone to see,
  and things that every victim can feel,
  so it provides some info about effect of disease on victim as well.
How victims are affected by malaria in their economic and social life is not covered here ;
  some info about that is in sections 'epidemic' and 'economic'.

How malaria affects a person depends on
  * type of plasmodium that person is infected with
  * whether that person has immunity against similar strains of malaria
  * physical fitness of that person
  * whether other diseases occur simultaneously
  * what treatment is available to that person

When another infection is also present, malaria is said to be 'complicated'.
When acuteness of malaria is life-threatening, it is said to be 'severe'.
Complicated malaria is usually severe.
Malaria caused by P.falciparum in non-immune individuals is usually severe too.
 

7.1 - Infection

Malaria is mainly transmitted by mosquitos,
  but there are also 3 other ways of infection :
  * from mother to child during pregnancy (apparently happens in circa 1/3 of cases).
  * by blood transfusion ;
    (only way a patient receiving blood can be protected from this in africa
     is by administering preventive medicines.)
  * by shared uncleaned needles.
 

7.2 - Uncomplicated malaria

In most cases, malaria causes
  fever, chills, headache, muscle ache, vomiting, malaise and other flu-like symptoms,
  which can be very incapacitating

Some persons infected with Plasmodium falciparum can develop complications
  such as brain disease (cerebral malaria), severe anemia, and kidney failure ;
These severe forms occur more frequently in people with little protective immunity,
  and can result in death or life-long neurologic impairment

Babies born to women who had malaria during their pregnancy
  are more often born with a low birth weight or prematurely,
  which decreases their chances of survival during early life

Classical (but rarely observed with P.falciparum) malaria attack lasts 6-10 hours.
It consists of (in order of appearance) :
  * a cold stage (sensation of cold, shivering)
  * a hot stage (fever, headaches, vomiting ; seizures in young children)
  * a sweating stage (sweats, return to normal temperature, tiredness)

Physical findings may include:
  elevated temperature, perspiration, weakness, enlarged spleen.
If spleen is enlarged,
  there remains an increased risk of rupturing it after patient is cured ;
A few days of extra bed-rest to allow it to shrink again reduce this risk.

In P. falciparum malaria, additional findings may include:
  mild jaundice, enlargement of the liver, increased respiratory rate.
 

7.3 - Chronic malaria

People subjected to frequent malaria infections
  (such as young children and pregnant women in high transmission areas)
  can develop anemia
  due to frequent destruction of the red blood cells by the malaria parasites.
Severely anemic patients might receive blood transfusions
  which, in developing countries, can expose them to bloodborne diseases
  such as HIV and hepatitis B .

In chronic malaria, spleen may become fibrotic, reducing it's funtionality.
Liver is often also affected,
  this is probably related to yellowish skin that victims of malaria often get.
 

7.4 - Complicated malaria

In developing countries,
  harmful effects of malaria relatively often combine with those of other diseases,
  such as malnutrition, HIV/AIDS, and anemia of all causes.
Such combinations can have severe results, especially if they occur repeatedly.

In children with severe malaria,
  non-typhoid Salmonella septicaemia is most common co-infection.
 

7.5 - Severe malaria

Mainly occurs when P.falciparum infections are complicated by
  serious organ failures or abnormalities in the patient's blood or metabolism.
Well known are cerebral and kidney failures ; cerebral malaria has high mortality.

Possible manifestations of severe malaria include :
* Cerebral malaria,
    with abnormal behavior, impairment of consciousness, seizures, coma,
    or other neurologic abnormalities
* Severe anemia due to hemolysis (destruction of red blood cells)
  In severe malaria, it is common to find severe anaemia.
* Hemoglobinuria (hemoglobin in urine) due to hemolysis.
* Pulmonary edema (fluid buildup in lungs) or
  Acute respiratory distress syndrome (ARDS),
    (may occur even after parasite density has been decreased by treatment)
* Abnormalities in blood coagulation, and
  Thrombocytopenia (decrease in blood platelets)
* Cardiovascular collapse and shock
* Acute kidney failure
* Hyperparasitemia, where more than 5% of red blood cells are infected
  According to one source :
  Bacteraemia was detected in blood cultures of 7-14% of patients admitted with severe malaria.
* Metabolic acidosis (excessive acid in blood and tissue fluids),
    often in association with hypoglycemia.
* Hypoglycemia (low blood glucose).
  This may also occur in pregnant women with uncomplicated malaria,
    or after treatment with quinine.

Final stage of malaria is often a coma.

Severe malaria is a medical emergency !
(which means: either victim is treated immediately, or (s)he dies).
 

7.6 - Classification of victims

Four groups are usually distinguished :

* Average population :
Do not have sufficient money for effective healthcare ;
Have a high level of immunity, but also get re-infected very frequently ;
Get infected with a new strain of malaria circa once a year, and suffer from it.
Are often too poor to be well-nourished, which reduces their capability to cope with malaria.

* Women at first (or second) pregnancy :
Are immune to all forms of infection that they experienced before, like rest of population ;
Are not immune to plasmodium variant that infects cells of placenta,
  and consequently suffer from malaria, which may kill them ;
Their illness also reduces chances for child to survive,
  as there is a greater risk of premature delivery and low birth weight,
  with consequently decreased chances of survival during the early months of life.
In 1/3 of cases, malaria is transmitted from mother to unborn child.

* Children between 2 months old and 5 years old :
Under 2 months they still have anti-bodies from blood of their mother.
Under 5 years their own immune-system is not fully developed yet.
They will be infected with malaria if they live in an endemic area,
  but their chances of survival are much better if rate of infection is lower ;
  sleeping under mosquito nets is often advised for them.
In developing countries, circa 5 % of these children dies of malaria.

* Tourists :
Do have money for healthcare, most of them take medication,
Most black african tourists (working abroad, visiting motherland)
  remain immune to P.vivax, but have lost any immunity to P.falciparum.
White tourists are not immune at all.
 

7.7 - Diagnosis

Simple malaria is very similar to flu in it's initial stage.
When it becomes acute, it presents symptoms that could also be caused by other diseases.
Complicated malaria is malaria mixed with other diseases,
  and symptoms of other diseases might overshadow these of malaria.
As result of these,
  only way to diagnose malaria is by looking at blood samples with a microscope.

In high-transmission areas nearly everyone has some level of plasmodia in their blood,
  so if someone gets some other disease,
  then they should not be diagnosed as having malaria,
  despite presence of plasmodia in their blood.
Very recently, number of infected RBCs that causes fever due to malaria has been determined,
  and how it varies with age,
  and from this it is possible to determine with reasonable certainty
    whether a fever is caused by malaria or not.

Even more recently, reagents have become available, that can detect
  presence of anti-bodies against malaria in blood-samples ;
They are only available in sophisticated institutions, and require expert handling,
  which causes results obtained this way to be
  available later then those of a microscopic examination.
Reliability of both methods is comparable.
Modifications of these reagents to make them suitable for use in local health facilities
  are being actively researched,
  and will probably become available "soon" (written in october 2006).

Microscopy requires trained laboratory personnel,
  for being able to identify malaria-infected RBCs,
  and for knowing how much blood needs to scanned.
Even an experienced microscopist needs a good stereo microscope,
  as infected RBCs are much more difficult to identify than bacteria.

Most blood-scans are done in under-resourced labs in developing countries,
  and they occasionally get it wrong.
There are reports of people diagnosed as having malaria who did not have it,
  due to name of bloodsample being exchanged with that of someone else.
Most of time they do get it right, however.

Blood samples can be prepared for microscopy as 'thin smear' or 'thick smear',
  they differ in thickness of layer of blood on glass plate.
Thick smears allow more blood to be scanned per look through microscope,
  but infected RBCs are much harder to detect in them.
Thin smears are usually best choice, though more labor-intensive.

When looking at blood samples,
  most easily recognized signs of malaria-infection are :
  * 'schizonts',
    which are infected RBCs where multiplication has already occurred
    and which are ready to burst, and
  * gametocytes
    these are also infected RBCs, and are comma-shaped (which normal RBCs never are).
Merozoites can also sometimes be seen, but they are much smaller than schizonts,
  and are not in RBCs, so they could more easily be confused with other things.

When blood samples are left at room temperature, gametocytes can develop,
  and consequently (although this is rare) microscope can show
  * exflagellated gametocytes
  * microgametes, or even
  * ookinetes (product of fusion of male and female gametes,
     usually found only in the mosquito).
 

7.8 - Treatment

Two forms of treatment are distinguished :
  preventive (to prevent getting it), and
  curative (to cure you when you've got it).

Preventive medications are listed in next chapter.

Curative treatment mainly consists of very high doses of anti-malarial medicines,
  administred in an intensive-care unit of a hospital.
These medicines need circa 12 hours to reach maximum effectiveness ;
  consequently survival rates in even best-equipped hospitals in west are not so good,
  because many patients report there too late.
Generally speaking, however, malaria is a curable disease if treated promptly.

After being cured of malaria,
  if it was likely to be caused by P.vivax or P.ovale,
  patient should be given primaquine to flush out any hypnozoites from liver.
  (unless they also have G6PD deficiency, in which case primaquine would kill them).

Curative treatment in development countries often includes blood transfusions,
  because many frequently infected patients that
  report there because they have developed complicated malaria
  are anaemic due to frequent reinfections.

Malaria treatments constitute more than 50 % of all medical treatments in Ghana.
 

7.9 - Relapses

P.ovale and P.malariae can develop dormant stages in livercells.
These can become active after years.
Travellers to malaria-endemic areas that
  have become infected,
  but have recovered from first episode of illness,
  or did not develop clinical symptoms because they used anti-malarials,
  can thus unexpectedly get malaria years later.
Their physicians, often not knowing that their client was ever in a malaria-endemic area,
  do not suspect malaria, and consequently misdiagnose at first,
  making correct diagnosis later, for which patient receives treatment,
  but, alas, too late, and patient dies.
So :
It is important to always tell your physician that you have been to a malaria-endemic area,
  especiacially when you develop symptoms that could be malaria.

If a relapse occurs, and is correctly diagnosed and treated, so that victim survives,
  treatment is followed-up with 'primaquine',
  which flushes any remaining hypnozoites out of liver,
  preventing any further relapses from existing infections.
 
 

8 - Anti-malaria medicines


 
 For more info about medicines that are used against malaria, see also wikipedia.org .
 
COMPLETELY SUPERFLUOUS WARNING :
Do not believe that the data about medicines shown here is correct.
I do not have complete data, my data are not fully reliable, and i am not a medical doctor.

Main things to know about these medicines are :

Medication to use varies per country.
Travellers must get country-specific information.
Some good places for that are (in order of preference) :
  their own country's tropical health facility,
  website of USA's center for disease control at www.cdc.gov ,
  health branch of traveller forum at www.lonelyplanet.org .

Medication to use in an area varies over time
  because plasmodium in all areas keep developing resistance to drugs.

There is a difference between preventive and curative medicines.
Curative medicines often are very high doses of preventive medicines,
  but some medicines are only usable for prevention, and some are only usable for curing ;
  These are marked as such in list below.
If, despite preventive medicines, malaria does develop,
  preventive medication should be replaced by curative medication.
If you visit places from where you can not reach a western-quality hospital within 24 hours,
  you should bring curative medication with you, for emergency treatment.

Preventive medicines should be taken regularly,
  to build up sufficient concentration in body.
Therefore they should usually be taken well before entering a malaria-endemic region.
Due to delay between getting infected and symptoms becoming apparent,
  which can be delayed from normal 6-14 days because of use of preventive medicine,
  they should continue to be taken for some time after leaving malaria-endemic area,
  typically for 1 additional month.
Even after having finished medication treatment after return from risk-areas,
  malaria may still develop within next 4 years,
  due to ability of some plasmodium species to remain dormant in liver (as 'hypnozoite').
There is medicine ('Primaquine') that flushes hypnozoites out of your body ;
  this should be used after you have experienced malaria caused by hypnozoites.

You should let your physician know that you have travelled to a malaria-endemic region,
  and remind them of that whenever symptoms develop that could be malaria.
 

8.1 - Classification of medicines

This presents an overview of basic medicines used against malaria.
These medicines are often used in combinations, some of which are mentioned in next paragraph.

For some medicines mentioned below, dosages are specified ;
  note that these only apply to use as prevention.
Those medicines that are only for prevention or only for curing are marked as such.

Main classification is in anti-malarials, anti-protozoans, and anti-biotics.
Classification as 'anti-malarial' probably reflects lack of data on how these medicines work ;
  it was recently found that quinines are also effective against some other protozoans.
 

8.2 - Vaccines

There do not yet (october 2006) exist vaccines to make everyone immune to malaria.
Even if such a vaccine would be developed,
  it would not make much difference for adults in perennially endemic areas,
  since these are all immune already.

There is much development in this area of research ;
Most promising candidate vaccine currently undergoing field-testing in africa, 'RTS,S',
  is reported to, in children,
  reduce clinical cases by 35 % and cases of severe malaria by 45 %.
It is estimated that a really good vaccine will be available by 2015.

