Update on Malaria

GIVE THE British foot soldier credit for creativity in medication: When treating patients in their care, 19th century British army doctors in colonial India prescribed quinine — the only available cure for malaria at that time. Young British army soldiers billeted to the region grew to hate the bitter taste of quinine, but after a bit of experimenting with different combinations of spirits, sugar and fruit, they came up with something palatable: the classic gin and tonic cocktail.¹ 

While British soldiers developed the gin and tonic cocktail, credit for the discovery of quinine lies with the indigenous peoples of the Andes who taught 17th century European Catholic missionaries called the Jesuits about the healing properties of the native cinchona tree’s bark, which is highly effective in treating fevers. The Jesuits went on to share this knowledge with their fellow Europeans. 

As trade and conquest brought Europeans into more and more tropical areas where the malaria-causing parasite Plasmodium was prevalent, the Europeans brought quinine with them to fight it. The Dutch were soon growing the cinchona tree in tropical Indonesia, while the British planted orchards in the Tamil and West Bengal regions of India. Both options were far less expensive and more reliable than importing the tree bark from the Pacific coast of South America.²

However, as delicious as a gin and tonic may be, it is no longer a recommended treatment for malaria. Modern tonic water contains far less quinine than it did in previous decades, making it medicinally ineffective. And, although there are five different Plasmodium species known to affect humans, it turns out that quinine is effective only against one of them: Plasmodium falciparum (P. falciparum).^3,4 

Fortunately, during World War II, research into developing synthetic alternatives to quinine was ramped up, resulting in primaquine. In the decades since then, modern medicine has developed numerous treatments for malaria that are not only able to work against all variants of the causative parasite, but that also spare patients the bitter taste of quinine and the not-insignificant side effects of gin. While capsule-form quinine is still prescribed for treating P. falciparum in locations where more modern prescriptions are unavailable, it is now only one option in the contemporary physician’s arsenal.

What Is Malaria?

Malaria is a serious, often deadly infectious disease caused by a single-cell protozoa of the Plasmodium genus. Like humans, Plasmodium are eukaryotes (organisms that have a cellular nucleus).⁵ This makes them more closely related to paramecia or amoeba than bacteria, which lack a nucleus.

Plasmodium cannot survive outside of a host, and the five Plasmodium species that can infect humans are all spread by mosquitoes. Plasmodium rely on both human and mosquito hosts for different parts of its life cycle, and need to move from human to mosquito to successfully reproduce. As with other blood-borne diseases, it can also be spread through blood transfusion, organ transplant and sharing dirty needles, and it can be passed from an expectant mother to her unborn child.

Of the five known species that can infect humans, four are specific to us while one is naturally hosted in macaque monkeys but can be spread to humans.⁶ The four that are unique to humans are P. falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Plasmodium knowlesi (P. knowlesi) is naturally hosted in macaque monkeys and is mostly found in Southeast Asia.⁶ 

Malaria is relatively rare in the developed world, particularly in temperate areas. The United States averages just 1,500 cases per year (about five of them fatal), with nearly all cases contracted by those who had traveled to other parts of the ^world.7 

Globally, however, malaria remains a deadly scourge, with 228 million cases per year resulting in more than 400,000 deaths.⁸ It is still endemic in more than 90 nations, leaving 40 percent of the globe’s population at risk — and it is especially dangerous in young children.9 (Another high-risk group is travelers from areas like the United States who are less likely to have developed immunity.⁹)

P. falciparum is by far the most prevalent species, accounting for 90 percent of all cases.8 As with the other four species, P. falciparum is spread to a human host via an infected female mosquito of the genus Anopheles — about four dozen species of which are known to carry malaria.¹⁰ 

The protozoa enter the bloodstream in a spore-like state when the mosquito injects infected saliva while feeding (a previously uninfected mosquito will become infected when feeding on an already-infected human host). These sporozoites migrate through the bloodstream to the liver, where they begin to rapidly multiply and are then rereleased back into red blood cells. After several cycles of this, these spores develop into gametes, and if the host is again bitten by a mosquito, these gametes will be transferred back to the mosquito where they will combine for sexual reproduction in the gut of the mosquito.⁶ 

Symptoms and Diagnosis

It is during the period when the sporozoites are multiplying in the liver and being released into the bloodstream that individuals will begin to feel sick. Symptoms are similar across all malaria variants, and can resemble those of viral infections:¹¹

• Fever (often a high fever)

• Chills

• Unusual sweating

• Nausea

• Diarrhea

• Fatigue

• Abdominal pain

• Muscle and joint pain

• Cough

• Increased heart rate 

If left untreated, malaria can cause significant side effects, several of which can prove fatal:

• Organ failure: The infection can cause the spleen to rupture or the kidneys or liver to fail.

• Cerebral malaria: The red blood cells increase in size when infected by the parasite, and these enlarged cells can block small blood vessels in the brain, causing a stroke or even coma.

