Malaria

Summary

• Early symptoms are non-specific and can easily be mistaken for those of influenza.
• Rapid diagnosis and early treatment are important, particularly for falciparum malaria, which is fatal in up to 20 percent of infected people and can kill within 24 hours.
• Symptoms can begin a month or more after the infecting mosquito bite.
• Drugs taken for prevention are not 100 percent effective.
• In Sub-Saharan Africa the important strain of malaria is Plasmodium falciparum, which can cause fatal infections.

What is malaria?
Malaria has been recognised as a disease for thousands of years. Descriptions of the disease date from as far back as 1700 BC in China, and 1570 BC in Egypt. The association between malaria and marshes (where mosquitos breed) has also been long recognised. In fact, the name “malaria” (from “bad air” in the marshes) is based on this association.

Malaria is an infection of red blood cells caused by a single-celled parasite. Malaria is almost always spread by the bite of an infected female Anopheles mosquito, but also potentially by a transfusion with contaminated blood, or an injection with a needle that was previously used by a person with the infection.

Malaria occurs most commonly in tropical areas of the world, such as Africa, Asia, and Central and South America. It was endemic in the United States and Canada at the beginning of the 20th century, but due to extensive programmes to eradicate it, is now usually only seen in the US in travellers from other parts of the world. Malaria occurs in the North Eastern parts of South Africa, particularly during rainy periods of the year.

What causes malaria?
The Parasite
There are four species of the parasite that cause malaria: Plasmodium vivax, Plasmodium ovale, Plasmodium falciparum, and Plasmodium malariae. The life cycle of the malarial parasite begins when a female mosquito bites a person with malaria.

The mosquito ingests blood containing malarial parasites, which reproduce in the mosquito’s gastro-intestinal tract, and then move to the salivary glands. When the mosquito bites another person, the parasites are injected along with the mosquito's saliva. Inside the human, the parasites move to the liver, where they multiply. They mature over an average of 2 to 4 weeks, then leave the liver and enter the blood stream. The parasites infect red blood cells, multiply inside the red blood cells and eventually cause the infected cells to rupture.

Plasmodium vivax, ovale and falciparum usually cause the red cells to rupture every 48 hours, and P. malariae cause rupture every 72 hours. The parasites released from the ruptured red blood cells go and infect more red blood cells, setting up the cycle once more. Occasionally, sexual forms of the parasites (called gametocytes) develop in the blood. These are the forms that reproduce in the mosquito if they are ingested.

P. ovale and P. vivax parasites preferentially infect young red blood cells, while P. malariae prefers to infect older red blood cells. For this reason the number of parasites in the blood is limited if one contracts any of these three forms of malaria. P. falciparum can infect red blood cells of any age, which means infection with this form of malaria results in a much higher number of parasites in the bloodstream.

Some of the liver stages of Plasmodium vivax and Plasmodium ovale can remain dormant in the liver. Periodically, mature parasites will be released into the bloodstream, causing recurrent attacks of malaria. Plasmodium falciparum and Plasmodium malariae do not remain dormant in the liver. However, if the infection is untreated or inadequately treated, the mature form of Plasmodium falciparum may persist in the bloodstream for months, and the mature form of Plasmodium malariae may remain in the bloodstream for years. This causes repeated attacks of malarial symptoms. In Africa the predominant strain is Plasmodium falciparum, which has a very high mortality rate.

What are the symptoms and signs of malaria?
The first symptoms are usually very similar to ‘flu – aches and pains, fever, headache and so on. After a few days, the typical paroxysms may occur – chills, followed firstly by a high fever for a few hours, and then by profuse sweating. Between these paroxysms, the patient may feel well, depending on the type of malaria that has been contracted. Some forms of malaria are more severe than others, and the time between the paroxysms differs, depending on the type of malaria. Malaria should be suspected in anybody with these sorts of symptoms who has been to a malaria area.

