Which came first:
The Mosquito or Malaria?
Jocelyn Woolworth, Priscilla Toy, Arpana Sood, Kristina Rodriguez
Math 4 / Professor Leibon
Final Group Project
March 6, 2002
Between 300 to 500 million clinical cases of Malaria occur every year and cause over 1.2 to 2.7 million deaths. This makes it one of the world’s 10 most prevalent and deadly diseases. 90% of Malaria cases occur in sub-Saharan Africa. It is a parasitic disease spread by the bite of an Anopheles mosquito which is active during the evening. Malarial symptoms can occur after 8 days following an infected bite. The principal symptoms are fever, malaise, headache, chills and sweats but it can be present as a respiratory or gastrointestinal illness. Children are especially vulnerable to malaria. In Africa, where 80% of malaria cases are treated at home, the disease kills one child in twenty before the age of five. Malaria kills one child every 30 seconds. It is a death toll that far exceeds the mortality rate from AIDS. Pregnant women are also at high risk. It causes severe anaemia, and is a major factor contributing to maternal deaths in malaria endemic regions. Pregnant mothers who have malaria and are HIV-positive are more likely to pass on their HIV status to their unborn child. There is a fourfold increase in risk of disease and a two-fold increase in death rates. In many African countries about 20-30% of doctor's visits are for malaria as well as 10% of hospital admissions. Unfortunately, Mosquitoes are developing resistance to the major classes of insecticide which have been used to control the disease. People are most at risk of malaria during the warm and rainy seasons since most of the farm work needs to be done at this time.
The malaria pathogen is not a bacterium or a virus. It is a unicellular parasite. There are four different species of the malaria parasite. Two are most common. Plasmodium falciparum, which is found globally but is commonest in Africa, is the most aggressive species. Infection of this type kills approximately 1-2% of those who come down with it. Falciparum malaria is a serious illness characterized by fever, headache, and weakness. It often kills through coma or anemia. Plasmodium vivax, which ranges widely throughout Asia, Africa, the Middle East, Oceania and the Americas (and is resurgent in Eastern Europe), can cause recurring and debilitating infection, but rarely kills. The other two forms are Plasmodium ovale and Plasmodium malariae.
The life cycle of malaria (plasmodia) is complex. The infective stage occurs when sporozoites are injected from the salivary glands of infected mosquitoes into a host. Sporozoites disappear from the blood within 30 minutes. Some are destroyed by white blood cells, but many enter liver cells very quickly. Sporozoites that enter liver cells differentiate into hypnozoites that can remain dormant for weeks, months, or even years. The Exoerythrocytic Phase occurs when sporozoites enter liver cells and multiply asexually. Eventually, invaded liver cells rupture, releasing thousands of merozoites into the bloodstream. This occurs 6 to 16 days after initial infection depending on the infecting species of malaria. In the Vector Phase, Anopheles mosquitoes that feed on infected hosts ingest sexual forms developing in red blood cells. The female macrogametocytes and male microgametocytes mature in the mosquito’s stomach and combine forming a zygote that undergoes mitosis. The vector phase of the life cycle, called sporogony, is complete in 8 to 35 days depending on species and environmental conditions. This is obviously a type of vicious cycle and therefore one wonders which came first: malaria or the mosquito?
The Cycle of Malaria as it Affects Humans
There are three categories of drugs available for the treatment of malaria. Quinie and Chloroquine fall into the same category, and mainly attack the new infected red blood cells. However, these do not affect the root of the problem. Thus, in the case of these drugs, it is better to use them for propholaxyis. The drugs are described in more detail: Quinine - For more than three centuries cinchona and its alkaloids, especially quinine, were the only drugs available that were effective against the malaria parasites. Supposedly superior drugs to quinine were produced and the parasites have become resistant in a short space of time, but quinine resistance had only very recently developed in limited geographic areas. Quinine is again the drug of choice for treatment of severe falciparum malaria, and is also widely used in uncomplicated falciparum malaria. The recommended adult dose is 600 mg (that is two tablets) three times a day for seven days, (=42 tablets in total). Side-effects include blurred vision, nausea, transient high tone deafness and rarely severe thrombocytopenia
As a drug for treating the established disease in a patient, Chloroquine is still effective for benign malarias world-wide and even falciparum malaria in restricted areas where resistant parasites are not found e.g. Dominican Republic and parts of the Middle East. The recommended adult dose by the World Health Organization is 600mg (base) on the first and second days of treatment, and 300mg (base) on the third day of treatment. The third treatment Mefloquine, is also known as 'Lariam'. The great advantage of lariam is that it can be given in a single dose of either 1000mg or 15mg / kg of body weight whichever is lower. On Thailand borders, however, the adult dose is 1000mg initially followed by 500mg 6-8 hours later. Resistance to the drug has also developed.