Compared to other medicines, which can have 90 % - 99 % effectiveness,
  vaccines are not yet very effective,
  so vaccines are not an option for travelers.

Compared to the use of insecticide-treated bednets,
  which reduce clinical malaria cases by circa 20 %,
  vaccines are already effective.

How usefull a vaccine will be will depend on it's cost, which is not yet known
  (but a bednet costs circa 4 - 10 dollar, and a vaccine will probably be much cheaper),
  and on how long it remains effective (18 months at least, for RTS,S).

It is estimated that 90 % of clinical cases and 50 % of deaths due to malaria occur in children,
  so vaccines can make an important difference in total cost of healthcare.
 

8.3 - Natural Drugs and their derivatives

There are two naturally occuring anti-malarials :
* Bark of Cinchona tree (Bolivia, 17th century).
* Leaves of Qinghao plant (Artemisia annua L, China, 4th century) ;

Barks and leaves contain many substances, many of which are not usefull against malaria,
  so from each of these natural medicines, one substance is extracted and refined,
  which is considered to cause anti-malarial effect :
  From Cinchona bark, Quinine is extracted, and
  from Qinghao plant, Artemisinin is extracted.
For various reasons,
  including:
    low bio-availability of artemisinin,
    injectability of quinine,
  both of these are only used for curing, not for preventing.
You may also encounter "Quinidine", which is a stereo-isomer of quinine.

From these natural extracts, some drugs are derived, by (partial) chemical synthesis.
Advantages of these derived drugs include :
  More effective per gram of medicine,
  More suitable for taking orally,
  Synthetic drugs are often cheaper to manufacture than natural extracts.
Disadvantages of these chemical drugs include :
  When plasmodium is attacked with a single drug, it is much more likely to develop resistance.
  Natural drugs may contain combinations of chemicals where one counters side-effects of other.
 

8.4 - Quinine

Quinine and Quinidine
warning Only for treatment
remarks Quinidine is a stereo-isomer of Quinine
Quinine is fluorescent
class natural alkaloids
brandname ???
contra-indicationsatrial fibrillation, conduction defects, heart block.
hemoglobinuria, myasthenia gravis, optic neuritis.
possible
side effects
irregular heartbeat.
cinchonism: impaired vision and hearing, confusion,
   headache, rash, abdominal pain,
   nausea, vomiting, diarrhea,
   (rarely) pulmonary edema.
hypo-glycemia, hypo-tension.
resistance ???
dosage form 300 mg tablets (very bitter and not well tolerated)
or intravenously.
method oral
frequency 2 tablets every 8 hours
last dose ???
max duration ???
parasite stage merozoite in RBC.
mechanism probably interferes with digestion of hemoglobin.
price ???

 

8.5 - Derivatives of quinine

These usually have names ending in '...quine',
  and conversely, drugs whose names end in '...quine' are usually derived from quinine.
Well-known examples include: chloroquine, mefloquine, amodiaquine, and primaquine.
Primaquine is in a class by itself, however,
  because it acts on sporozoites in liver hepatocytes,
  so is used for flushing hypnozoites out of liver, thus preventing relapses.

Chloroquine used to be drug of choice for preventing malaria everywhere,
  but P.falciparum in many countries has developed resistance against it,
  and so has P.vivax in some countries,
  so it is currently only used in countries where
    P.falciparum does not occur and P.vivax is not resistant.
 
 
Chloroquine ('chloroquine phosphate') and Hydroxy-Chloroquine
remarks Tablets have unpleasant metallic taste
class Quinine-derivate.
brandnames Aralen (chloroquine)
Plaquenil (hydroxy chloroquine)
generic medicines available.
resistance Resistance of P.falciparum against chloroquine is becoming widespread,
P.vivax is also developing some resistance in some places.
Chloroquine is still advised for :
  Mexico, Haiti, DominicanRep, some CentralAmerica,
  some MiddleEast, some EasternEurope.
indications Is more effective when taken together with proguanil,
  so is by itself no longer preferred treatment anywhere.
contra-indications chloroquine-allergy, epilepsy
possible
side-effects
Most travelers do not have side effects serious enough to stop taking it.
Nausea, vomiting, headache, dizziness, blurred vision, itching.
May worsen symptoms of psoriasis.
When used for long time and blurred vision occurs,
   regular visits to opthalmologist are necessary,
   as blindness may eventually develop.
Difficulty sleeping
dosage format 300 - 500 mg tablets
method take on full stomach
frequency (adult) weekly, always on same day of week
first dose 1 week before arrival :
on two consecutive days take 300 mg each day.
last dose 4 weeks after leaving
max duration more than 5 years
parasite stage merozoite inside RBC
mechanism Diffuses into digestive vacuole of plasmodium inside RBC,
  blocking polymerization of heme there,
  thus poisoning parasite with it's own waste products.
price ???

 
 
Mefloquine
class quinine-like synthetic
brandnames Lariam (Roche).
generic drugs available.
resistance in Thailand, Cambodia and Myanmar. not in Africa (2006/09)
indications for prevention and treatment,
especiaLLy for treating chloroquine-resistant P.vivax
contra-indications depression, psychosis, anxiety disorder, schizophrenia,
  major psychiatric disorder, tendencies to torture or murder.
seizures, epilepsy, heart-rhythm irregularities,
high altitude, scuba-diving.
mefloquine-allergy.
breast-feeding.
possible side-effects Most travelers do not have side effects serious enough to stop taking it.
headache, nausea (immediate), vomiting, diarrrhea (after a few weeks),
psychic problems:
   difficulty sleeping, anxiety,
   vivid dreams/nightmares, visual disturbances, dizzyness, disorientation.
   seldom: depression, panic, seizures, psychosis
     (usually happens before 4th dose or not at all)
     (more frequent with (high) curative dosage).
Patients that develop psycho problems,
   first get dizzyness, vomiting, and headache,
   which then rapidly worsens into depression of central nervous system.
dosage format (adults) tablet of 250 mg .
method take tablet on full stomach, with a full glass of liquid.
frequency weekly, always on same day of week.
first dose 3 weeks before arrival,
  (so any psychic problems have time to show themselves).
  (maximum blood level only reached after 7 weeks)
last dose 4 weeks after leaving.
max duration 1 year
parasite stage ???
mechanism ???
price 45 euro for 8 pills (Cairo 2008)

 
 
Amodiaquine
remarks half as effective as sulfadoxine/pyrimethamine
4 times more effective than chloroquine.
side-effects same as chloroquine.
probably chosen for ACT because it stays in body long.
class ???
brandname ???
contra-indications ???
possible side-effects ???
resistance ???
dosage
form ???
method ???
frequency ???
first dose ???
last dose ???
max duration ???
parasite stage ???
mechanism ???
price ???

 
 
Lumefantrine
class quinine-like synthetic
brandname Benflumetol
contra-indications ???
possible side-effects ???
resistance ???
dosage form ???
frequency ???
first dose ???
last dose ???
method ???
max duration ???
parasite stage ???
mechanism ???
price ???

 

8.6 - Primaquine

Primaquine, 'Primaquine-diphosphate'
remarks is N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine
WARNING DO NOT USE AS CURE.
Only use for travellers who can not take other anti-malarials.
Consultation with malaria expert is necessary before prescription.
class quinine-like synthetic
brandname Primaquine
generic drugs available
indications Unlike most drugs in this list,
primaquine does not work against malaria parasites in blood ;
instead it is used to rid liver of (possibly dormant) infections,
after (or while) blood-infection are cured with some other medicine.
contra-indications glucose-6-phosphate-dehydrogenase (g6pd) deficiency
   (will cause all red blood cells to burst -> lethal)
women pregnant of or breast-feeding children that
   have not been tested for g6pd-deficiency.
primaquine-allergy.
possible side-effects stomache-cramps, nausea, vomiting, headache, itching.
resistance ???
dosage form (adult) tablets of 15 mg primaquine each
method oral
frequency 2 tablets per day, both simultaneously
first dose 1 - 2 days before arrival
last dose 1 week after leaving
max duration
parasite stagesporozoites in liver hepatocytes
mechanism ???
price ???

 

8.7 - Artemisinin


Extract of leaves of Qinghao plant (Artemisia annua L).
Due to low bioavailability of artemisinin,
  semi-synthetic derivatives artemether and artesunate are more frequently used
  (see next section for those).

Due to short half-life of artemisinin-likes, and to prevent resistance,
  they are usually given in combinations with other anti-malarials (see next section) ;
  such combinations are know as Artemisinin Combination Therapy (ACT).
 
 
Artemisinin
remarks currently unavailable in US and Canada.
(can be gotten in europe, asia, and africa)
WARNING only for curing ???
brandname ???
class natural
indications
contra-indications ???
possible side-effects"minimal"
resistance none
dosage form ???
method ???
frequency ???
first dose ???
last dose ???
max duration (curative use removes malaria in 3 days)
parasite stage kills sporozoites in liver-hepatocytes and merozoites in RBCs
also inactivates or kills gametocytes
mechanism Peroxide lactone group in artemisinin
releases reactive oxygen substances
when brought into contact with high iron concentrations ;
this damages plasmodium, by inhibiting Ca++ transport.
Also inhibits hemoglobin-polymerization (like primaquine does).
price ???

 
 

8.8 - Derivatives of artemisinin

Artemisinin derivatives such as artemether have several advantages :
  they act rapidly, cause few side effects,
  and plasmodia are not yet resitant to them nearly everywhere.
I have very little data about them.

artemether
  Derivative of artemisinin.
  Some resistance against it is already reported from French Guiana.

artesunate
  Derivative of artemisinin.
 

8.9 - Anti-protozoans


 
Pyrimethamine (+ Sulfonamide + Folinic acid)
WARNING (was) not recommended for prevention.
remarks Has now been successfully used for prevention in pregnant women,
Is now being tried (already successfull in studies)
  for intermittent preventive treatment in children.
This is being (20071007) implemented in Ghana
   for children upto 2years of age.
class synthetic
brandname Daraprim (pyrimethamine)
Fansidar (pyrimethamine + sulfadoxine)
indications
contra-indications megaloblastic anemia, pyrimethamine allergy
possible side-effects changes in blood due to depletion of folic acid,
irregular heartbeat.
(folinic acid is added to reduce side effects for humans).
hyper-phenylalanin-emia.
resistance resistance is widespread.
"still has varying degrees of efficacy in Africa".
dosage form (adults) 200 mg tablets
method take after meal with water (or other fluid)
frequency daily
first dose 1 day before arrival
last dose 4 weeks after return
max duration ???
parasite stage ???
mechanism inhibits dihydrofolate reductase,
thus blocking RNA synthesis in protozoa.
price ???

 
 
Proguanil
WARNING is used for prevention only
remarks is mainly used in combination with atovaquone and chloroquine ;
  these combinations are in list furtheron.
class synthetic?
brandname Paludrine (proguanil-hydrochloride)
indications
contra-indications serious kidney malfunction
possible side-effects stomatitis,
rare: mouth- and throat-ulceration, 'skin-reactions', anorexia, loss of hair.
resistance
dosage form (adult) 200 mg tablet (or two 100 mg tablets)
method take with half glass of fluid,
preferably on same time each day.
frequency daily.
first dose 1 day before arrival
last dose 4 weeks after leaving
max duration ???
parasite stage merozoite in RBC.
mechanism blocks production of folium-acid in protozoa,
thus blocking reproduction.
price ???

 
 
Atovaquone
remarks also effective against pneumocysts and cyst forms of toxoplasma.
class synthetic, lipophilic analog of ubiquinone
brandname Meprone, Malarone
indications  
contra-indications skin alllergies, allergy to atovaquone.
possible side-effectsdiarrhea, fever, headache, rash, vomiting.
resistance ???
dosage FOR CURING:
  achieve >= 10 mg atovaquone / liter blood,
  initial dosage usually 750 mg, 3 times daily.
parasite stage ???
mechanism Acts on cytochrome bc1, inhibiting electron transport,
  thus inactivating enzymes of mitochondria,
  causing blockage of nucleic-acid synthesis and ATP synthesis.
price Germany: Wellvole: 0.25 liter, 750mg atovaquone/5ml (= 50 doses)
= DM 1449 (~EU 700)
Germany: Malarone: 12 tablets, 250 mg atovaquone/tablet (= 4 doses)
= DM 109 (~EU 50)

 

8.10 - Anti-biotics


Doxycycline
remarks Is also effective against various other infections,
  ranging from acne to bubonic plague,
  and including filariasis and onchocerciasis (river blindness).
  (but DO NOT give it to anyone suffering from river blindness !!)
class antibiotic, member of tetracycline antibiotics group.
brandname Many brandnames
generic drugs available
contra-indications child less than 8 years old, woman pregnant or breast-feeding.
doxycycline-allergy, allergy to other tetracyclines.
possible side-effects Most travelers do not have side effects serious enough to stop taking it.
Accelerates sunburn.
May cause minor stomache problems,
  especially when taken on an empty stomach.
May cause reflux of stomach acid,
  usually preventable by taking it with food or drink.
May cause? vaginal yeast infections.
Impairs effectiveness of contraceptive pill.
resistance No resistance in Africa (200609) or anywhere else.
dosage form (adult) 100 mg capsule
method Take tablet on full stomach with full glass of liquid.
Do not lie down within 1 hour of taking it, to prevent reflux.
frequency daily, at same time each day.
first dose 1 - 2 days before arrival.
last dose 4 weeks after leaving.
max duration 6 months
parasite stage merozoite in RBC ?, others ?
mechanism inhibits matrix metalloproteinases
(including those working on hemoglobin ?)
price ???

