Leukemia (Blood Cancer)

 

Malaria

Malaria is an infection that can be caused by a few different types of Plasmodium species, which are single-celled parasites that get spread around by mosquitoes. Once the plasmodium gets into the bloodstream, it starts to infect and destroy mainly liver cells and red blood cells, which causes a variety of symptoms and sometimes even death. 

Malaria is a serious global health problem that affects millions of people, particularly young children under the age of 5, pregnant women, patients with other health conditions like HIV and AIDS, and travelers who have had no prior exposure to malaria. Tropical and subtropical regions are hit the hardest, together the most affected regions form the malaria belt, which is broadband around the equator that includes much of Latin America, sub-Saharan Africa, South Asia, and Southeast Asia.

There are hundreds of types of Plasmodium species, but only five cause malarial disease in humans, and those are Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. Plasmodium vivax uses a specific erythrocyte surface receptor called the Duffy antigen, and some individuals, particularly those with sickle-cell anemia lack this receptor, meaning that Plasmodium vivax cannot get into their cells. In other words, having sickle cell anemia is genetically related to having relative protection from Plasmodium vivax.

Other diseases, like thalassemia and G6PD deficiency, make the parasite-infected erythrocyte more susceptible to dying from oxidative stress. So despite the obvious downside to having any of these diseases, they do offer an upside when it comes to warding off a malaria infection. In fact, because malaria has historically circulated in Africa, the genes underlying these diseases are thought to have conferred a natural selection advantage and therefore become more common in the genetic pool. Now, malaria begins when a plasmodium-infected female Anopheles mosquito hunts for a blood meal in the evening and through the night.

Like a tiny flying vampire, the mosquito is drawn to carbon dioxide that gets breathed out as well as bodily smells, like foot odor. At this point, the Plasmodium is in a stage of development called a sporozoite, waiting patiently in the mosquito’s salivary gland. When the mosquito pierces a person’s skin with its long and needle-shaped tusk, called a proboscis, the tiny, worm-like sporozoites spill out of the mosquito’s saliva and make it into the bloodstream. Within minutes, the sporozoites reach the liver and mount an attack on hepatic parenchymal cells where they begin asexual reproduction also known as schizogony. At this point, the plasmodium species vary a bit.

Over the next 1-2 weeks, Plasmodium falciparum, Plasmodium malariae, and Plasmodium knowlesi sporozoites multiply asexually and mature into merozoites, while host hepatic parenchymal cells die. In contrast, over the next few months to years, Plasmodium vivax and Plasmodium ovale sporozoites enter into a dormant hepatic phase, where they are called hypnozoites. Hypnozoites don’t divide - instead, they snooze for a period of time before entering the process of schizogony, causing a long delay between the initial infection and symptoms from the disease. This is called the exoerythrocytic phase because it happens outside of the erythrocyte or red blood cell, and it’s generally asymptomatic.

The merozoites are then released into the blood, and each one binds to a surface receptor and invades a red blood cell. Plasmodium ovale and Plasmodium falciparum invade red blood cells of all ages, whereas Plasmodium vivax prefers to invade reticulocytes which are young, immature red blood cells, and Plasmodium malariae and Plasmodium knowlesi prefer to invade older red blood cells. Once inside the red blood cell, the merozoite undergoes asexual reproduction and a series of transformational changes. This phase is known as the erythrocytic phase of malaria because it happens inside of the red blood cell and generally lasts 2 to 3 days.

In the first stage of the erythrocytic phase, the merozoite looks like a tiny ring within the red blood cell and is called an early trophozoite or a ring form. In the second stage, the ring from trophozoite grows and is referred to as a late trophozoite. In the third and final stage, the parasite grows some more by digesting hemoglobin and leaves behind hemozoin, which under a microscope looks a little like a brown feces smudge on the red blood cell, and at this point, the parasite is called a schizont. This is the actual replicative phase in which the parasite undergoes mitosis and differentiates into lots of merozoites which can get released into the blood. Now, instead of going into the erythrocytic phase again, some of the merozoites undergo gametogenic which is where they divide and give rise to gametocytes which are little sausage-shaped sexual forms that can be either male or female. These gametocytes remain inside of a red blood cell and can get sucked up by another female Anopheles mosquito that might take a blood meal from the infected person. The gametocytes can then reach the mosquito's gut where they mature a bit more and then fuse together to form a zygote.

This part of the plasmodium life cycle is called sporogony, and it’s sexual reproduction, as opposed to the schizogony or asexual reproduction that happened in the liver and red blood cells. The zygote then goes on to develop further, it becomes an ookinete and then an oocyst that ruptures in the mosquito’s gut, releasing thousands of sporozoites that navigate their way into the mosquito's salivary gland, in order to repeat the cycle all over again. Now, the incubation time, which is the period of time between infection and symptom onset, varies depending on the plasmodium species.

Plasmodium falciparum incubates for a few days, whereas Plasmodium malariae incubates for a few weeks.

The release of tumor necrosis factor-alpha and other inflammatory cytokines causes fevers that typically occur in paroxysms or short bursts, and correspond to the rupture of the infected red blood cells, which happens in waves of reproductive cycles unique for each Plasmodium species.

