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Malaria, & How to Avoid It
Julia Pinnix - February, 2005
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Here's a copy of Julia's tips, together with some tips from other Club members, on how to avoid getting malaria during travel to endemic countries, presented at the February, 2005 meeting of the Travel Club:
What is malaria?
Malaria is caused by single-celled protozoan parasites of the genus Plasmodium. Four species infect humans by entering the bloodstream:
• P. falciparum: found throughout tropical Africa, Asia and Latin America
• P. vivax: worldwide in tropical and some temperate zones
• P. ovale: mainly in tropical west Africa
• P. malariae: worldwide but very patchy distribution
Infection occurs when a female mosquito carrying the parasite bites a person (these mosquitoes are active in the evening, night, and early morning). Malaria begins as a flu-like illness 8-30 days after infection. Symptoms include fever (with or without headache, muscular aches and weakness, vomiting, diarrhea, cough). Typical cycles of fever, shaking chills, and drenching sweats may then develop. The periodicity of these cycles depends on the species of parasite, coinciding with parasite multiplication and destruction of red blood cells (RBC), which also leads to anemia. Falciparum malaria may not show this cyclic pattern and can be fatal if untreated or treated with insufficiently effective drugs.
Death may be due to infected RBCs blocking blood vessels supplying the brain (cerebral malaria), or damage to other vital organs. In areas where the disease is highly endemic, people are infected so frequently that they develop a degree of acquired immunity and may become asymptomatic carriers of infection. Epidemics are often associated with non-immune people moving to highly-endemic areas, where they quickly succumb to infection. Epidemics and atypical increases in malaria incidence have been increasing.
Pregnant women are especially vulnerable to malaria, which remains an important cause of stillbirths, infant mortality, and low birth weight. Pregnant women are twice as attractive to malaria-carrying mosquitoes as non-pregnant women, perhaps due to a greater volume of exhaled air (21%) and a warmer (0.7 degrees C) skin surface.
How big a problem is malaria?
Malaria is a public health problem in more than 90 countries, inhabited by a total of some 2.4 billion people, representing about 40% of the world’s population. Best estimates currently describe the annual global burden of malaria as: 1.1 million deaths, 300-500 million cases. It has been estimated that the economic burden is also extremely high, accounting for a reduction of 1.3% in the annual economic growth rate of malaria endemic countries, and that the long-term impact in these countries is a reduction of GNP of more than half.
Malaria is not a uniform disease. It has many manifestations and its impact varies. Over 90% of the disease burden is in sub-Saharan Africa, and almost all deaths (due to Plasmodium falciparum ) occur in Africa. Most of the remaining burden is distributed between the Indian sub-continent, south-east Asia and Oceania, and the Americas. After P. falciparum, P. vivax is the next most significant malaria species. It may cause up to 80 million cases per year, approximately 15% in Africa and 85% outside Africa.
The malaria burden differs according to age and gender. Almost all deaths occur in African children under 5 years old. Older Africans have reduced risk due to an ability to develop a degree of immunity to the disease as a result of continuous exposure. Outside Africa, where continuous exposure does not occur, the disease burden extends into adulthood. Pregnant women in Africa are at high risk, and are the major adult risk group in Africa. The malaria burden associated with pregnancy has an additional impact due to the effect on the health of the fetus.
There is a strong social and economic dimension to the malaria disease burden. Those at greatest risk of malaria are poor people, and populations that are marginalized, such as ethnic minorities and people displaced as a result of civil unrest. The border of Thailand with Myanmar, for instance, is afflicted with some of the world’s most drug-resistant strains of malaria, in part because of the great social upheaval in Myanmar and the consequential numbers of refugees.
Major trends over the last few decades point to a worsening situation if effective action is not taken. These trends include:
• an increase in epidemic malaria
• upward trends in mortality over the last three decades, including in sub-Saharan Africa
• an upward trend in drug-resistant P. falciparum malaria
• the re-emergence of P.vivax malaria in areas from where it had been previously eradicated e.g. Caucases and Central Asia
• an increase in imported malaria in the developed world.
How can I protect myself against malaria?
• Spray properly screened room with insecticide before evening.
• Wear protective clothing.
• Minimize nocturnal exposure.
• Sleep in screened areas.
• Use mosquito netting and check for holes in the net.
• DEET insect repellents may be applied to exposed skin (NOT on children).
• 30ml of DEET in 250ml water to impregnate cotton garments.
• Electronic buzzers are not effective.
• Use permethrin-containing pesticide for clothing and mosquito netting 0.2g/m2 of material every 6 months.
• Use pyrethrum-containing sprays and mosquito coils.
• Long sleeved clothing and long trousers should be worn if outdoors after sunset.
• Refined lemon eucalyptus oil is also repellent on the skin.
What drugs can be used to prevent or cure malaria?
An update from the University of Oxford in Drug Safety 8(4) 1993 stated that a careful risk-benefit analysis is required to balance the risk of acquiring potentially serious malaria against the risk of harm from the prophylactic agent. Chloroquine and Proguanil have an excellent safety record in the recommended dosages. Recent publicity has been given to side effects of Mefloquine which is used extensively in areas of resistance to Chloroquine and Proguanil.