 

8.11 - Medicines that are combinations of drugs

Several plasmodium species have developed resistance against one or more of these medicines,
  to which medicines resistance exists varies per area,
  and therefore medication to use also varies per area ;
Most of resistance is against quinine-like drugs,
  artemisinin-like drugs having been developed more recently.
To prevent buildup of resistance against artemisinin-like drugs,
  most usual medication consists of a combination of an artemisin-like and a quinine-like drug ;
  if one doesn't kill plasmodium, other one will,
  and as they work in different ways, combination is more effective than any single drug.
These are generally referred to as ACT (for 'artemisinin combination therapy').

Some combinations that are used in practice include :
  artemether + lumefantrine (artemisinin-like + quinine-like)
  artesunate + mefloquine (artemisinin-like + quinine-like)
  artesunate + amodiaquine (artemisinin-like + quinine-like)
  artesunate + sulfadoxine/pyrimethamine (artemisinin-like + foliumacid-blocker)
  chloroquine + proguanil (quinine-like + foliumacid-blocker)
  atovaquone + proguanil (foliumacid-blocker + foliumacid-blocker)

From a study in Kenya,
   where malaria is highly endemic, and resistance against some drugs exists :
Failure rates after 14 days
amodiaquine 42 %
amodiaquine + sulfadoxine + pyrimethamine 20 %
amodiaquine + artesunate 11 %
lumefantrine + artemether 1 %

NOTE TO IGNORANTS :
   these numbers are only an illustration, will change over time, and should not be relied upon.
 
 
Lumefantrine + Artemether
WARNING only for treatment
remarks Effect of combination :
Artemether, a fast acting drug with a short half-life,
   rapidly reduces parasite biomass and quickly resolves clinical symptoms,
Lumefantrine, which is slower and has a longer half-life,
   is thought to prevent recrudescence.
class ACT
brandname Coartem, Lumerax
contra-indications severe malaria.
first 3 months of pregnancy, and when breast-feeding.
heart-rhythm abnormalities.
disturbed electrolyte balance.
use of halofantrine less than 1 month ago.
use of neuroleptics and tricyclic anti-depressants.
possible side-effects Dizziness, headache, sleep disorder,
abdominal pain, anorexia, diarrhea, vomiting, nausea, palpitation,
cough, arthralgia, myalgia, pruritus, rash, asthenia, fatigue.
Somnolence, involuntary muscle contractions, paresthesia,
hypoesthesia, abnormal gait, ataxia.
(rare) Hypersensitivity.
resistance ???
dosage form 20 mg artemether + 120 mg lumefantrine tablets,
used in doses of 4 tablets
method use on full stomach
(food, especially fats, increase uptake of this medicine)
frequency adults : 2nd dose 8 hours after first,
  thereafter a dose every 12 hours.
children: fraction of adult dose proportional to body weight,
  using 40 kg as weight of adult.
first dose  
last dose  
max duration  
parasite stage merozoites and gametocytes in RBC
mechanism  
price  

 
 
Proguanil + Chloroquine
class synthetic + quinine-derivate
brandname This medication does not have a brandname, since it is supplied as two separate medicines.
contra-indications same as for chloroquine.
possible side-effects see entry for Chloroquine. i don't know about Proguanil
resistance Resistance against chloroquine is widespread and also applies to combination with proguanil.
dosage: Proguanil is taken daily, while chloroquine is taken weekly.
See entries for individual medicines for more info.
parasite stage  
mechanism  
price  

 
 
Proguanil + Atovaquone
class synthetic + synthetic
brandname Malarone (GlaxoSmithKline)
contra-indications child weighing less than 11 kg, pregnant, breast-feeding.
severe renal (kidney) impairment.
atovaquone- or proguanil-allergy.
possible side-effects some experience stomache-pain, headache, nausea, vomiting
resistance No resistance in Africa (200609)
dosage form adults: 1 tablet of 250mg atovaquone + 100 mg proguanil.
children: 1/4 of that.
method take tablet with food or milk.
frequency daily, at same time each day.
first dose 1 - 2 days before arrival.
last dose 1 week after leaving.
max duration 3 months
parasite stage  
mechanism Beside mechanisms of each of these drugs,
  proguanil multiplies capability of atovaquone to collapse 'DeltaPsim',
  which causes depolarization of mitochondrial membrane.
This causes this combination to have 100 % success rate,
  while atovaquone by itself only achieves 70 %
price ???

 

8.12 - Curative therapies

For curing malaria, injectable drugs are preferred over drugs that are swallowed,
  because injectable drugs work faster.
Quinine and artemisinin are injectable.
If injectable drugs are not available, or for other reasons not used,
  drugs for curing are often same ones used for preventing,
  but dosage for curing is much higher,
  up to level where further increasing it would risk patient dying from medication.
Because of this, curative dosage depends on body-weight,
  and should be determined by your tropical-health provider.
 

8.13 - Special therapies

For pregnant women, there is apparently only one safe medication :
  proguanil + chloroquine + folium-acid-supplement .
It's success-rate is only 70 % .
 

8.14 - Resistance against medicines

Drug resistance has been confirmed in only 2 of human malaria parasite species,
  namely P.falciparum and P.vivax.
Chloroquine resistant P.falciparum
  first developed independently in 3 to 4 foci in Southeast Asia, Oceania, and South America,
  in late 1950's and early 1960's.
Since then, chloroquine resistance has spread
  to nearly all areas where falciparum malaria is transmitted.
P.falciparum has also developed resistance to
  nearly all of the other currently available antimalarial drugs,
  such as sulfadoxine/pyrimethamine, mefloquine, halofantrine, and quinine.
Although resistance to these drugs is much less widespread geographically,
  in some areas impact of multi-drug resistant malaria can be extensive.

Currently malaria is not yet resistant to artemisinins.
Artemisinins are considerably more expensive than other medicines,
  so resistance to other medicines is a major setback.
If artemisinins are going to be used as main treatment,
  there is a large risk of such resistance developing fast,
  which would leave us with no effective medication at all.

In West Africa there is a high rate of resistance to Chloroquine.
Newer anti-malarial drugs such as Mefloquine, Doxycycline, and Malarone,
  are around 90% effective.
One in five people experience some side effects.

Plasmodium gene responsible for chloroquine-resistance, called 'pfcrt',
  is widely distributed in parasites from around world.
Pfcrt moved across continents very quickly,
  requiring between 6 to 30 years to become established,
  which was presumably caused by high transmission rate of malaria.
Resistance spreads between continents via human travel, particularly by air.

To reduce development of new medicine-resistances, two general measures are taken :
  * Medications are composed of two of more medicines,
     so that plasmodia would have to become resistant to both of them at same time,
     which is a lot less likely, and will thus happen a lot later.
    Such therapies are called 'combination therapies' ;
     most well known of them is ACT (artemisinin combination therapy).
  * Where and when plasmodia are not resistant to chloroquines,
     chloroquines are used as main treatment,
     until success-rate of treatment drops below 80 % .

While there is a lot of resistance against quinine-derivatives,
  quinine itself remains relatively effective,
  presumably because it is a plant-extract and thus contains multiple substances.

Fact that quinine contains multiple substances, many of which have no effect on malaria,
  causes it to have a lower ratio of anti-malarial effects per adverse-side-effects,
  so that it is only used in hospitals, with doctors monitoring effect of therapy,
  and is therefore only used curatively.
Exception to this are herbal-doctors that include plant-extracts in their medications ;
  these have a lower success-rate than medical establishment,
  but are often only health-care providers that population can afford.
Same applies to artemisinins, presumably.
 

8.15 - Herbal medicines

Besides quinine and artemisinin, there are no known effective anti-malarial herbs.
There are some plant-extracts that have some beneficial effects,
  and these can be the only thing that the population can afford.
Artemisinin was developed relatively recently,
  from a herbal medicine that was used in traditional chineses medicine.
Thus it remains possible that
  more herbs are discovered from which effective medicines can be made.
 

8.16 - Future medicines

8.16.1 - Glutathione-reduction inhibitors

Garlic is known to have some antifungal and antibacterial effect,
  and also somewhat (but not enough) works against cancer and malaria in animals.
Some disulfide components from garlic were identified as having such effects.
These appeared to be effective due to interfering with 'glutathione system',
  with which normally antioxidant and detoxifier glutathione is reduced
  to store it for use later, when it is needed to absorb damage.
Cells that reproduce rapidly, as found in cancer and malaria,
  are particularly dependent on this glutathione system
  because toxins are natural byproducts of metabolism.
Researchers hope that these disulfides may one day be usefull against malaria and cancer.
 

8.16.2 - Protease inhibitors

Researchers in 2000 tried to use protease-inhibitors to strengthen membrane of RBCs.
They did not succeed in this, but did find that
  it strengthened membrane that clusters of merozoites have around themselves
    when they burst out of RBCs,
  to extent that merozoites were unable to get out of their membrane.
Perhaps this effect could someday be used in a medicine.
 

8.16.3 - Anti-Sticky Medicines

These are a class of drugs that are effective against (severe) falciparum malaria,
  by preventing red blood cells from becoming sticky.
Drug 'heparin' that was previously used
  had too many possible side-effects
  (including interference with normal blood coagulation, as is needed to close wounds,
   and even including death of patients sometimes).
New modification of heparin, called dGAG (depolymerised glycosaminoglycan),
  that is currently under development in Karolinska Institute
  and that seems to lack such side-effects,
  is not available on market yet.
When it hits market, it will be good against acute falciparum malaria,
  but can not lower occurrence of malaria in endemic areas.
 

8.16.4 - Vaccines

There is a lot of ongoing research to find a vaccine against malaria, with a lot of funding.
From level of effort being made, it is expected that a good vaccine be available by 2015.

An article i found on web has it that :
"Pierre Druilhe of Pasteur institute reported (sci-am nov 2005)
   about a vaccine that
   produces recognition of an essential merozoite surface protein (MSP-3)
   by immune system,
   leading to production of white blood cells (macrophages)
   that kill protozoan parasite while it is in blood.
 Recognition is triggered when sporozoites enter body,
   but immune response is not fast enough to catch them on their way to liver,
   it does strongly decrease their number when they leave liver to go attack red blood cells.
 It's mechanism is reportedly same as
   that found in mature people who have developed resistance to malaria
   (which normally takes daily exposure to malaria for many years)."
However, if this really is mechanism of immunity in endemic areas,
  then malaria attacks can only be explained by assuming that
  different strains of malaria have different 'essential merozoite surface proteins'.
So it might be that they need to develop a combined vaccine against all 50 such proteins.
Or it might be that there are multiple mechanisms of acquired immunity,
  and this is only one of them, which by itself is insufficient to rid body of malaria.

There is currently a promising vaccine made by GlaxoSmithKline, named 'RMS,S',
  undergoing field tests in a.o. ghana.
I don't know how it works.
It is aimed at adminstering to very young children, who never had malaria yet.
Tests show that it increases time to first get malaria by about 40 %.
 

8.17 - Medicine policies

In USA, malaria was eradicated, but mosquitos were not,
  so they remain at risk of new malaria epidemics,
  which they fend off with medicinal treatment of new cases as soon as they appear.
It is therefore necessary for them that effective medication remains available.
Their society however breeds a class of rich people
  with mentality that they should always have all new things first,
  and even that only best is good enough for them.
Such people succeeded in acquiring and using artemisinins
  in areas where quinine-derivatives were still successfull,
  thus increasing speed of development of resistance to these drugs.
This has led to new anti-malarials being less easily available in USA than elsewhere.
It is probably also one of motivating reasons for
  current high level of funding of anti-malaria research and interventions.

In development countries, artemisinins are available for who have money,
  but of all medicines bought in pharmacies in developing countries that
  should contain artemisinins, according to text on box,
  30 % were found to contain no artemisinins at all.
 
 

9 - People

This section looks at malaria from perspective of local populations.
People are affected by malaria mainly by getting ill, or having family-members that are ill.

How victims in endemic areas are affected depends on level of malaria transmission :
  if transmission is high, most people are bitten often, and have immunity.
  if transmission is low, most people do not have immunity, and get ill when bitten.
Malaria transmission and, therefore, immunity are low in both Thailand and KwaZuluNatal.
  Thais and South Africans typically get sick when they are infected, and seek treatment.
In African countries where malaria transmission is high,
  semi-immune individuals often do not feel sick enough to seek treatment,
  and function as a disease-reservoir for continued transmission.