Another category of drugs is the tetracycline, an antibiotic. These drugs have proved to be a useful addition to quinine especially in areas where resistance to quinine is emerging. The drugs are blood shizontocides. Doxycycline is considered to be an effective drug for multiresistant falciparum malaria, and is used especially in areas where mefloquine resistance is now common, for example Thailand. The recommended adult dose is 100mg a day, but in patients with severe falciparum malaria treatment should not be started until their renal function has returned to normal. These drugs should not be used in pregnant or lactating women, or in young children because they can have damaging effects on the development of bones and teeth. Therefore tetracyclines are useful drugs but use should be limited in areas where resistance would develop, until it is really necessary, or the same scenario would be seen as happened with mefloquine.
The newest and most effective drug thus far is Malarone. Studies have shown in that in Sub-Saharan Africa, there is a 95-100% efficacy in malaria treatment with Malarone. Malarone works on two parts of the parasitic lifecycle, both the production of red blood cells and the incubation of parasites in the liver. Thus, by killing of new red blood cells, spread of disease in the society can be prevented because other mosquitoes cannot bite and carry infection to a new host. Thus, by killing both the source (liver), and the newly produced parasitic red blood cells, Malarone prevents the spread of malaria inside and outside of the body.
Recommended doses for Malarone vary depending on age.
1 adult tablet daily (250 mg atovaquone/ 100 mg proguanil)
11-20 kg: 1 pediatric tablet* daily
21-30 kg: 2 pediatric tablets daily
31-40 kg: 3 pediatric tablets daily
>40 kg: 1 adult tablet daily
Contraindicated in infants <11 kg. Pregnant women or women breast-feeding infants weighing less than 11 kg should not use Malarone to prevent malaria. Contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min).
"While waiting for new drugs with novel mechanisms of action to be discovered, developed and hopefully deployed, appropriate measures should be taken to safeguard the few compounds available to us." (N. White, 1996)
By using combination chemotherapy it is possible to delay the onset of resistance. "If the antimalarial resistance mechanisms are not linked, then the chances of a resistant mutant arising in any parasite life cycle are the product of the individual chances for each drug administered. The drugs used in combination should have compatible pharmacokinetics and pharmacodynamics, no adverse pharmacological interaction and no additional toxicity." (N. White, 1996)
There are several examples of drug combinations to treat malaria. 'Metakelfin' is a combination of pyrimethamine with sulfamethoxypyrazine which is used to treat drug resistant malaria. 'Fansidar' is a combination of pyrimethamine with sulfadoxine and was once valuable to treat chloroquine resistant falciparum parasites, but resistance has emerged. 'Maloprim' or 'Deltaprim' is a combination of pyrimethamine with dapsone and is used as a prophylactic against resistant malarial parasites. The Chinese drug pyronaridine has occasionally been given with pyrimethamine and sulfanamide. Recent attempts for combined chemotherapy are artemisinin derivatives combined with mefloquine, which is currently being used in Southeast Asia and a fixed combination of atovaquone and proguanil which is in advanced stages of clinical development.
The chances of a drug resistant mutant appearing are reduced considerably when combination chemotherapy is used. This is of great importance with new drugs being used, as it is desirable to maintain their efficacy against the multi-resistant falciparum parasite for as long as possible.
Combination chemotherapy is a rational approach to the containment of drug resistance in malaria, as combination therapy can provide significant improvement in the treatment of mild malaria than monotherapy.
Resistance is a very serious problem in the fight to eradicate malaria. The falciparum parasite is developing resistance to whatever drug is used against it, the only possible exception are the artemisinin derivatives. Even resistance to quinine has developed in Thailand. It is not only the anti-malarial drugs that have encountered problems with resistance, the mosquito has developed resistance to many of the insecticides that have been used to try to eradicate it. The most famous of these insecticides is DDT.
Development of new drugs and insecticides is a very costly process, both in time and money. It takes a long time to develop a new drug that would be effective, and then it has to go through various tests and trials to prove it is safe for use in humans and very few will ever make it to the stage of being approved for use as an anti-malarial drug. The same is true for the development of a vaccine.
The greatest problem with developing resistance in the falciparum parasite is that if the use of the drugs had been monitored carefully the resistance would not have developed so quickly. If a drug e.g. chloroquine was administered in doses not high enough to destroy the infection, there is a selective pressure for the parasites to develop resistance to the drug. This happened when a government decided to mix chloroquine with an ingredient for cooking e.g. salt of flour etc. The dose was not high enough to eliminate the parasite. Drugs with long half-lives exert greater selection pressure to develop resistance as the drug will last a long time in the body at levels which will not destroy the parasite (subtherapeutic levels).
There is a possibility that chloroquine resistance may be reversed by using calcium channel blockers, which prevent the drug from being pumped out of the cell before having any toxic effect on the parasite. If studies prove that they are effective, it will be a great breakthrough in the fight against the parasites, and chloroquine may again be used to treat malaria all over the world.
Combination chemotherapy will help a great deal in slowing down the development of resistance, and the development of new drugs will structures that are not similar to the drugs that the falciparum parasite is resistant will help prevent cross resistance.