• Chloroquine: 150mgs(base)-2 tablets/week.
• Proguanil-hydrochloride (Paludrine): 200mgs/day alone or with weekly Chloroquine. Used with Chloroquine in pregnant women, children, and others who cannot take mefloquine or doxycycline.
• Mefloquine: 250mgs(salt) once per week. Not recommended for patients taking betablocker drugs or quinidine, for pilots and others who need fine motor skills, known neurologic or psychiatric disorders, pregnant women in first trimester, or children less than 15kgs. Mefloquine may provoke severe neuropsychiatric reactions with a frequency of 1 in 15,000-20,000 users at the prophylactic dosage.
• Pyrimethamine-sulfadoxine (Fansidar): 25mgs of Pyrimethamine and 500mgs of Sulfadoxine/tablet. Has been associated with a relatively high incidence of potentially fatal reactions and is no longer recommended for prophylaxis. May be used for standby treatment. Should not be taken by pregnant women or if sensitive to sulphonamides. Serious adverse reactions include Stevens Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hypersensitivity, pneumonitis, and hepatitis.
• Pyrimethamine-Dapsone (Maloprim): 1 tablet/week 12.5mgs of Pyrimethamine and 100mgs of Dapsone. Used with Chloroquine. Not on sale in the USA. Pyrimethamine-dapsone has been associated with agranulocytosis and should be reserved as a second line drug for travellers to high risk areas.
• Doxycycline: Used if unable to take Chloroquine or Mefloquine in high risk areas and areas of mefloquine resistance in South East Asia. Unsuitable for children and during pregnancy and lactation. Must be taken after meals standing up and with a lot of fluid. Use for more than 3 months to be avoided.
• Halofantrine: 250mgs/tablet. 2 tablets in one dose, then 2 tabs after 6 hours and 2 more 6 hours after that one. Course repeated 7 days later. Halofantrine is well tolerated and has a rapid antimalarial activity. It is more expensive than other antimalarials, and the existence of cross resistance links its usefulness to the demise of mefloquine. The discovery of a potentially lethal cardiotoxicity associated with Halofantrine limits its use. Sudden deaths have occurred. Was used as standby treatment, not prophylaxis. No longer recommended for standby treatment.
• Quinine: Standby treatment, not prophylaxis. 300mgs/tablet. 2 tabs 3 times per day for 7 days. Note that it is not a suitable standby if mefloquine is used as a prophylactic.
Newer drugs
• Artemisinin or Qinghaosu: Artemesia annua (sweet wormwood) is found in many parts of the world. In the early 1970's Chinese scientists recognized its potential for treating malaria and isolated the active principle, artemesinin or qinghaosu. Qinghaosu can be produced from natural sources and has been well studied. One of the best compounds (arteflene) was selected for detailed preclinical evaluation. It had low acute toxicity after oral or subcutaneous administration. To combat increasing problems with drug resistance to Plasmodium falciparum, Viet Nam has turned increasingly to the artemisinin derivatives. Oral and suppository formulations are produced from locally grown plants. These compounds have been rapidly effective in a large number of studies.
• Arteflene: A synthetic derivative of Qinghaosu was evaluated extensively against various drug-sensitive and drug-resistant Plasmodium falciparum in vitro and Plasmodium berghei in mice. The potential therapeutic and prophylactic activities were studied comparatively with chloroquine, mefloquine, and quinine as well as Qinghaosu and the derivatives artemether and artesunic acid. Experimentally, arteflene proved to be a highly effective antimalarial drug. The suppressive and prophylactic properties were comparable to chloroquine and superior to Qinghaosu, artemether, and artesunic acid. It was consistently rather more active against drug-resistant than against drug sensitive strains of Plasmodium falciparum.
• Artemether: The use of drug combinations may be necessary in areas where drug resistant parasites exist. In eastern Thailand a study was done using artemether 300mgs single dose followed by mefloquine 750mgs at 24hrs and 500mgs at 30hrs,or oral artemether 300mgs on day 1,followed by Mefloquine 750mgs at 24hrs and placebo at 30hrs. No serious adverse effect was seen in either group; mild and transient nausea and vomiting and loss of appetite were noted. The results suggested that a single oral dose of artemether(300mgs)can markedly improve the cure rate of mefloquine in multiple drug resistant malaria.
• Artesunate: Artesunate has been shown to be effective against Plasmodium falciparum but is associated with a high recrudescence rate. A study done in Bangkok Hospital for Tropical Diseases compared quinine plus tetracycline with oral artesunate in patients with acute uncomplicated Plasmodium falciparum malaria. Oral artesunate had faster parasite and fever clearance times than the combination but the cure rate was not significantly different. Nausea and dizziness were common with artesunate. They drew the conclusion that oral artesunate can be considered as an alternative drug for multiple drug resistant Plasmodium falciparum malaria but adverse effects, especially neurotoxicity, must be closely monitored before its widespread use can be recommended.