Most people in endemic areas are very poor, often illiterate,
  live from small scale farming or unskilled labour,
  and have little if any access to medical facilities.
To cope with effects of malaria, they generally employ a number of coping strategies :
* other members of extended family take over their work, where possible.
* they borrow money from friends and neighbours to buy medication (if possible).
* if more than one child is ill,
  only one is brought to health centre (if health centre and money are both available),
  and medication is divided over all ill children.
* they visit traditional healers (priests, faith-healers, herbalists, 'medicinemen')
* as last resort, they try to ignore disease.

Due to their poverty, they are often also not well nourished,
  and their diet is not well balanced.
On top of that,
  anemia caused by malaria makes them need more iron,
  and lack of vitamins and proteins, and generally not getting enough food,
  makes their body, including their immune system, weaker.
  
The commitment of the people to combat diseases in their communities is generally high,
  especially for malaria, which is often the dominant disease ;
Nevertheless, since they work as hard as they can to remain alive,
  the efforts they need to make should not be out of proportion to the benefit they derive,
  which may be relevant to areas where other diseases are more prevalent.
This will become more important as the incidence of malaria is reduced.
It may then become necessary to also combat other diseases, to maintain their commitment.
  
 

9.1 - Illustration

As an illustration, here is some info about an area where malaria is endemic :
Study was conducted from January 2003 to October 2004 in Ganze, in Kilifi district.
Kilifi district is second poorest in Kenya,
  education levels are low (53.4% of population has not received any education),
  and it has highest female illiteracy rate in country.
Circa 64% of Kilifi residents cannot afford to meet minimum food requirements,
  even if they were to spend all their income on food alone.
Mean monthly per capita expenditure was
  KES 989 (US $12.7) in wet season and
  KES 913 (US$ 11.7) in dry season.
Main sources of income for household heads are
  small scale farming (62.2%), and
  unskilled labour such as building and construction (17.5%).
Dry season is difficult for households
  because casual farm jobs are not available and food is scarce.
Expenditure was unequally distributed among poor and less poor households ;
  those in wealthiest quintile spent ten times more than those in poorest quintile.
About 80% of survey households live below US$1 per day.
Majority of households own land (88.4%).
For about four years, crop yields have been low due to rain shortages ;
  Year that case study took place (2003-2004)
  was reported as particularly bad, with people living 'hand to mouth'.
Since land and casual labor are critical income generating sources
  drought limited people's access to cash and made their livelihoods vulnerable.
Attempts to diversify income sources (small businesses, selling local brew, or weaving, etc)
  were often futile
  because market for such goods was constrained by cash flow problems across community.
An important safety net is having livestock,
  which can be transformed into cash when need arises,
  thereby acting as a form of bank.
Main types of livestock are
  chickens (87.1% of households)
  goats (67.3% of households).
  cows (19.5% of households).
Market for livestock was also constrained by the drought:
  people found it difficult to sell livestock,
  and animals fetched much lower prices than they would normally.
Other key assets owned by households were
  radios (46 % of households),
  bicycles (20 % of households), and
  sewing machines (46% of households).
Among some highly vulnerable households
  even KES 10 would require adoption of some form of coping strategy ;
  primarily borrowing from friends.

Ganze location is hot and humid.
Malaria transmission is low and stable, with peak seasons between April and July.
There is one government dispensary, serving a population of 35,299 persons,
  next closest government facilities are
  a health center located twenty kilometres away and
  Kilifi district hospital 35 kilometres away.
Other providers in area include
  two private clinics,
  numerous shops selling drugs without prescription, and
  traditional healers.
Dispensary and private clinics are situated at Ganze trading centre.
Majority of the population live in interior,
  so a long walk or bike ride are needed to reach these services.

When a member of family fell ill with malaria,
  other members of household would take over work of victim,
  (causing higher workload on others, and children staying home from school)
  and would try to borrow money for buying medicines ;
  As their relatives are also very poor, this often was not possible.
Other coping strategies did not aim to raise cash
  for example: borrowing drugs from neighbours, and sharing drugs between siblings.
Drugs were mainly shared among siblings who fell ill within same period.
  This strategy was common among households with many young children.
  Usually younger or more seriously ill child was taken to a health facility
    and drugs received were used to treat siblings too.
Where raising cash or other strategies were impossible,
  'ignoring' illness and struggling on was common among highly vulnerable households.
 
 

10 - Epidemic

This section reflects on malaria as an affliction that exists in areas of world,
  and how it can spread from one area to another.
It also tries to explain per-area malaria prevalence as resultant from conditions in that area.
It is based on a simple model of
  how a population of mosquitoes interacts with a population of humans
  in conditions where these humans are nearly unprotected
  (such as exist in rural areas without anti-malaria interventions).
 

10.1 - Some theory on computing prevalence of malaria

In this section i try to do some math on prevalence of malaria among humans and mosquitoes.
This will be used in next section to compute some practical values.
 

10.1.1 - Symbols used

In math equations, it is necessary to use symbols, such as Tfs,
  instead of their meaning (eg Tfs represents average survival time of a female mosquito).
To make it easy to see which symbol represents what thing,
  names of symbols are constructed systematically :

Symbols starting with 'T' denote amounts of time, measured in days.
Symbols starting with 'R' denote rates, measured in number of things per day.
Symbols starting with 'F' denote fractions, which is like a percentage, but in range 0 to 1 .
Symbols starting with 'C' denote chances, also in range 0 to 1 .
Symbols starting with 'N' denote numbers, as in 'the number of mosquitoes'.

Added to these firstletters are some specifiers :
  'f' stands for 'female mosquito' (males are irrelevant for infection).
  'F' stands for the entire population of female mosquitoes.
  'is' stands for 'infectious', while
  'id' stands for 'infected', and
  'i' stands for incubation time'.
  'us' stands for 'not infectious', while
  'ud' stands for 'not infected'
  'p' stands for 'people', meaning one person, and
  'P' stands for whole population of people.
  's' stands for 'survive'.
  'g' stands for 'generated'.
  'b' stands for 'bloodmeal'.
 

10.1.2 - Math

In an area there are a number of people and a number of mosquitos.
In this mathematical description, i assume that those numbers are constant over time
  (ie a 'steady state' has developed).
This causes results of this math to be valid for cases where these numbers are
  either constant, or variations in them are small (say 10 %).
Still, these results can be used for larger variations,
  by interpreting that large variation as a sequence of small variations.

Main parameters of model, which are not determinable by this model, are :
NP number of people
NF number of female mosquitoes ('mossies')
Cfs chance for a mossie to survive to next day


There are also a number of parameters that describe physical facts,
  so that they are fairly constant, irrespective of intensity of malaria.
These are :
Tps average lifetime of a human
Rfb biting rate per mossie
Tfi incubation time in mossie
Tpi incubation time in human
Tpud time for immune-system to clear human of a malaria infection


From above parameters, two others can be derived straighforwardly :
Tfs average lifetime of a mossie
RFg female births/day of mossie population


Tfs is determined from Cfs.
For simplicity of model, survival chances are assumed to be constant,
  irrespective of what mossie is doing or what it's age is ;
This is allowable because what we are interested in (and therefore what we derive from model)
  is the chance for a mossie to survive a mating/biting/egglaying cycle,
  and in practice it appears that this chance does not depend on age of mossie
  (in other words: mossies normally die of accidents, not of old age).
As the mossie population is assumed to be constant,
  time-average over mossie life is same as ensemble-average over mossie population,
  so i use that for easy computation :
In a population of mossies, fraction of mossies that are still alive after time T is
FFs(T) = exp(-T/T0)
  in which T0 is a timevalue that is to be determined, and T is measured in days.
Then chance for a mossie to survive to next day is
Cfs = exp(-1/T0)
  from which it follows that
ln(Cfs) = -1/T0
T0 = -1/ln(Cfs)
Also, chance for a mossie to survive over next period of dT days is
exp(-dT/T0)
  so chance to not survive that period is
1 - exp(-dT/T0)
In a group of mossies that have reached age T,
  there are a number of them that will not reach age T+dT ;
  these are the mossies whose lifetime is T days.
Number of mossies whose lifetime is between T and T+dT is
NFl(N) = NF exp(-T/T0) (1-exp(-dT/T0))
Taking dT very small (ie dividing mossie population in a large number of agegroups)
  this is equal to
NFl(N) = NF exp(-T/T0) (1 - (1 + (- 1/T0) dT))
= NF exp(-T/T0) 1/T0 dT
Average of lifetimes of all mossies is then found by
  for each group multiplying number of mossies by their lifetime,
  adding numbers for all agegroups, and dividing result by total number of mossies in population :
   sum( NF exp(-T/T0) 1/T0 dT T ) / NF
= sum( exp(-T/T0) 1/T0 dT T )
Letting dT approach zero, this is equivalent to
integral(1/dT exp(-T/T0) 1/T0 dT T, T, [0;+inf] )
= integral( 1/T0 exp(-T/T0) T, T, [0;+inf])
= 1/T0 { (-T0) T exp(-T/T0) - T0^2 exp(-T/T0) } [0;+inf]
= { -1 T exp(-T/T0) - T0 exp(-T/T0) } [0;+inf]
= T0
So i find that average lifetime equals T0 :
Tfs = T0
Combining this with Cfs as found above :
T0 = -1/ln(Cfs)
  and therefore
Tfs = -1/ln(Cfs)

RFg can then be derived from Tfs.
As size of population of mossies is assumed to be constant,
  number of mossies born per day equals number of mossies that die per day,
  which is simply total number of mossies divided by their average lifetime :
RFg = NF / Tfs

Now age-distribution of mosquito population can be computed.
Number of mosquitoes of age 0 equals number of newborns per day (= RFg),
  and for rest of agegroups,
  their number equals that of previous agegroup multiplied by daily survival chance Cfs .

For each agegroup, i also need to know
  fraction of mosquitoes that are infected, and
  fraction of mosquitoes that are infectious.
This is needed to later compute average number of infectious bites per day,
  from which i then compute fraction of humans population that is infected or infectious.
However, before fraction of infectious mosquitoes can be computed,
  i already need to know fraction of people that is infectious (FPis),
  because mosquitoes become infected by biting an infectious human.
It is for this reason that this model is implemented as a spreadsheet,
  since this enables me to
  try some value for FPis and
  see if it results in that same value of FPis at end of computations,
  by doing a goalseek.
This would be difficult to do analytically, as it results in a transcedental equation,
  and to solve that it must be approximated,
  for which practical values of all parameters need to be known,
  but since determining these values is purpose of making the model,
  analytical way is not all that usefull.
So, a value for FPis is simply tried.

Then, for each agegroup,
  number of bloodmeals that a mosquito in each agegroup took is easy to compute,
  and "knowing" FPis,
  fraction of mosquitoes in that group that have become infected can be computed too.
Fraction of infectious mosquitoes is computed same way.

Way to compute these is as follows :
For agegroup 0, we know number of mossies,
  and none of them have taken a bloodmeal yet,
  so none of them are infected yet,
  and none of them are infectious.
As the model assumes that mosquitoes bite every other day,
  first bite occurs after day 1,
  so agegroup 2 is first that had a bloodmeal,
  and chance that they are infected equals fraction of people that are infectious (FFis),
  for which we had assumed a value.
  None of agegroup 2 are infectious,
    as this only occurs Tfi (incubation time in mossie) after being infected.
Similarly, for agegroup 4,
  only ones who can become infected are the ones who are not yet infected,
  so we take number of mossies in that agegroup, and subract number of infected mossies,
  and multiply result by FFis.
Continuing like this, we get a whole column with number of infected mosquitoes per agegroup.

Then, number of infectious mossies of an agegroup is computed from it,
  by taking number of infected mosquitoes of agegroup that is Tfi days younger,
  and multiplying that by survival chance Cfs to the power Tfi .
As you see, it is assumed that being infected does not change mossie's survival chance,
  which is indeed what is found in practice.

Then, having this table of agegroups,
  total number of mossies is computed from it
  by simply adding number of mossies of each agegroup ;
This is done because
  chunkyness of per-day agegroups causes this total number of mossies to be
  slightly different from NF that was specified as parameter.
Similarly, total number of infectious mossies is computed.
Then these are combined to yield fraction of mossies that are infectious.

Now the total number of mossies is known,
  their biting rate is known, and
  fraction of them that are infectious is known,
  so from these i compute
  total number of infectious bites per night that mossies make,
  which is same as
  total number of infectious bites that human population receives (RPbis).

In literature about malaria, this is often represented as EIR (effective inoculation rate),
  which is computed as RPbis / NP .