There are drugs which may be able to reverse chloroquine resistance, to prevent the parasite from pumping the drug back out of the cell so it doesn't become concentrated in the parasites cytoplasm. These drugs are calcium channel blockers e.g. verapamil and nifedipene. If these were proved to be effective in reversing chloroquine resistance in humans it would be a very important discovery, and a very popular drug would again be able to be used effectively around the world. This would decrease the need for new antimalarial drugs to be produced, but this would not mean for research to stop. There is still a need for new effective drugs against multi-resistant falciparum parasites in case the calcium channel blockers are not as effective as hoped, or the parasite develops ways for combating their action too.
A person’s risk of becoming infected with malaria or of showing extreme symptoms of malaria can be significantly reduced for two reasons. The first is if a person has Sickle Cell Anemia, a group of inherited red blood cell disorders. A normal red blood cell has the appearance of a doughnut and it delivers oxygen to the body via small round blood tubes. Inside a normal blood cell is a substance called hemoglobin whose function is to carry oxygen inside the walls of the cell. However, one microscopic change in the hemoglobin causes it to form long “rods” inside the cell when it gives away oxygen. When these long, pointed, hard red blood cells try to pass through the narrow, round blood tubes, they clog the flow of the tube and break apart. This often causes damage, pain, and a low blood count, also known as anemia.
anemia, like malaria, cannot be caught and is not contagious. Unlike malaria however, a person is born
with this disease because the alleles for sickle cells have been passed down
from the parents to a newborn baby. Due
to the way genetics plays out, a child will only show symptoms of sickle cell
if both parents pass on the allele
for this disease. If only one parent
passes on the allele, the child will carry the sickle cell trait (and possibly
pass the allele onto his or her offspring), but the child will not have the
symptoms of the disease.
The importance of sickle cell anemia in this discussion of the malaria epidemic is that it has been proven that individuals with sickle cell anemia appear to have a distinct advantage over individuals with normal hemoglobin alleles. However, this advantage seems only to be effective in the case of Plasmodium falciparum malaria. The way this advantage functions is that when a red blood cell containing P. falciparum undergoes the sickling process, it is destroyed. Other researchers suggest that the infected red blood cell first sickles and is then destroyed somewhere in the vascular system, liver, or spleen. Yet whatever way this occurs, the important result is that malarial infection only exists for a short period of time and the incidences of cerebral malaria and subsequent death is quite low. Therefore, although a person with sickle cell anemia is not completely immune to malaria, his or her chances of contracting or developing severe symptoms of the disease are significantly lower.
Sickle Cell Statistics
1 out of 400 African Americans has sickle cell
Sickle Cell affects 8 out of 100,000 people
The other way in which a person becomes partially immune to malaria is after a person has already had the disease and has recovered from it. At this point, people have antibodies in their systems prepared to fight the disease so they have a lesser chance of contracting the disease or showing extreme symptoms again. It is important to remember that again, this is only partial immunity – sadly, there is no 100% immunity to malaria. We have attempted to model this phenomenon in our equations and graphs. Using dA/dt to refer to the immune class (we used A so as not to confuse ourselves with the infected class – dI/dt), we take into account both the effects of sickle cell anemia and partial immunity after recovery.
There are four medications designed to treat malaria which are discussed above. However, we chose to model malerone because it is the most effective (98% effective). It is the newest drug to treat malaria and it not only affects the red blood cells, but it also enters the liver. This way new infected blood cells cannot form and therefore, there is less of a chance of a mosquito contracting malaria from a person taking malarone and transferring it to a new host. This decreases the rate of spread of malaria in an area.
However, the problem with this seemingly perfect drug is the high cost. “Coverage for a two week trip using Malarone daily or Larium weekly may cost between $75 and $100. Malarone becomes more expensive than Larium after two weeks because it requires a daily pill whereas Larium is taken weekly.” Therefore, if cost was no factor, we would suggest that malarone be distributed all throughout Africa and other areas where malaria is present to control and eventually eradicate the disease. However, realistically we know that this is not possible as cost is a crucial factor in this context.
In this realistic world, we therefore suggest that more simple, inexpensive methods be employed. Perhaps insecticides and insect repellants could be more widespread and simple mosquito prevention such as bug nets could be used. As you can see in our model, the insecticides are not as effective as malarone, however, they at least provide some resistance to mosquitoes. It would perhaps be best to use some combination of more inexpensive solutions such as bug nets and insecticides. Finally, an overall downside to any treatment measure is that the strains of malaria can develop a resistance to the drugs used to treat the disease. As new drugs are created, malaria finds new ways to resist them.
In conclusion, our quandary in this situation is that although we know what the most effective treatment would be to eventually eradicate malaria, the financial situation does not allow for us to follow through with this ideal plan. In addition, even if we could implement malarone world-wide, the resistance factor is a problem as well. We therefore are faced with the predicament faced by thousands of disease epidimeologists in the past and present. We know what would be most effective, but cost and resistance prevents us from instigating our plan.