Plasmodium vivax, ovale and malariae
The incubation period (the time between being bitten by the mosquito and developing symptoms) is variable – usually between 2 and 3 weeks. However, in some cases it may take months for the disease to manifest itself. The initial symptoms are often similar to those of influenza:

• an intermittent mild fever
• headache
• muscle aches and chills
• a general feeling of illness (malaise).

After a few days (three to five) the typical malarial paroxysms start. These are usually characterised by chills, followed by fever (up to 40 degrees Celsius), and then sweating. The paroxysms normally last about 8 to 10 hours. In between paroxysms patients often feel remarkably well. In vivax and ovale malaria the paroxysms typically recur every 48 hours, while in malariae malaria, the paroxysms recur every 72 hours. The paroxysms occur at about the same time that the red blood cells burst and release more parasites, and this explains the 48 or 72 hour cycle (see previous section “The parasite”). Eventually, the body will eliminate the parasites from the blood, and the paroxysms will get less and less severe and disappear.

Plasmodium falciparum
Symptoms usually begin 10 to 35 days after a mosquito injects the parasite into a person. Again, there are initial “prodromal” symptoms, followed by the malarial paroxysms. However, unlike the other forms of malaria, the paroxysms are not usually as regular, and patients often have a fever between paroxysms.

Although P. falciparum also causes rupture of the red cells every 48 hours, the timing is not as well co-ordinated as with the other forms of malaria, hence the less well delineated paroxysms. In addition, there are usually more parasites in the blood with falciparum malaria than with the other forms, which is one of the reasons that falciparum malaria is more severe than the other forms.

Malaria caused by Plasmodium falciparum is the most severe form of malaria. The most important, and potentially life threatening complication is cerebral malaria. Symptoms of cerebral malaria include:

• high fever
• severe headache
• drowsiness
• delirium and confusion.

Cerebral malaria can be fatal. It most commonly occurs in infants, pregnant women, and travelers to high-risk areas.

What is the outcome of malaria?
Other complications of falciparum malaria include:

• “Blackwater fever” – caused by the rupture of large numbers of red blood cells, releasing haemoglobin (the pigment found in red blood cells) into the urine which gives the urine a darker colour
• Kidney failure – probably also due to the haemoglobin going through the kidneys
• Anaemia – due to all the red blood cells being destroyed
• Pulmonary oedema – fluid in the lungs, making breathing very difficult. It is not a common complication

In the other forms of malaria, delirium may occur when the fever is high, but otherwise brain symptoms are uncommon.

In all types of malaria, the total white blood cell count is usually normal, but the numbers of lymphocytes and monocytes, two specific types of white blood cells, increase. Usually, mild jaundice develops if malaria is untreated, and the spleen and liver become enlarged. Low levels of blood sugar (glucose) are common and may be there in people who have high levels of parasites. Blood sugar levels may drop even lower in people being treated with quinine.

Sometimes malaria persists when low levels of parasites remain in the blood. Symptoms include apathy, periodic headaches, a feeling of illness, poor appetite, fatigue, and attacks of chills and fever. The symptoms are considerably milder, and attacks don't last as long as the first attack. If the person is untreated, the symptoms of vivax, ovale, or malariae malaria subside spontaneously in 10 to 30 days but may recur at variable intervals. Relapses of vivax and ovale malaria may be related to the dormant liver stages periodically releasing parasites into the blood. Although P. malariae does not have a liver stage, the parasites can persist in very low numbers in the blood for years, and occasionally reach high enough numbers to cause symptoms. Untreated falciparum malaria is fatal in up to 20 percent of people.

How is malaria diagnosed?
Malaria should be suspected in the following circumstances:

• when a person has periodic attacks of chills and fever with no apparent cause
• if within the previous year the person had visited an area where malaria is prevalent. Any person who has a fever and who has been to a malaria area recently should be screened for malaria.
• if the spleen is enlarged, or there is jaundice or anaemia without an obvious cause.

Identifying the parasite in a blood sample confirms the diagnosis. Blood is taken, smeared onto a slide, stained, and examined under a microscope. More than one sample may be needed to make the diagnosis because the level of parasites in the blood varies over time. The laboratory will (whenever possible) identify the species of Plasmodium, because the treatment, complications, and prognosis vary depending on the species involved.