For the model, a slightly more precise approach is needed,
  because i need to compute the chance that a human is not infected.
Consider one human.
During one day (ie a 24-hour period), there are RPbis infectious bites given to human population.
For each bite, chance that this human receives this bite is 1/NP .
Therefore, chance that this human does not receive this bite is 1 - 1/NP .
This chance is the same for every bite,
  so chance that this human does not get bitten this night is
(1-Cpbis) = (1-1/NP)^RPbis
Chance that he does get bitten is also computed, although it is not used any further
Cpbis = 1 - (1-1/NP)^RPbis

If a person does not receive an infectious bite for Tpud (self-cure time for humans) days,
  then this person is not infected.
So fraction of people that are infected can be computed :
(1-FPid) = (1-Cpbis)^Tpud

People who are not infectious are those people who
  were not infected during the last Tpud days, or
  who were infected during the last Tpud days, but this took place less than Tpi days ago,
  (so they have not yet become infectious).
So these people did not receive an infectious bite between Tpud and Tpi days ago,
  and consequently chance of that happening to a person is
(1-Cpis) = (1-CPbis)^(Tpud-Tpi)
  which, because population size is constant,
  equals fraction of people that are not infectious
(1-FPis) = (1-CPbis)^(Tpud-Tpi)

From this FPis can be computed,
  and it is used for goalseek until it equals FPis that was assumed earlier.
When goalseek is completed, all parameters are known.

Two other values were computed in this model,
  because i wanted to know whether one was negligible compared to other.
They are
  the chance per day for an infectious person to get cured by his immune-system, and
  the chance per day for an infectious person to die.
If an infected person dies, because population is constant,
  he is replaced with a newborn, who is not infectious,
  so both cure-rate and die-rate represent a decrease in part of population that is infectious.
What i found was that
  death rate is negligible,
  except when number of infectious bites per person per day was extremely high
    (much higher than what already causes nearly entire population to be infectious).
So for practical purposes death-rate can be neglected compared to cure-rate,
  because what i am interested in are cases where
  infectious fraction of population is between 10 and 90 % ,
  because these represent conditions that occur when malaria is successfully combatted.
 

10.1.3 - Spreadsheet

A printout of what my spreadsheet looks like is given here :
Parameters NP 100 number of people
NF 100 number of mossies
Cfs 0.6563 daily survival chance for mossie
Tps 18250 lifetime of person (50 years)
Rfb 0.5 bites per mossie per day
Tfi 6 incubation time in mossie
Tpi 12 incubation time in person
Tpud 20 self-cure time of adult
FPis 0.5000 fraction of people that are infectious (goalseek)
Values Tfs 2.37 average lifetime of a mossie
Rfg 42.11 birhtrate of mossies
AgegroupsNFrNfbrNfid+rNfidrFfidrNfis+rNfisr
0 42.110 0 0 0
1 27.640 0 0 0
2 18.141 9.079.070.5
3 11.911 0 5.950.5
4 7.81 2 1.955.860.75
5 5.132 0 3.850.75
6 3.373 0.422.940.8800
7 2.213 0 1.930.8800
8 1.4540.091.360.940.720.72
9 0.95400.890.9400.48
100.6250.020.6 0.970.160.47
110.41500.4 0.9700.31
120.27600.260.980.030.24
130.18600.170.9800.15
140.12700.110.990.010.11
150.08 7 00.080.9900.07
160.05 8 0 0.05100.05
170.03 8 0 0.03100.03
180.02 9 0 0.02100.02
190.01 9 0 0.01100.01
200.01 100 0.01100.01
210.01 100 0.01100.01
220 110 0 1 00
230 110 0 1 00
240 120 0 1 00
250 120 0 1 00
260 130 0 1 00
270 130 0 1 00
280 140 0 1 00
NF 122.53Nfis2.69
FFis 0.0219fraction of mossies that are infectious
RPbis 1.34rate of potentially infective bites per day
1-Cpbis0.9169
Cpbis 0.0831Chance for a person to become infectious today
1-FPid 0.176481581
FPid 0.82352Fraction of people that are infected
1-FPis 0.499665949
FPis 0.50033Fraction of people that are infectious
C-cure 0.010239472chance for person to recover today
C-die 0.000054795chance for a person to die today


Reasonable values for parameters are :
NP 100 can choose anything ; it is NF/NP that is important
NF ??? was completely unknown, see results section below
Cfs 0.7 often between 0.7 and 0.9
Rfb 1/2 true for A.gambiae iirc, in A.malariae is 1/3 iirc
Tfi 6 5-7 days to divide in gutwall for P.falciparum
Tpud 20 for adults with passive immunity ; 100 for children
one report says infections in children in Keny can last for a year
Tpi 12 usually 10-14 for P.falciparum

 

10.1.4 - Results

Using this spreadsheet for various values of NF/NP and Cfs
  has yielded following table of most important values.

Note that FPis represent fraction of infectious persons,
  and therefore also represents fraction that are seriously affected by this disease,
  because their immune-system is working at full speed.
It is however a somewhat gross approximation,
  as effect of multiple infections is not taken into account ;
  in this model a person is infected or not infected, and that's all.
 
 
NP NF Cfs Tfs FFisCpbisFPidFPis
10010000.7 2.80.06 0.89 1 1
10010000.6 2.00.0170.5 1 0.996
10010000.55 1.70.0080.29 0.9990.93
10010000.5 1.40.0260.11 0.90 0.60
10010000.45 1.20 0 0 0
NP NF Cfs Tfs FFisCpbisFPidFPis
100300 0.8 4.50.17 0.84 1 1
100300 0.7 2.80.06 0.48 1 0.99
100300 0.65 2.30.03 0.30 1 0.95
100300 0.6 2.00.01 0.16 0.97 0.74
100300 0.55 1.70.0020.03 0.45 0.21
100300 0.5 1.40 0 0 0
NP NF Cfs Tfs FFisCpbisFPidFPis
100100 0.9 9.50.42 0.76 1 1
100100 0.8 4.50.17 0.45 1 0.99
100100 0.75 3.50.10 0.30 1 0.94
100100 0.7 2.80.05 0.18 0.98 0.79
100100 0.65 2.30.02 0.07 0.77 0.44
100100 0.6 2.00 0 0 0
NP NF Cfs Tfs FFisCpbisFPidFPis
10030 0.9 9.50.42 0.34 1 0.97
10030 0.8 4.50.15 0.15 0.96 0.71
10030 0.75 3.50.06 0.07 0.75 0.43
10030 0.7 2.80.0010.0010.02 0.01
NP NF Cfs Tfs FFisCpbisFPidFPis
10010 0.9519.50.95 0.16 0.97 0.75
10010 0.9 9.50.38 0.12 0.92 0.64
10010 0.85 6.10.20 0.07 0.75 0.42
10010 0.8 4.50.05 0.02 0.31 0.14
10010 0.75 3.50 0 0 0


The first thing to notice is that what is usually called a 'highly endemic area'
  doesn't really have all that many mosquitoes per human.
One report of an area that was considered extremely endemic
  had it that EIR was slightly more than 1 ,
  which is equivalent to a Cpbis of circa 0.7 .
Even with a low-ish Cfs of 0.7, this means only 10 mossies per human.

'Low-endemic areas' on the other hand, are those which in above table have FPis near zero.
If it is true what i read that Cfs lower than 0.6 is unusual,
  then this means that these are areas that do not support a large mosquitoe population.

And then there are areas that only have malaria sometimes, usually at the end of the rains ;
These would have zero FPis in above table,
  and as malaria does thrive there some part of the year, Cfs would not be unusually low,
  so these too must be areas that only support small mosquito populations,
  except after the rains, when more sugarfood and waterpuddles are available.

Another interesting thing is that it seems possible to
  find out the paramaters of prevalence from FFid and FPid/FPis .
FFid can be measured by catching mossies in a trap,
  and sending them to a lab to determine how many of them are infected.
Neither FPid nor FPis can be determined,
  but, using microscopy or reagents, it is possible to determine
  which fraction of people has a relatively large amount of merozoites in their blood,
  and that result will be between FPid and FPis.

It is also clear from results that malaria is spread by a small fraction of mosquitoes,
  namely those that grow old enough for sporozoites to mate and mature inside them.
 

10.2 - Limitations of this model

It is a simple model, so it has important limitations.
 

It does not take multiplicity of infections into account

This is true, but doesn't seem to present much of a problem.
Multiple infections cause less effort of immune-system per infection,
  which could increase Tpud,
  but Tpud is really only important when the infection rate is low,
  and in that case the chance for having multiple infections is also low.
 

It assumes that every bite of an infectious person infects mossie.

This is inaccurate, as i don't know
  chance for mossie to ingest sufficient gametocytes as function of parasite density.
For multiple simultaneous infections, i would also need to
  keep track of how many infections each person has,
  and would need to know how his immune-system regulates parasite densities.
 

Coupling factor

This model supposes that mossies have no problem getting a bloodmeal
  (other than that it might affect their daily survival chance).
If the entire population shields itself from the mossies
  with windowscreens, long sleeves, bednets, etc,
  then this is no longer true.
What a mossie will do if she can not get access to a victim to bite,
  is apparently not fully known yet ;
I presume that they will
  either settle down somewhere where they may have a better chance later,
  or, especially if they are hungry, look for sugarfoods.
These are both delays, and in endemic areas a delay is only important for first bloodmeal,
  because nearly whole human population is infectious.
This would decrease fraction of mossie population that are infectious,
  and therefore also fraction of humans that are infectious,
  so it does look like this effect should be added to the model,
  but as long as there is no data about amount of delay that is caused, this is not possible.
 

Non-constant population size

In practice this happens in areas that have seasonal changes in mosquito population size.
I think that NF becomes higher because the stress-factor that determines it is relaxed,
  which means that at that moment Cfs increases,
  and then population grows rapidly, perhaps in a few weeks,
  after which a new stable situation comes into existence, to which the model can be applied.
The dynamic behaviour of the population size
  can be computed using the same parameters as the model uses,
  so for practical purposes the model is fairly compatibel with a (separate) dynamic description.

To give an idea about effects of seasonality :
In two villages, in similar surroundings,
  but one practising irrigated agriculture, while other did not,
  it was found that :
In the village in the irrigated zone,
  incidence of malaria fevers was fairly constant over the year
  at 0.7 per 1000 children per day.
In the village without irrigated agriculture,
  incidence was low during the dry season (at 0.6 per 1000 children per day),
  whereas it was high during the rainy season (at 3.2 per 1000 children per day).
 

10.3 - Relevance of this model

Most important thing of this model is that it characterizes malaria by two parameters :
  NF, number of female mosquitoes, and
  Cfs, average chance for a female mosquitoe to survive to the next day.
Models similar to this one have been checked against correctness with data from the field,
  and apparently provide a good match.
Thus, effectiveness of measures to combat malaria can be expressed as
  effectiveness to reduce NF and/or Cfs.

Consequently, it would probably be interesting to take a look at
  which factors determine the values of NF and Cfs .
 

10.3.1 - NF

Rather surprisingly, i found nearly no researchpapers about what determines NF .
Only exception was dr. Gary's thesis, in which need for sugarfood is investigated.

NF would be determined by those things that mossies need and that they need to compete for.
  (in theory it could also be that humans kill mossies if their numbers become too high,
   but this has not been found in practice).
In this context, 'what mossies need' means what is needed for entire lifecycle of mosquitoes,
  not just what a flying adult needs.
These needs can be summed up :
  mossie needs
    if possible, get a sugarmeal,
    find a swarm,
    mate successfully,
    find a bloodmeal victim,
    take a bloodmeal successfully,
    a restingplace to develop eggs,
    a suitable oviposition site.
 egg needs
   quietness of water
   permanency of water
 larva needs
   micro-organisms as food in toplayer of water
   permanency of water
 pupa needs
   just some time
 emerging adult needs
   reasonably quiet weather
 male adults need
   sugarfood
   find others to swarm with

Looking at this list, there are only few entries that mosquitoes might need to compete for :
  sugarmeal,
  access to bloodmeal victim
  suitable place for eggs to develop (ie a waterbody)

I had already computed earlier that where any waterbodies are available
  the size of these would suffice for very large amounts of mosquitoes.
So this could only be limiting factor in very dry areas where there is no stream
  (but that usually also implies there are no people)
  and in non-slum parts of cities.
For most areas where malaria is endemic, lack of water would not limit mossie population size.

Acces to a victim for a bloodmeal is, in the literature,
  often named as a possible restraint on mossie population size,
  but really this not all that likely,
  because in very-high-endemic areas EIR can be more than 1 infectious bite per person,
  while in low-endemic areas EIR can be 300 times lower.
So i presume that access to blood may be limiting factor in high-endemic areas,
  but that it is not the main constraint in all the other areas.

So that leaves availability of sugarfood.
Idea that this is limiting factor on mossie population size
  seems to be supported by seasonality of populationsize around Canadian lakes,
  where water can never be the problem, and it is reported that
  population size increases very strongly in those parts of summer that forest is flowering.
With the large amounts of plants per human in most malaria-endemic regions,
  and the small amount of mossies per human,
  it is a bit surprising that this could be competition factor ;
Perhaps it is not so easy for mossies to find sources of sugarfood,
  as these are not easily visible and do not emit much smell,
  and random searches include a large risk of getting caught by predators
  such as flying insects and spiders,
  so they might be restricted to some few easily findable sources.
With current amount of knowledge about this,
  it is not yet possible to compute NF if type of vegetation is known.
In future, this might however be used as a way of attacking mossies,
  for example by providing them with easily findable sources of poisoned sugar,
  or by increasing population of predators that are effective agains them.
One complication that would arise for poisoning sugarfood is that
  it has been shown that some of main foodcrops in Africa
  (which as a whole is most endemic region of world)
  namely cassava and corn,
  are suitable sources of sugarfood for mosquitoes.
On other hand, it has also been shown that
  mosquitoes will feed from artificial sources of sugarfood if that's all that's available.
 