• Pyronaridine: An hydroxyanilino-benzonaphthyridine derivative synthesized in 1970 has been in use in China for more than 10 years(date of article 1992). The drug is highly effective against Plasmodium falciparum and Plasmodium vivax. It is efficacious against Chloroquine resistant Plasmodium falciparum in vitro and in vivo. It has been given orally or by I-V drip and has low toxicity.
Increasing areas of chloroquine resistant Plasmodium falciparum have been reported. Resistant forms of P.vivax are appearing and have been reported in Papua New Guinea, Indonesia, Thailand, and India. The use of chloroquine and/or proguanil is under extensive review and alternative regimens using mefloquine or doxycycline have been discussed. Resistance to Fansidar, Chloroquine, Maloprim, Lariam and Halofantrine, Malarone, and quinine have all been reported. Resistance is important because falciparum malaria can be rapidly fatal. The newer Artemisinin derivatives show promise and are being tested particularly in Thailand. Azithromycin has been shown in animals to be promising.
Protective measures have become of increasing importance due to serious side effects of newer drugs, in particular Mefloquine. A balanced decision must be taken based on the risk of getting Plasmodium falciparum malaria with a high mortality and weighed against serious side effects. The type of prophylaxis used depends on the area being visited (e.g. country, city, rural area) and local parasite drug resistance patterns.
The recommendations for prophylaxis vary greatly from country to country and there is no generally accepted regime in areas of chloroquine resistance. Protective measures plus chloroquine and proguanil still represent the most generally recommended regimes together with standby drugs in areas of chloroquine resistance.
The future of malaria: Malaria vaccines are not yet in use by the WHO but trials are still being considered. Early trials have had mixed results. At least one organization is investigating genetically altered mosquitoes, with an aim to introducing them in the wild and driving out natural mosquito populations that harbor the disease. Clearly, the cure may be as controversial as the disease itself.
Meanwhile, malaria continues to spread into regions where it was previously unknown or where it had been eradicated. Resistance to both mosquito-killing pesticides and malaria-killing drugs is on the rise. A coordinated world-wide effort is underway to fight malaria, much as smallpox was attacked.
Additional Comments
1. Before travel to any foreign country, it is imperative that you check the web site of the Centers for Disease Control and Prevention (www.cdc.gov/travel). Here you will find an account of any health risks in the destination country (or countries) and what measures to take to reduce or avoid exposure and/or infection.
This is particularly important in the case of malaria, because:
• various countries periodically are added to, or removed from, the list of malarial countries, according to the state of their mosquito control, or the natural variation in malarial epidemiology.
• the recommended drug for prevention of malaria varies from country to country according to the species of Plasmodium endemic in that country.
• The CDC also recommends that you check with your own physician to ensure that the recommended drug is not contraindicated by your medical history, current medical conditions, or other medications you are taking. Also, you should check with your children's physician for children's dosages of all medications you intend to give your children, as these dosages need to be carfully calculated. The CDC recommends that you and your children take any anti-malarial drugs EXACTLY as prescribed.
• Finally, the CDC recommends that you purchase your anti-malarial drugs in the USA before you leave, because drugs purchased in some foreign countries may be ineffective or even dangerous. This is of course mandatory if you are going straight to a country where malaria is endemic, as anti-malarial drugs need to be started 2-7 days (depending on the drug) BEFORE you enter the endemic area. However, if you have time, and if you are traveling to a country where you can rely on the efficacy and safety of pharmaceuticals, you will probably be able to buy anti-malarial drugs at substantially cheaper prices that in the USA, and in many cases without a prescription. Remember to continue taking the drug for the recommended time AFTER you leave the malarial area (usually 7 days).
2. Equally important to drug prophylaxis, are measures to avoid being bitten by mosquitos. (This is well covered by Julia's comments above). It is important that you do not rely solely on drug prophylaxis, ignoring anti-mosqito measures.
3. Julia's material recommends that DEET not be applied directly to the skin of children, (it can be neuro-toxic). However, the CDC makes this restriction only for children under the age of two months. Both the CDC and the American Academy of Pediatrics allow DEET application to the skin of children over two months of age, but recommend that children not be allowed to apply the DEET themselves, and that particular care be taken to avoid the child's eyes and mouth, and any cuts or scrapes. DEET should not be applied to the hands of young children who might put their hands in their mouth. It should be washed off as soon as the child comes indoors. For children under two months of age, instead of DEET, careful use of mosquito netting sprayed with the insecticides permethrin or deltamethrin is recommended, both over infant seats or carriers, and over beds or cots.
4. Anti-malarial prophylaxis for residents (as opposed to travelers) in areas where malaria is endemic is more controversial. Because of the side effects of anti-malarial drugs, residents of countries where malaria is endemic often elect to rely on anti-mosquito measures, and to take no anti-malarial drugs for prophylaxis. Instead, they get vigorous treatment of any malarial infection. That requires vigilance for the protean symptoms of malaria, and a low clinical threshhold for blood testing for malarial parasites.
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