• Anemia: If too many red blood cells are infected, there may not be enough healthy red cells left to deliver oxygen throughout the body. 

Diagnosis is usually made by a blood smear, which can also identify the species of Plasmodium and how many are in the bloodstream, which is useful in plotting treatment.¹² Because of the rapidity at which malaria progresses, it is recommended that any undiagnosed fever be considered for malaria, as a fast diagnosis is key to effective treatment. Tests should be ordered immediately if patients report travel to areas of active malaria infection, or when tests for other diseases come back negative. If the first round of blood smear tests are negative, they should be repeated at 12 and 24 hours to confirm the negative diagnosis.

While several blood assays can indicate a malaria infection, they do not yet accurately indicate the species nor the parasite count, so a positive blood test should still be followed by a blood smear.

Since malaria is a reportable infection in the United States,¹³ physicians who confirm a diagnosis will be in contact with public health authorities and have access to their information and resources when working with patients to chart their treatment.

Treatment

Treatment will primarily consist of prescription drugs to kill the invading parasite in patients’ bodies. The main drug currently used in treating malaria is chloroquine phosphate; dosage and frequency will vary based on patients’ age and severity of infection. 

P. falciparum is developing resistance to chloroquine phosphate in many parts of the world, though, so now artemisinin-based combination therapies (ACT) are often recommended as the first-line treatment. These multi-drug cocktails gain their efficacy by killing the P. falciparum in all its different stages of development, from spore to gamete. Examples of ACT treatments include artemether-lumefantrine, artesunate-mefloquine and atovaquone-proguanil.¹⁴ 

Other drug treatments that may be used, depending on the species, resistance and previous bouts with malaria by patients, may include quinine sulfate (Qualaquin) with doxycycline or primaquine phosphate. In addition, the efficacy of quinine has been found to improve significantly when administered along with tetracycline or clindamycin.¹⁵ 

The Centers for Disease Control and Prevention (CDC) has a chart to aid physicians in treating malaria (available at www.cdc.gov/malaria/resources/pdf/Malaria_Treatment_Table_202306.pdf). The chart organizes treatment based on the region in which a patient contracted the malaria, which species of Plasmodium is present (if detected in the blood smear test), whether the species is known to be drug-resistant and recommendations based on age.

If a patient is pregnant, quinine can still be used in combination with clindamycin during the first trimester to avoid developmental harm to the child.¹⁵ The standard ACT treatments listed above can safely be used during the second and third trimesters.

For severe cases of malaria, the drugs need to get into a patient’s system as quickly as possible. Prescriptions will typically be injected, either intravenously or intramuscularly, for 24 hours until high-dosage oral versions can be tolerated.⁸ Again, the CDC chart provides specific, updated guidance for each combination of region, patient age and drug-resistance.

Because of the risk of rapid progression of the infection and the dangers of lethal complications, it is recommended that all P. falciparum and P. knowlesi patients be admitted to a hospital immediately.⁸ 

CDC maintains a hotline for physicians to call to get the latest information on treating malaria: (855) 856-4713 during East Coast regular business hours, and (770) 488-7100 on holidays, weekends and overnight.

Prevention

Prevention remains the best treatment option. While malaria was formerly endemic in parts of the United States, particularly in warmer regions in the Southeast, a coordinated effort organized by the federal government led to its elimination by 1951. This was accomplished by destroying the breeding habitat of the mosquitoes that transmitted malaria through wetlands drainage and spraying of insecticides.¹⁶ 

This federal effort was, in fact, what led to the formation of the CDC. However, many developing nations lack the resources to mount such a campaign.

While there is no vaccine to prevent malaria, those who are traveling to an area where malaria is endemic can lower their risk by taking antimalarials ahead of time and throughout the trip.¹⁷ The specific drug or drugs to be prescribed will depend on their itinerary.

Even if travelers are taking precautionary prescriptions, avoiding infection should be their ultimate goal. Covering arms and legs and using repellents are all important parts of prevention, as are insecticide-treated netting to keep out the malaria-carrying mosquitoes.

Looking Forward

As with most diseases caused by protozoa, there is, as mentioned above, currently no vaccine for malaria. (Only three protozoa-caused diseases currently have an approved inoculation.¹⁸)

However, given the severity and human cost of malaria worldwide, the U.S. Food and Drug Administration’s clinicaltrials.gov website lists 300 recent or ongoing trials into a malaria vaccine. Still, until a vaccine is developed, even physicians in countries where malaria no longer exists in the wild will have to be prepared to treat patients who travel abroad and contract the disease.

Given the growing resistance of the Plasmodium parasites to existing antiprotozoal drugs, many of the 1,300 total clinical trials studying malaria are looking at new classes of drugs, or new combinations, some of which will undoubtedly enter the pipeline before too long.

Keeping that CDC hotline number handy will be the most effective way of determining state-of-the-art treatment when a blood smear comes back positive.