10.3.2 - Cfs

In nature, some areas have higher Cfs than others,
  to extent that this makes some areas suitable for mosquitoes while other areas are not.
Thus entire range of Cfs occurs in nature.
In very endemic areas, Cfs would often be on the high side.

Decreasing Cfs is one of main countermeasures against malaria.
This will be discussed in more detail in next chapter.

As was found with this model,
  to eradicate malaria by lowering Cfs, it is necessary to kill half of mosquitoes every day,
  which requires very effective methods.
 

10.4 - Localizedness of malaria

Mossies can fly 5 or 10 miles per day,
  but usually do not do this and prefer to sit and hide
  in small crevices, or among foliage, near waterbodies used for breeding ;
  (those species that prefer to rest indoor often rest on walls or in roofs).
Thus if a village, with it's mossie population and it's plasmodium population,
  is more than 5 miles from the next village,
  how effective would it be to remove malaria from this village ?

If both villages have 100 people and 100 mossies,
  then village that has no malaria might receive 1 mossie from other village per day,
  and fraction of these mossies that are infectious would be 40% or less.
Nevertheless, as soon as any mossie would succeed in infecting only one human,
  malaria would become established in that village again.
If the biting rate would 1 per day per person,
  and the probability for a mossie to survive the next 2 days (ie 1 gonadotrophic cycle)
  would be 50%, then one more human would be infected after 4 days,
  and would become infectious circa 12 days after that,
  after which infection rate would increase roughly exponentially,
  so entire population would be infected again in circa 7 weeks.
If, on other hand, biting rate would just be 1/100 per person per day,
  then spread of infection would take circa twenty times as long,
  so in that case, prevalence of malaria in that village could be considered local.

10 by 10 square miles per 100 inhabitants is roughly same as 1 inhabitant per square mile
  (circa 2.56 inhabitants per square kilometer).
Taking Ghana as example, which has 22 million inhabitants,
  of which circa 40% live in larger settlements,
  and which has a surface area of 92,000 square miles (238,000 km2)
  so average population density in rural areas is 143 people per square mile.
The southern half of ghana is forest,
  while the northern half is tree-savannah or treeless savannah,
The biggest province ("Northern region") in the northern half
  has a land surface of 70,000 square kilometres and a population of 1.8 million,
  yielding a population density of 25.7 people per square kilometer
  (circa 10 people per square mile).
If they lived in villages of 100 people, then these villages would be circa 3 miles apart.
There are no data about this, but it could be guessed that
  if a village there were cleared of malaria,
  then it would receive perhaps 10 mosquitoes per day from surrounding villages,
  of which perhaps 5 % would be infectious (because life is harder for mosquitoes there),
  so they would get one infectious bite per 2 days,
  which would cause new establishment of malaria there
  (unless that person would be put on medication very promptly,
    which is not realistically feasible),
  but, assuming that Cpbis is circa 1/10 per person per day,
  it would take 30 weeks for malaria to become fully endemic there again.
In this area malaria is endemic,
  and on average, each person needs medicines against it once per 2 years.
Thus treating one village's malaria prevalence as a local disease
  costs 3 times as much medicines.

If a large area is cleared of malaria ('rolling it back'),
  then time for a village to become reinfected is increased
  by time needed for mossies to migrate to a village, establish themselves there,
  and move on to next village.
As model indicates, fraction of mosquitoes that are infectious
  is proportional to fraction of people that are infectious,
  and as establishment of malaria in a village happens exponentially over time,
  time needed for migration of malaria over an area can be estimated as
  time needed for one village to be infected, and infection to become established there,
  after which next village could be infected from there.
So it seems that eradicating malaria from a large area
  could result in villages in interior of that area to remain free of malaria for a long time.
For this to be cost-effective in medicine use,
  they would need to remain free of malaria for at least circa 90 weeks,
  so if time for epidemic to become established in a village would be 7 weeks
  (as was roughly estimated earlier),
  then diameter of that area would need to be at least 40 villages,
  which, if villages are 3 miles apart, is an area with a diameter of 120 miles.

For more accurate computation of minimum size of such an area,
  it would be necessary to know parameters (mainly Cpbis or EIR)
  of epidemic in villages in that area.
Please note that it is assumed that malaria is eradicated there, but mosquitoes are not.

Speed of spread of a new strain of malaria
  would be equal to speed of reinfection computed above,
  except that there is additionally much faster spread between large cities,
  due to travellers.
  Then from cities or roads between them it spreads more slowly over rural areas.
One source reported that medicine-resistant strains of malaria can
  completely spread over a continent within 40 years.
Intercontinental spread is completely caused by travelers,
  since mosquitoes can not fly that far without stops.

Development and spread of Plasmodium's resistance to chloroquine has been investigated.
Resistance started developing more than four decades ago,
  and today the gene responsible for this resistance, called pfcrt
    (for 'plasmodium falciparum chloroquine resistant thingy')
  is widely distributed around the world.
Pfcrt moved across continents very quickly,
  requiring less than 80 generations (between six to 30 years) to become established.
This indicates a speed of spread of circa 60 miles per year.

As it is hard to find areas where main cities are more than 240 miles apart,
  it seems that rolling back malaria in this way would
  only be cost-effective in areas with very low biting rates per human per day
  (which means: with very small mosquitoe population relative to human population) .

Malaria that occurs on an island is ofcourse locally treatable.

One problem of Africa is that it is a very large landmass,
  so it is very difficult to remove malaria from it.
(Australia is similar, but the inhabited part is south of the tropic).
 

10.5 - Occurrence

Malaria is one of the most severe public health problems worldwide,
  causing more burden on the people of the world than HIV/aids.
It is leading cause of death and disease in many developing countries.

In olden days, malaria was very widespread,
  including south-USA and Italy.
Since then it has been eradicated in many places,
  mainly the developed countries and
  the underdeveloped countries that are islands or had a low infection rate.

Today, most of it occurs in Africa, between the Sahara and the Kalahari
  (ie between tropic of cancer and tropic of capricorn).
  which has a total population of circa 1 billion people.
Worldwide, 2.2 billion people are at risk from malaria.

300 to 500 million clinical cases occurred in 2006
  of which most (circa 70 %) are found in Africa,
  and of the cases outside Africa, 75 % (in 1990) occurred in these 9 countries :
  India, Brazil, Afghanistan, Sri Lanka, Thailand, Indonesia, Vietnam, Cambodia, and China.
Malaria causes circa 2 million deaths annually ;
  roughly half of them children under 5 years old.
57% of these deaths occur in Africa, 30% in Asia and around 5% in the Americas.

In 2002, malaria was the fourth cause of death in children in developing countries,
  (after perinatal conditions, pneumonias, and diarrhea),
  causing 10.7% of all children's deaths in developing countries.

Malaria is the greatest burden on the healthcare system in Africa.
It causes more than half of out-patient visits in Ghana.
The large majority (84%) of blood transfusions in the Congo (in 2000)
  were caused by it, due to malaria causing anemia.

The distribution of malaria varies greatly from country to country
  and within the countries themselves.
Where malaria is found depends mainly on climatic factors
  such as temperature, humidity, and rainfall.

Malaria is transmitted in tropical and subtropical areas, where:
  Anopheles mosquitos can survive and multiply,
  Malaria parasites can complete their growth cycle in the mosquitos,
    (Temperature is particularly critical for this,
     as P.falciparum does not live long enough for that if temperature is below 20 oC,
     and for P.vivax this is 14 oC).

Even within tropical and subtropical areas, transmission will not occur :
  At high altitudes
  During cooler seasons in some areas
  In deserts (excluding the oases)
  In some islands in the Pacific Ocean,
    which have no local Anopheles species capable of transmitting malaria
  In some countries where transmission has been interrupted through successful eradication.

Generally, in warmer regions closer to the equator:
  Transmission will be more intense
  Malaria is transmitted year-round
  P. falciparum is main parasite.
  A. gambiae is often main vector.
In drier areas, malaria tends to be spread by mosquitoes adapated to that climate,
  especially those that have capability to survive periods of drought.

Malaria also occurs outside of the areas where it is endemic,
  mainly in people that have returned from travels to endemic areas ;
France has circa 7000 cases per year,
  of which 300 are severe, requiring hospitalization in an intensive care unit,
  of which circa 10 % (mainly whites) die, despite optimal medical care.
USA had 1337 cases of malaria in 2002, including 8 deaths
  (presumably americans travel to south america more often, where malaria type is less severe).
 
 

11 - Anti-malaria measures

Anti-malaria interventions are all aimed at removing or reducing plasmodium.
Eradicating mosquitoes is considered to be unachievable, or at least much more costly.

While eradicating malaria would be most desirable,
  malaria is practically impossible to eradicate from a large area such as Africa.
Consequently, most of measures focus on making the problem manageable,
  by making prevalence low enough that remaining cases can be treated at affordable cost.

Clearly, every anti-malaria method must be evaluated
  for it's cost-effectiveness (for comparing different methods),
  and for it's remunerativeness
  (ie to what extent costs can be recovered as decrease of health expenditure).

Possible anti-malaria measures can be divided in :
  measures to reduce daily survival chance of mossies
  measures to reduce size of mossie population
  measures to reduce contact between mossies and people
  measures to reduce fraction of people that are infectious
 

11.1 - Measures to reduce daily survival chance of mossies

Because these measures are aimed at
  reducing average survival chance for entire population of mossies,
  they are only effective if they are practised throughout community ;
  individual efforts have negligible effect.
  (except where these efforts are also effective as personal protection).

Life of mossies consists of
  mating, bloodfeeding, resting for egg-development, oviposition, and optional sugarfeeding.
With each of these activities, there are some opportunities for attacking them,
  often optimized for the characteristic behaviours they exhibit during these activities.

Some of these measures tend to make mossies fail activities of gonadotrophic cycle,
  or at least delay them in completing it,
  while others tend to kill them during their typical activities.
Please recall that in previous chapter it was mentioned that what is really important is
  not daily survival chance, but chance to survive a gonadotrophic cycle.

For mating, they first need to find a swarm.
They often start from an oviposition site that has been used previously,
  so that this is also site where males were born,
  and consequently hang around if sugarfood is available in the neighbourhood.
Nevertheless, finding a swarm may not be all that easy ;
Earlier i already discussed that they may prefer victim-seeking by flying against the wind,
  so they would return against the wind, and could then not locate swarm by it's smell.
Dr Gary found that mossies can not identify an individual mate
  until they are a few decimetres away ;
  so it is likely that they cannot visually recognise a swarm from more than a few metres.
So how will they find a swarm then ?
I did not find data about this,
  but think it might be possible that they do this by sound ;
  swarms are known to make noise.
If this is true, then either drowning out the sound of the swarm,
  or misguiding the mossies with pre-recorded swarm-sounds
  might be used to make the mossies fail.
Such things have not yet been tried in practice, as far as i know.

Another possibility would be to reduce size of swarms.
Fact that males swarm makes them easy to find,
  and i imagine that using simple methods (a butterfly net or somesuch)
  if used everydays, might suffice to seriously reduce number of males in a swarm,
  which might cause serious problems for locating a swarm.
Not all males of a swarm fly about at same time, many of them resting nearby,
  so it would take an effort that was continued for relatively long times everyday.
But a displacement of swarm to a place that is less suitable as breeding ground,
  or even an unsuccessfull attempt to kill them
  that results in so much stress that it interferes with their sugarfeeding efforts
  might produce significant results.

When they have found a swarm, they mate,
  and the chance of successfull mating depends on whether the males have found enough sugarfood.
Depriving the males of sugarfood is near-impossible in practice in areas with a lot of foliage.
Poisoning the males might be an alternative ; it has not been tried in practice, as far as i know.

After mating, mossies usually immediately search for a human to bite.
Over larger distances, they locate their preys
  by smells, such as those of unwashed feet, and by CO2,
  while flying at an altitude presumably near height of a rooftop, or a bit lower.
Building houses higher than this is a countermeasure used among indiginous peoples in South Egypt.
Washing your feet with soap is a countermeasure used by anyone who can afford it.
Mossies can not efficiently be intercepted during this flight.

When they reach a dwelling from which such smells emerge,
  they try to follow smells in reverse direction, to find an entrance.
Screening all houses in a community has been used, and was effective, in USA and Italy.

I have observed that mossies, despite being cold-blooded, do not seem to dislike cold places,
  but that they prefer places with much moisture in the air.
So airconditioning is maybe not repellent to them
  (but well built houses that aircos are usually found in would be a major hindrance to them).
Some claim that ceiling fans make mossies dislike flying in that room ;
  perhaps there is truth to it,
  but perhaps not to extent that you should let you health depend on it.

Once inside that dwelling, or perhaps encountering a victim outdoors,
  mossies identify possible victims still mainly by smell,
  although maybe they also use infrared vision.