Recently, new diagnostic tests have become available. The most commonly used of these is a test that detects one of the malarial proteins in the blood. The advantage of this test is that it can be done in clinics with relatively little training. However, it is probably not as sensitive as the examination of smears, and it cannot identify the different forms of malaria.

Can malaria be prevented?
General precautions:
People who live in malaria-infested areas and people who travel to those areas must take precautions. It is especially important that South Africans recognise that large areas of our holiday terrain are still classified as malarious areas. The following are general preventative measures:

• use long-lasting insecticide sprays in homes and buildings
• place screens on doors and windows
• use mosquito netting over beds. Mosquito netting can be soaked in certain types of insecticide as well.
• apply mosquito repellents on the skin.
• wear sufficient clothing, particularly after sun- down, to protect as much of the skin as possible against mosquito bites. It is a rule of thumb that mosquitoes are less likely to land on white areas of clothing.
• Many people who live in malaria-infested areas sleep with strong fan currents in a room, which seems to discourage mosquitoes from feeding.

The above measures are at least as important as taking medicine to prevent malaria, since none of the medicines are 100 percent effective in preventing malaria.

Drugs to prevent malaria
Certain drugs can be taken to prevent malaria during travel to a malaria-infested area. If you are travelling to an area that is known to have malaria, it is important to take the drugs properly. Some drugs are:

• started a week beforehand
• continued throughout the stay
• extended for a month after leaving.

As mentioned before, remember that no drug therapy is completely effective in preventing the infection!

Chloroquine
This is the best drug to prevent malaria if someone is going to an area where the malarial parasites are not resistant to chloroquine, or if the rate of resistance is very low. Although chloroquine is still effective against P. vivax, P. malariae and P. ovale in almost all areas of the world, P. falciparum shows significant resistance to chloroquine in many areas of the world, including SE Asia, Central America and Africa. Chloroquine alone is not recommended for Southern Africa any longer.

Chloroquine is generally very safe, with few side effects at the doses used for prophylaxis of malaria. Side effects include headaches and dizziness, and can often be lessened by taking half a tablet twice a week rather than one tablet every week. It is also safe for children and pregnant women.

Chloroquine can be combined with a drug called proguanil to offer some protection against chloroquine resistant P. falciparum (especially in some areas of Africa), but proguanil needs to be taken daily, which makes it less convenient than some of the other options. The combination of cloroquine/proguanil, while offering some protection against chloroquine resistant malaria, is not the most effective regimen for prophylaxis.

Mefloquine (Lariam or Mefliam)
Mefloquine is very effective in preventing all forms of malaria in most parts of the world, but resistance has been reported in some areas of SE Asia. It is also taken weekly (like chloroquine). Mefloquine has unfortunately received bad publicity because of its neuropsychiatric side effects – such as hallucinations, seizures and anxiety. However, these reactions are very rare especially at the doses used for prophylaxis.

It is recommended that people who have known psychiatric problems or epilepsy should not take mefloquine. Some people recommend that people who need fine motor co-ordination should also not take mefloquine, but this recommendation is controversial. Mefloquine is generally considered to be the best alternative to chloroquine for preventing chloroquine resistant malaria.

Atovaquone/proguanil (Malarone)
This combination has been shown in various studies to be very effective in preventing malaria in areas were chloroquine resistance is a problem. The drug is taken daily, which is a potential problem (since people are more likely to forget the occasional dose), but it has the advantage that it only needs to be taken for one week after leaving the malaria area, unlike many other prophylactic drugs. Side effects are few, the most common being headache, abdominal pain and diarrhoea. One other major disadvantage at present is that this option is a lot more expensive than the other agents available for prophylaxis.