For Plasmodium malariae, fevers happen every 72 hours and is called quartan fever. For Plasmodium vivax and Plasmodium ovale, fevers happen every 48 hours, and these are called tertian fever. For Plasmodium knowlesi, the fever happens every 24 hours, and for Plasmodium falciparum, the pattern can vary - sometimes following the pattern of tertian fever, while other times the fevers happen daily, earning it the name malignant tertian fever.

In addition to fevers, hemolytic anemia, which is the destruction of red blood cells, also causes symptoms like extreme fatigue, headaches, jaundice, and splenomegaly. Most plasmodium infections have a mild course of symptoms and are generally regarded as uncomplicated malarial infections. Out of all of the Plasmodium species, though, Plasmodium falciparum is known for causing the worst infections.

Most plasmodium-infected red blood cells get screened and destroyed by the spleen.

Plasmodium falciparum, though, avoids this fate by generating a sticky protein that coats the surface of the infected red blood cells and these look like “knobs” or little bumps. The protein causes the red blood cells to clump together and jam up tiny blood vessels - a process called cytoadherence. This literally blocks the flow of blood so that infected cells aren’t able to flow into the spleen, and it also blocks blood flow from reaching other vital organs which can wreak havoc on them. Between hemolytic anemia and ischemic damage from blocked blood flow, organ failure can set in pretty quickly. When the brain is affected, it's termed cerebral malaria, and it results in altered mental status, seizures, and coma. 

When the liver is affected, it's termed bilious malaria, and it results in diarrhea, vomiting, jaundice, and liver failure. Other commonly affected organs include the lungs, the kidneys, and the spleen, which taken together create a sepsis-like clinical picture that can eventually lead to death. Together, all of these scenarios are called complicated malaria.

Malaria is usually diagnosed with a thick blood smear that locates parasites sitting within the red blood cells and a thin blood smear, which directly identifies the plasmodium species. It’s also important to know the percentage of red blood cells infected by a parasite because patients with greater than 5% parasitemia can have worse outcomes. Some common lab findings include thrombocytopenia, which is a low platelet count, elevated lactate dehydrogenase levels due to hemolysis, and a normochromic, normocytic type of anemia, meaning that the red blood cells are few in number but those that remain are of normal size and color.

           Treatment for malaria is generally divided into the different stages of infection. Suppressive treatment or chemoprophylaxis is aimed at killing sporozoites before they infect hepatocytes, so it’s usually given to travelers that are headed to a country with endemic malaria. Therapeutic treatment is aimed at eliminating merozoites in the erythrocytic phase, so it’s usually given during an active infection. The exact medication or group of medications that are to treat an active infection depends largely on the severity of infection, the age and pregnancy status of the patient, the local malarial resistance pattern which depends on the geography, and the plasmodium species causing the infection.

It’s also important to not take the same medication to treat an active infection that was previously used as chemoprophylaxis. Gametocidal treatment is aimed at killing gametocytes, which prevents the spread of disease, and thus, the creation of future resistant forms of the parasite. Lastly, radical treatment is aimed at killing hypnozoites in the liver from a Plasmodium vivax and Plasmodium ovale infection. For the most part, cases of uncomplicated malaria resolve with treatment. Even after recovery, some individuals can get symptoms after a period of time – and this is called recurrent malaria, and it’s broadly divided into three underlying causes: recrudescence, relapse, and reinfection.

Recrudescence refers to ineffective treatment that didn’t completely clear the infection – a problem common when there are high rates of antimalarial resistance. Relapse refers to situations where the blood was cleared of merozoites but hypnozoites persisted in the liver and then emerged to cause more problems. And reinfection is when an individual was effectively treated, but a completely new infection caused a new bout of malaria - a problem common in endemic areas since a single infection doesn’t make an individual immune to malaria. Instead, there is an acquired ability to tolerate Plasmodium infections, which relates to the degree of exposure to a variety of different strains.

Since malaria is spread by mosquitos, anything that prevents mosquito bites can help, like full-body clothing, mosquito repellent, sleeping in insecticide-covered mosquito nets, and using indoor insecticide sprays. In addition, Anopheles mosquitoes like to lay their eggs in small, shallow collections of fresh water, like containers sitting outdoors during the rainy season in tropical countries. To control the mosquito population, it’s important to empty out these containers and any other stagnant collections of water. Finally, an emerging vaccine against malaria is currently being studied in clinical trials, and it’s called, the then brace yourself, RTS, S/AS01 vaccine.

Guessing “malaria-be-gone” was already taken? All jokes aside, though, this vaccine consists of a recombinant fusion protein that targets an antigen found on the P. falciparum membrane. And while more clinical trial results are necessary before recommending widespread employment of the vaccine, it looks really promising!

All right, as a quick recap, malaria is a life-threatening mosquito-transmitted infection caused by plasmodium parasites in which the parasite feeds and grows inside hepatocytes and red blood cells. Symptoms are primarily caused by the rupture of red blood cells, which usually result in high-grade fever paroxysms that improve over time but can occasionally cause severe complications and death.

 

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