It is known that mossies can be caught in traps using hot objects such as incandescent bulbs,
  but i have no data of which fraction of mossies can be caught with these.
Inside a house would be a place where such traps could be set and would be relatively effective.

They often do not go in for a bite immediately ;
If victim is up and about, they often sit down on a wall or in a crevice,
  waiting there until all is quiet.
Indoor residual spraying can kill them there, or at least seriously reduce their lifetime,
  and mosquito coils or citronella candles presumably have similar effects
  (but i am not sure of that ; it might be that these repel mosquitoes instead of killing them).
They may however, decide to go in for the bite immediately.
Whichever they do, before they really bite, they tend to sit down near selected biting site,
  often on clothes of victim, or if victim is under a bednet, on bednet itself.
Treating bednets with insecticide is a common and effective countermeasure.
Treating clothes with insecticide has also been found to be surprisingly effective.
Treating skin with DEET or somesuch, to dissuade mossies from going there
  is used for people who are outdoors, and is said to be effective.

If an object that to a mosquito resembles a bitable human were to be placed in a bedroom
  such that it would be more available to the mosquito than the human,
  then treating that thing with insecticide could kill mosquito.

If mossie is infected with malaria, it may need to take several bites for a complete bloodmeal.
This does not offer extra opportunity to attack them.

If blood of victim is enriched with a substance that is poisonous to mossies,
  they might get killed by it.
As far as i know this has not been tried yet
  (while it might be combinable with taking anti-malaria profylaxis).

When mossie has finished her meal, she finds a place to rest,
  which for most effective vector, A.gambiae, she prefers to do indoors.
Again this exposes her to getting killed due to indoor residual spraying (IRS).
For IRS to be effective, it must be done to a large (70% or more) fraction of households.
One source mentioned that
  "the recent success of IRS in reducing malaria cases in South Africa by more than 80%"
  was the cause of the renewed interest in IRS.
Another noted that mosquitos can become resistant to an insecticide within a few years.

After eggs have matured inside her, she flies outside,
  presumably guided by drafs to get out of dwelling.
Then she presumably flies downwind to somewhere near breeding site that she came from.
How she locates a suitable oviposition site was not reported in what i read ;
  water does not make sound,
  and to the human nose it does not produce a smell,
  but mosquitos seem to like moist places, so maybe to them it smells strongly.
The temperature of water is probably near that of surroundings,
  but still it seems possible to find it by (sensitive) infrared vision.
As they will often mate at dusk, just before dusk might be time they like to oviposit,
  so water would be slightly warmer than surroundings then,
  and it might be attempted to use warm water to attract them,
  to see whether they find oviposition sites by heat.
Likewise, it might be tried whether they are sensitive to level of moisture in air.

Removing possible oviposition sites from around the house is a common countermeasure.
Poisining surface of possible oviposition sites is also a frequently used measure,
  but as these poisons are not harmless to humans,
  it is not suitable for areas where children roam.

After oviposition (for which some species do not even land on the water),
  mossies may look for a meal of sugarfood.
When it has been determined how they locate a source of sugarfood,
  a method to misguide or kill them might be devised.

This concludes their gonadotrophic cycle.

Besides dangers that humans put on their paths deliberately,
  mossies are also affected by natural dangers,
  and of these, increasing presence of any natural enemies to mosquitoes might be feasible.
 

11.2 - Measures to reduce mosquito population.

Earlier, i said that size of mossie population is probably often determined by
  availability of sugarfood from foliage.

There does not seem to be much that can be done about amount of foliage.
How mosquitoes locate sources of sugarfood is not yet known,
  so that does not yet provide possibility to reduce size of population.
One thing that might be doable, is to
  introduce mosquito populations of a species that can not transmit malaria ;
  these would compete with Anopheles for a scarce and vital resource,
  thus reducing number of Anopheles.

There is also another aspect to consider :
Mosquito's lifecycle consists of egg, larva, pupa, and flying adult,
  and for each stage of lifecycle there is some chance to survive to next stage.
Now if one mossie lays 100 eggs,
  and the end result of the development of these eggs is that more than one adult emerges,
  then the mosquito population will thrive (to be limited by some factor such as sugarfood).
But if those 100 eggs on average only result in less than one adult,
  then the population will dwindle.

The number of eggs oviposited by an average mossie over it's lifetime
  times the survival chance of each egg to result in an adult mossie (female),
  this i call 'loopgain'.
If loopgain is greater than 1, population thrives,
  if it equals 1, size of population stays constant,
  and if it is less than 1, population dwindles.

An important aspect of this approach is that
  when combined effect of all efforts is big enough to reduce loopgain below 1,
  then this set of measures is successfull, presumably even very successfull.
But if combined effect is not large enough for that,
  then effect will be negligible
  (though if prevalence is seasonal, effect will manifest itself as reduction in ramp-up rate).
So it is easy to incorrectly conclude that such measures are ineffective,
  and, to avoid this, it is important to quantify effect of each measure.

So, let's look at the lifestages of Anopheles,
  and find ways to minimize survival chances.

As egg, they are dependant on quality of water, which might be poisoned
  (this has been tried on large scale, by spraying areas that had many puddles and somesuch).
If they live in large waterbodies, they might share that waterbody with a Gambusia Affinis,
  which is a fish that likes to eat mosquito eggs.
Removing access to suitable oviposition sites
  may induce mossie to lay her eggs in a not-so-suitable place.
This is widely practised, for example: covering of drains.

As larva, they are much like eggs, except that they move about to feed themselves,
  and can dive underwater in case of danger ;
In many cases their breeding sites are small, and they can not leave them.

Perhaps it would be possible to provide oviposition sites, near ones that mossies already use,
  and sterilize these from time to time with ultraviolet or somesuch.

Larval habitats may be destroyed
  by filling depressions that collect water,
  by draining swamps, or
  by ditching marshy areas to remove standing water.
For some mosquito species, habitat elimination is not possible,
  so next best attack on habitats is to apply chemical insecticides to these habitats.
Chemical insecticides have some disadvantages for the environment,
  and some alternatives exist :
Oils may be applied to the water surface, suffocating the larvae and pupae.
  Most oils in use today are rapidly biodegraded.
Toxins from bacterium Bacillus thuringiensis var. israelensis (Bti)
  can be used like chemical insecticides, but are very specific,
  affecting only mosquitos, black flies, and midges.
Insect growth regulator methroprene is specific to mosquitos
  and can be applied in the same way as chemical insecticides.
Mosquito fish (Gambusia affinis) effectively control mosquitos in larger bodies of water.

Destroying larval habitats is not always feasible,
  as they may be small, widely dispersed, and transient.
A.gambiae breeds in numerous small pools of water that form due to rainfall,
  and the larvae develop in a few days, before their pool dries out.
It is difficult to find and treat these pools before the adults emerge.
Therefore, larval mosquito control has not been attempted on a large scale in Africa.

As pupa, they do nothing, but are somewhat larger.
I have not heard of natural enemies that could prey of them.

As adults they are attackable, as was noted in previous paragraph,
  as they have needs that they need to take actions to satisfy.
Those that prefer to rest and bite outdoors are hardest to kill,
  even poisongas tends to miss them, as they like to rest in crevices and similar small spaces ;
  (Most effective measure against them is destruction of their breeding sites).

If a set of measures results in dwindling A.gambiae populations,
  which would then be replaced by other Anopheles species,
  it would already make a significant contribution,
  as malaria is hard to eradicate from A.gambiae.

An other lifeform of Anopheles are adult males ; these were not yet discussed.
If there are no males, entire lifecycle can not take place at all.
If number of males is halved, mating would probably occur at same rate,
  although mossies chances of succes would be less (as discussed above).
For purpose of reducing overall survival chance of lifestages of Anopheles,
  a complete wipeout of males would be the goal ;
Swarms are easily identifiable,
  and as long as large vacuumcleaners and the like have not been tried,
  i remain optimistic about their possible effect.
Sterile male release has been successfully applied in several small-scale areas,
  but the need for large numbers of mosquitos makes this approach impractical for most areas.
Genetic modification of malaria vectors
  aims to develop mosquitos that are refractory to the parasite ;
  This approach is still several years from application in field settings.

In areas where sustainability of malaria is strongly seasonal,
  often there is a dry or cold period that mosquitoes must survive,
  which they can do as eggs, fertilized adult females or larvae.
Eggs, larvae, and pupae must have water to develop.
In theory they could be dealt with by creating the conditions of the malaria season
  so that the mosquitoes would start developing,
  and then stop this simulation, so that they would die ;
  In practice this is probably not feasible.

I have no numeric data about effectiveness of the measures that i know about,
  so i have to leave this subject here.
 

11.3 - Measures to reduce contact between mossies and people

Some of these measures are also advisable from goal of making mossie unsuccesfull,
  thus delaying it and consequently reducing fraction of mossies that is infectious ;
Here these measures have a different goal :
  to reduce infectionrate of humans, in an environment with
  a given size of mossie population and a given fraction of mossies that are infectious.
This reduced infectionrate is then to result in a lower disease burden.

For preventing contact with mossies for babies and tourists,
  these measures have the goal of keeping them alive, because they have little immunity.
Children build up their immunity, and are often not-so-wellnourished,
  so they can die from malaria.
Tourists have no immunity at all,
  but are somewhat protected by their anti-malarial medicines,
  which have an effectiveness of circa 90 %,
  meaning that they take care of 9 out of 10 infectious bites.

First and foremost of these measures is to wear clothing.
You had originally not expected this ofcourse,
  as you had thought it would be best to be in Africa like the children,
  innocently playing under waterfalls without any clothes on,
  and making large swings through the forests, suspended from a liana,
  wearing nothing but a short tarzan-like skirt.
However, that was before you realized that
  acting that way would get you killed by malaria within a few weeks.
So, for a tourist it is wise to dress like the natives,
  and it is even wiser to dress more defensively thant that.
This means :
Loose clothing that covers most of the body, preferably of light colors ;
Around dawn and dusk and in the evening,
  you would wear long sleeves and long pants or skirts,
  (also preferable during rest of the day).
Shoes are also a very good idea.

Second most frequently used measure is the bednet.
It is used for people without immunity if the house they are staying in is
  not so well built that mossies can not possibly get in.
The bednet protects during sleep, while clothes protect during waking hours.
The widespread use of insecticide treated nets can reduce child mortality by 20 per cent.
They also have a repellent effect.
Bednets are reported to yield a 90 % decrease in Effective Inoculation Rate.

Related to the bednet are residual indoor spraying (IRS), mosquito coils, and citronella candles.
They protect you when you are indoors.
Poisons used for them vary ;
  For bednets and for spraying rooms, pyrethroids are used, for their low toxicity to humans.
  For indoor residual spraying, currently use of DDT is becoming accepted again.
IRS is : coating the walls and other surfaces of a house with an insecticide
  that remains active there for several months, killing insects that come in contact with it.
IRS can kill mosquitoes before they bite, but usually kills them after they have fed,
  and perhaps it's main effect is that it reduces lifetime of mossies,
  so that only a small fraction of them reach an age at which they can be infectious.
Correct and timely use of IRS can reduce malaria transmission by up to 90 per cent.
IRS is reported to, in some areas, reduce effective inoculation rate by upto 100 times
  and infant mortality by 40 %.

Another measure, also mentioned in section about mossies,
  is the use of repellent body lotions/creams/sprays.
These protect you when you are outdoors.

In somewhat richer households, screening doors and windows is a good measure ;
It is however ineffective if the house has cracks in it's walls or roof,
  and is also not effective against mosquito species that prefer to bite outdoors.

A completely different method might be the provision of non-human bloodmeal victims.
This would only work in areas where mosquito species are (facultatively) zoophilic
  (or can be replaced by zoophilic species),
  and would work better if access to human victims is made difficult.
Most Anopheles mosquitos are not exclusively anthropophilic or zoophilic,
  but A.gambiae and A.funestus, the main vectors in Africa, are strongly anthropophilic.

A seldom used method is protection of indiginous mothers and children by preventive medicines.
As this reduces disease burden of child, it's survival chances increase,
  and for the mother it can protect her in period that she has a placenta.

Unfortunately i have no data at all about to which extent these measures are effective.
 

11.4 - Measures to reduce fraction of people that are infectious

One of these measures is to give the population more and better food,
  so that they clear themselves of malaria more quickly.
I have no data about how effective this measure is.

For the rest, these are medical interventions,
  that actively fight existing infections in human populations.
If a community has access to effective healthcare services,
  then the model given in the previous chapter no longer applies.
This could be taken into account by
  replacing value of Tpud by time it would take for infection to be removed by doctor.
Result is that people are cured from malaria quickly,
  in the process also killing any infections that had not yet manifested themselves
  (except for liver stages),
  so that fraction of population that is infectious to mosquitoes decreases,
  thus fraction of mosquitoes that are infectious decreases,
  and number of infections that doctor has to cure decreases too.