Doxycycline
Doxycycline can also be used to prevent malaria, and is particularly useful in areas where there is both chloroquine and mefloquine resistance, or for people who cannot take either of the other two drugs. Doxycycline needs to be taken daily, and can cause photosensitivity reactions. It should not be taken by pregnant women or by children less than about 10 years old, since it can interfere with growing teeth and bones.

Primaquine
This drug is normally used to treat the liver stages of P. vivax or P. ovale malaria. It has been advocated by some as a suitable drug for prophylaxis as well, and has been shown to be up to 95% effective in preventing both P. falciparum and P. vivax malaria. This drug also needs to be taken daily. As yet, it is not a widely accepted drug for malaria prophylaxis.

Tafenoquine
This drug is closely related to primaquine, the major difference being that it is much longer acting, and does not need to be taken daily. Studies have shown it to be effective in preventing malaria, although more work is probably necessary. However, it is an agent that may well be commonly used in the future.

One important side effect of both primaquine and tafenoquine is that they can cause rupture of red blood cells in certain susceptible individuals (people with a genetic predisposition), and this genetic risk would need to be screened for in a traveller before they could take the drug.

Before going to a malaria area, it is very important to get updated information on whether prophylaxis is required and what the current recommendations are. Consult either your doctor or pharmacist.

How is malaria treated?
The choice of which drug to use to treat malaria depends on where the patient acquired malaria (ie whether chloroquine resistance is common or not), whether prophylaxis was taken, and what form of malaria the patient has.

If the patient has P. vivax, P ovale, P. malariae, or has been in an area where there is no chloroquine resistance in P. falciparum, chloroquine is the best drug to use to treat malaria.

If the patient is infected with P. vivax or P. ovale, primaquine needs to be given as well. This drug is able to kill the liver stages of the parasites, unlike chloroquine. If primaquine is not used, the chloroquine will cure the acute attack, but the dormant liver stages will be able to cause recurrences in the future.

In cases where chloroquine resistant P. falciparum is suspected, either quinine, mefloquine, halofantrine or the artemesinins can be used. Parasites that are resistant to mefloquine are also often resistant to halofantrine. Mefloquine is also not licensed for use as treatment in South Africa. Halofantrine has been associated with cardiac side effects, and should not be used for routine treatment. Quinine was the first drug used to successfully treat malaria, and with increasing chloroquine resistance, it is making something of a “comeback”. It is thought to be the best available agent for treating complicated chloroquine resistant falciparum malaria. Unfortunately, resistance to this drug is also being described.

A new class of drug is the artemesinin derivatives. This drug has been known for centuries in China and is derived from the wormwood plant. It shows great potential in being able to treat resistant falciparum malaria, and has been used often in SE Asia. Unfortunately, resistance to this agent is also being described. When these drugs are used to treat malaria, they should be combined with a second agent to try and reduce the development of resistance.

In South Africa, treatment is usually with either an artemesinin derivative called artemether in combination with lumefantrine (Coartem), or with quinine combined with doxycycline. The artemether/lumefantrine combination has been used since 2001 in Kwazulu Natal with good results. It can be used for uncomplicated malaria if the patient is able to take medication orally. For severe or complicated malaria, quinine given intravenously is a recommended treatment.

Vaccines
Although no effective malaria vaccine exists at present, there is a lot of research going into finding an effective vaccine, which would certainly help to reduce the number of cases of malaria seen worldwide.

When to see the doctor
If you have been to a malarial area – even if you have taken prophylaxis – you must see a doctor immediately if you develop any of the following:

• Chills
• Fever
• General aches and pains
• Headache

Remember to tell your doctor that you have been exposed to malaria when you see him or her.

How to know you may have malaria
The first symptoms are usually very similar to flu – aches and pains, fever, headache and so on. After a few days, the typical paroxysms may occur – chills, followed firstly by a high fever for a few hours, and then by profuse sweating. Between these paroxysms, the patient may feel well, depending on the type of malaria that has been contracted. Some forms of malaria are more severe than others, and the time between the paroxysms differs, depending on the type of malaria. Malaria should be suspected in anybody with these sorts of symptoms who has been to a malaria area.