As a numeric example :
A village with 100 people and 100 mosquitoes and CFis = 0.8 would have FPis = 0.99 ,
  assuming that Tpud is 20 .
Now if Tpud is reduced to 12 days, due to extremely prompt medical intervention,
  FPis is reduced to 0 .
If Tpud is reduced to 14 days, a more likely expectation of prompt treatment,
  then PFid is still nearly 1, but PFis is reduced to 0.64 .
The interesting thing is that if medical attention is extremely prompt,
  then the result is that the medical intervention is never needed
  while if attention has a normal level of promptness,
  then it saves 35% of health expenditure on malaria.

This is admittedly a bit of a cooked up example,
  because it is a situation in which
  a small decrease in Cfs would produce a large decrease in FPis .
Eventhough it is a completely realistic example, which does occur in practice,
  expecting a large area to be that near to improvement would be too optimistic.

A prerequisite for this measure to have this desirable effect is that
  there is a well-equipped healthpost so nearby that it can be reached within a day ;
In practice the traveltime to the healthpost would often be
  the largest part of the delay between first symptom and treatment,
  in a situation such as that in Ghana
  where majority of the population have basic medical insurance.

Availability of prompt medical care also strongly reduces the death rate,
  thus preventing grief and loss.
 
 

12 - Economic

There are several economic sides to malaria :

Eradicating malaria from the world (by giving every one who is at risk a therapy simultaneously)
  would be somewhat cheaper than to keep treating malaria victims.

Tropical countries where malaria is most endemic do not have sufficient funds.

Many medicine producing companies
    now deliver medicines to developing countries on non-profit base,
    and distribution and guaranteed buying volume are taken care of by WHO

Lack of money among the populations leads to incomplete treatments,
  which speeds-up rate at which plasmodium becomes resistant.

Costs of various anti-malarial measures vary,
  and while generally all available means must be used,
  restricted availability of money still necessitates evaluating optimum mix of measures.
 

12.1 - Total cost of malaria

Macro-economic viewpoint

Malaria has a significant impact on the economies of countries it occurs in.
Gallup and Sachs made a model of world economy, which features a malaria prevalence parameter
  (fraction of land with endemic malaria multiplied by fraction of malaria that is falciparum)
  which was then found to have effect that
  a 10% reduction in malaria was associated with 0.3% higher growth per year, and
  countries severely affected by malaria grew 1.3% per year less.
These macro-economic figures were noted to not tally well with
  costs of malaria as found by micro-economic methods (ie summing up all costs).

Micro-economic viewpoint

The total "cost" of malaria - health care, treatment, lost production, etc.,
  is currently (2006) estimated to be more than $US1,800 million.

The cost seems to be rising at least as fast as the increase in population size.
As quinine and it's derivatives become less effective, due to plasmodium becoming resistant,
  they have to be replaced by much (7 times) more expensive ACT therapies.
 

12.2 - Direct costs

Total health-ministry expenditure on malaria in Ghana (22 million inhabitants) in 2006
  was circa 70 million dollar.

In 1995, average recurrent cost per outpatient visit for suspected malaria in malawi
  was $0.96 (in 1995 US$) in government and mission facilities.
That same year, inpatient treatment for severe malaria in a Kenyan district hospital
  cost $35 per admission (in 1995 US$).

Monthly per-capita expenditure per african household on malaria prevention
  is in the 1 to 2 US$ range,
  except for where the people are simply too poor to be able to afford that.
Similarly, monthly per-capita expenditure per african household on malaria treatment
  is (if possible) in the 1 to 4 US$ range.
 

12.3 - Indirect costs

In 1958, Miller found that average West African men lost 4.2 days per episode; 3 workdays per year.
In 1967, Hall and Wilkes found that average Tanzanian lost 1.16 days per person per year.
In the Gezira in the Sudan,
  labour hours lost to agriculture due to malaria were completely compensated for by family members,
  though primarily by women and children
  whose household activities and schooling suffered as a result.

A study by Pehrson in 1984 found no difference in the work capacity
  of industrial workers who received malaria prophylaxis and those who did not.

Total cost of malaria figures given above (1.8 billion US$),
  probably do not include the present value of future earnings lost due to mortality.
It was found that the value of loss of time due to mortality accounted for
  74% of total indirect costs in Rwanda (which has seasonal transmission), and
  88% in a district in Burkina Faso (where malaria is perennial).

In Kenya,
Primary school students in Kenya were estimated to have 4 episodes of malaria per year,
  and to miss 5 school days per episode, amounting to 20 school days missed per child per year,
  which is 11% their 186 day school year.
Secondary school children lost 8 days per year on average, equalling 4.3% of a school year.
In Nigeria,
  number of school days missed per year varied between the rural/urban primary/secondary school
  in the range of 3 to 12 days per year per student or 2% to 6% of the school year.
Teachers in primary school in Nigeria experience 3 episodes of malaria per year
  and miss 2 days per episode, yielding 6 schooldays missed.
 

12.4 - Total funding of anti-malaria effort

Total funding was said to be 1.4 billion dollars (in 2006),
  but i do not know what level of funding per year that represents.

President Bush has committed 1.2 billion dollar to fighting malaria.
The Gates foundation has given 207 million dollar to GlaxoSmithKline's vaccine development program.

One source said that
  "There is no lack of money to buy anti-malarial drugs in Africa
   thanks to finance from the U.N.-backed Global Fund to Fight AIDS, Tuberculosis and Malaria."

Swiss drugmaker Novartis AG has cut the price of its Coartem malaria drug by more than a third.
Novartis has provided Coartem at no profit since 2001, in collaboration with the WHO.
Coartem, an artemisinin combination therapy, would now cost around $1 per treatment,
  has a cure-rate of more than 95 %, with few side effects,
  and is meant for treatment of acute uncomplicated falciparum malaria.
After the WHO in 2005 called on Novartis to ramp up production,
  as resistance to older treatments such as chloroquine increased,
  Novartis had increased production to more than 100 million courses of the drug per year.
 

12.5 - Cost of medication

The cost of treatment is between $US0.08 and $US5.30
  according to the type of drugs prescribed, as determined by local drug resistance.

The average cost for potentially life-saving treatments of malaria are estimated to be
  US$0.13 for chloroquine,
  US$0.14 for sulfadoxine-pyrimethamine, and
  US$2.68 for a 7-day course of quinine.

A course of ATP is said to cost circa 2.40 US$.
There is current research in biotechnology for producing artemisinin much cheaper,
  aiming to provide a dose for 0.25 US$,
  and they expect to be able to produce in 5 - 10 years time (ie 2012 - 2017).

A survey in Southeast Asia in 1999-2000 showed that
  of 104 shop-bought samples purportedly containing the antimalarial drug artesunate,
  38% contained no artesunate.
 
 

13 - Politic

Battle against malaria has seen successes in many countries already.
Most malaria cases currently occur in Sudan ;
South-Sudan has large swampy areas that are ideal breeding places,
  and population is poor,
  but most importantly :
  Government in Khartoum seems to be trying to eradicate people in south of country
  which brings so much instability that anti-malaria measures can not be implemented effectively,
  and also causes a lot of migration of poor and infected people to neighbouring countries.
This is likely to present a major problem for malaria-eradication.
Political problems in Sudan seem to be related to these in Cote d'Ivoire,
  as their presidents seem to be learning tricks from eachother.
Fortunately WHO, UN, USA and China are taking an active interest,
  so some (very slow) progress is already being made in Cote d'Ivoire,
  after which Sudan may be tackled in same way.
In practice it will probably mean one or more decades delay.
(i wrote this in 2006)

Rich countries (USA, EU) and China (who seem to be main source of artemisinins)
  are taking an interest in helping poor malaria-endemic countries.
Among their reasons for this would be : real concern for the people,
  stimulating the world economy, and increasing the world's food-producing capacity.

USA also subsidizes anti-malarials, in order to use quinine derivatives as long as possible,
  and among their reasons would be fear that
  if malaria becomes resistant agains artemisinins, it may become endemic in South USA again.
Between 1957 and 2003, in the United States,
  63 outbreaks of locally transmitted mosquito-borne malaria have occurred ;
In such outbreaks, local mosquitos (mainly A.quadrimaculatus and A.freeborni)
  become infected by biting persons carrying malaria parasites (acquired in endemic areas)
  and then transmit malaria to local residents.

When, in the 1950s (i think), malaria was eradicated in the US,
  the 'roll back malaria' program was carried out worldwide,
  and it did succeed in eradicating malaria in many countries (middle america, caribbean islands).
That means that all these countries also remain at risk
  for malaria epidemics imported by travelers.
 
 

14 - History

Plasmodium falciparum is older and more genetically diverse than previously thought.
Jianbing Mu et al looked for genetic differences among five P. falciparum samples
  from Southeast Asia, Africa, South America, Central America and Papua New Guinea.
They examined single nucleotide polymorphisms from 204 genes on chromosome 3 of the parasites.
They estimate that the most recent common ancestor existed between 100,000 and 180,000 years ago.
They speculate that when the human population grew, the malaria parasite grew with it.

Sarah Tishkoff tracks malaria's origins by looking at mutations in the human gene that
  encodes for G6PD (glucose-6-phosphate dehydrogenase)
  of which some people have a mutation that makes them immune to malaria.
When tracing the mutation back, she found that it emerged simultaneously with early agriculture.
  which started circa 10,000 years ago.
Between 7,000 and 12,000 years ago, temperature and humidity in Africa increased dramatically,
  and larger human populations that stayed in one place made it easier for malaria to spread.
One mutation found throughout Africa arose within the past 3,830 to 11,760 years,
  while another one that occurs in the Mediterranean, the Middle East and India,
  developed not more than 6,640 years ago.

Malaria has been known for thousands of years.
Oldest written references to malaria are egyption hieroglyphs of 1500 bc.
Greeks wrote about it in 400 b.c. ; they already knew it was connected with wet ground.

Although people were unaware of the origin of malaria and the mode of transmission,
  protective measures against the mosquito have been used for many hundreds of years.
The inhabitants of swampy regions in Egypt were recorded as
  sleeping in tower-like structures out of the reach of mosquitos,
  whereas others slept under nets as early as 450 B.C.

Alphonse Laveran, a French army doctor, in 1880,
  described the malarial parasite and proposed that it caused malaria.
British physician Ronald Ross, working in India in 1897,
  observed the development of oocysts in mosquitos that had been fed on infected individuals.
He got the 1902 Nobel Prize for Medicine
  for his description of the complete life cycle of Plasmodium.

In the first months of 1900,
  Italian epidemiologists engaged reliable families who lived in malarial regions
  and protected each home with tight screening,
  on condition that the family would remain indoors from sunset to sunrise.
Malaria struck only 10 among 207 well-screened experimenters,
  whereas 44 of 51 unscreened next-door neighbors fell ill as usual.
Thus it was proven that it were the mosquitos that brought the disease.

Four Nobel prizes have been awarded for work associated with malaria, to
  Sir Ronald Ross (1902),
  Charles Louis Alphonse Laveran (1907),
  Julius Wagner-Jauregg (1927), and
  Paul Hermann Muller (1948).
 
 

15 - Malaria in Ghana

Ghana has a population of 22 million, has 3.5 million clinical malaria cases per year,
  and 3,200 deaths per year that are directly caused by malaria.

Malaria transmission is intense in the whole country, though less in the north in the dry season.

Main vectors are A.gambiae in the south and A.arabiensis in the north,
  while A.funestus is also important.

Since 2005, Ghana stopped using chloroquine, as it had become ineffective in over 20% of cases.
Now they exclusively use Artesunate/Amodiaquine (an ACT),
  for which it is essential that dosage is based on patient's weight.
For treatment of complicated malaria, quinine is used.

Malaria causes more deaths in ghana than anything else,
  and is very costly due to lost productitivity and cost of healthcare.
In 2006 Ghana's health minister said that Ghana annually spends about 120 million US$
  from the National Health Insurance Scheme on malaria treatment.
He also said that good lifestyles would help reduce the expenditure on preventable diseases.

On November 5, 2006, it was reported that the WHO reintroduced DDT for malaria control,
  saying it is most effective and safe,
  and promoting it in epidemic areas as well as areas with constant and high malaria transmission.
DDT was banned about 30 years ago, but later extensive research had shown that
  well-managed IRS programme using DDT pose no harm to wildlife or humans.
Using IRS with DDT requires
  a clear specification of where and how the spraying should be implemented
  in accordance with WHO guidelines.
Correct and timely use of IRS can reduce malaria transmission by up to 90 per cent.

South Africa, Mozambique and other African countries have successfully reintroduced DDT for IRS.
Of the 14 Sub-Saharan African countries using IRS, 10 are using DDT at present.
AngloGold Ashanti gold mine in Obuasi is the first to introduce and spearhead the IRS usage in Ghana.
Due to resistance of anopheles to DDT and various other insecticides,
  they spray with Pirimiphos Methyl (an organophosphate).
After three halfyearly spraying rounds
  (covering 130,000 structures with 230,000 inhabitants,
  per spraying round using 20,000 kg insecticide,
  applied by 200 people with 160 pumps and 8 vehicles),
  amount of clinical malaria cases decreased by 75 % .
They combine their IRS with targeted spraying of some breeding sites with the same chemical.