Wednesday, March 30, 2011

Malaria Part 3: The disease

Malaria can be one of the most devastating diseases to affect human beings, with children bearing the greatest burden. The disease defines tragedy for countless families across the world. But it can also be asymptomatic. In areas where the parasite is highly endemic, children may exhibit parasitemia prevalences as high as 50% or more, but, cross-sectionally, most of these parasitemic children will not display any symptoms. Notice the emphasis on the "cross-sectional" perspective. Malaria due to P. falciparum, which causes the most deadly malaria, can also range from asymptomatic to overwhelming disease and rapid death.

The Plasmodium parasite is probably the most intense stimulator of the human immune system at the population level. The reticuloendothelial system is hyperactivated with enhanced phagocytosis in the spleen, liver and lymph to remove infected erythrocytes from circulation. There is a major increase in antibody production, with several g/L of immunoglobulin directed toward the malaria parasite. Ongoing cytokine cascades are an important and sustained component of the immune response. This combination of immune component activation can lead to some of the severe aspects of malaria. For example, cerebral malaria results from the convergence of pro-inflammatory cytokines (especially TNF-α), metabolic acidosis, and the sequestering of erythrocytes. Here is a chart that shows different immune responses to different stages of Plasmodium development in the human host. Keep in mind that the parasite has developed effective pathways to evade all of these!

Sporozoites can be prevented from binding to hepatocytes in the liver by way of antibodies that target the circumsporozoite protein on the surface of this stage of the parasite. Interferon-¥-producing T cells are an important part of cell-mediated immunity and can kill infected hepatocytes should the sporozoites have bypassed the innate and humoral lines of defense. Both humoral and cell-mediated immunity are responsible for targeting and killing parasitized erythrocytes. The merozoites are targeted by antibody-dependent cellular inhibition.
Despite the intense mobilization of the human host immune system, the Plasmodium parasites have evolved to become very effective at evading the host defenses. As such, persistent or repeated infection is common. Because of this co-evolution between primates and Plasmodium species, protective immunity following natural infection takes many years to develop over the course of many serial infections. And even then, the protective immunity is not complete. Individuals are still often susceptible to milder forms of disease by the time they reach adulthood.

Typical symptoms of clinical disease include listlessness, fever, shivering, body aches, cramps, coughing, drowsiness, varying levels of mental disorientation, convulsions and coma.

While not all of these symptoms will always present in each case of malaria, the progression form mild to severe forms can be extraordinarily rapid, making timely intervention often difficult or impossible. This is especially the case for falciparum malaria.

Sever malaria typically occurs in relation to infections caused by P. falciparum. In those areas with the highest occurrence, malaria can often account for half the mortality rate for children under 5 years of age. It can be particularly dangerous because falciparum malaria will frequently not progress from mild to moderate disease and then on to severe disease. Rather, severe malaria typically strikes abruptly in children. The lack of warning means that a parent cannot get the child to the required treatment in time, even in areas where adequate health care is readily available. This rapid onset of severe disease is a hallmark of falciparum malaria in the geographic locations of  greatest transmission. In the last post in this series on malaria, we will discuss this phenomenon in more detail when we examine the nuance and importance of geography in malaria transmission.

The World Health Organization (WHO) defined specific criteria for severe malaria in 1990, with additions in 2000:

1990 WHO criteria for severe malaria

1. Coma
2. Severe anemia
3. Respiratory distress
4. Hypoglycemia
5. Circulatory collapse
6. Renal Failure
7. Spontaneous bleeding
8. Repeated convulsions
9. Acidosis
10. Hemoglobinuria

2000 WHO additions

11. Impaired consciousness
12. Prostration
13. Hyperparasitemia
14. Hyperpyrexia
15. Hyperbilirubinemia

Typically when a child presents with severe malaria, they manifest 1 of 3 distinct syndromes. These are neurologic deficit, or cerebral malaria, respiratory distress, and severe anemia. The first two can be readily identified upon initial examination because of their distinguishing symptoms. The third, however, is not immediately apparent by clinical examination but can still be life threatening. Let's take a look at each of these individually.

Cerebral malaria is pathologically due to the sequestration of infected red blood cells in the cerebral microvasculature. The case-fatality can be quite high ranging from 10% to 50%. Cerebral malaria is quite heterogeneous and is comprised of different, yet overlapping, syndromes. First is prolonged postictal state, which is characterized by deep sleep, headache, confusion, and muscle soreness. Second is covert status epilepticus, which is characterized by ongoing seizures. Third is severe metabolic derangement, which involves hypoglycemia and metabolic acidosis. It is common for more than one syndrome to appear concurrently. In this situation it is critical to recognize and manage each of the clinical syndromes of cerebral malaria, while also implementing treatment to eliminate the parasitic infection.

Comatose child with cerebral malaria

Respiratory distress is another important form of severe malaria. The critical feature of this syndrome is the pulmonary edema that often attends acute respiratory distress. Indeed, this has long been recognized as a serious and often fatal complication of malaria. As serious as respiratory distress is, it can also be very useful in quickly recognizing and treating severe malaria. Hyperventilation is the most important clinical sign because it is highly sensitive and specific for respiratory distress, has very good interobserver agreement, and requires little training. Respiratory distress is a multi-system syndrome that can involve pneumonia, cardiac failure, direct sequestration of erythrocytes in lung tissue, and increased central drive to respiration. Metabolic acidosis is the key component to respiratory distress and results from lactate build-up caused by decreased oxygen delivery to tissues. The pictures below depict some important clinical signs of respiratory distress in children and adult patients:

Severe anemia is the third major syndrome associated with severe malaria. It has a complex pathogenesis because of its interaction with protein-energy malnutrition and iron deficiency, both of which can be quite common in many malaria endemic areas. Nutrient deficiencies are often coincident with malaria, leaving children particularly susceptible to infection because of the weakened immune system. Iron deficiency is one of the most common nutrient deficiencies in the economically poor regions where malaria is endemic. As such, this setting promotes initial infection. The malaria parasites are responsible for the large scale undermining of red blood cell viability due to the massive destruction and sequestration of the erythrocytes. The result is a vicious circle which promotes greater infection and more severe anemia. Severe anemia is especially insidious because it is silent. It does not present with the clear clinical warning signs characteristic of cerebral malaria or respiratory distress. It simply kills quietly. Severe anemia varies greatly by geographic region, tending to predominate as the main form of severe malaria in areas with the highest malaria transmission. I will discuss these important geographic distinctions in the next post in the malaria series.

It is important to keep in mind that malaria is a contributing factor to most deaths in children in sub-Saharan African countries that exhibit high malaria transmission even if death may be directly attributed to another cause, such as pneumonia. In these areas, control of malaria transmission can lead to a dramatic decrease in overall childhood mortality.

Malaria during pregnancy is the last form of malaria disease that we'll discuss. Malaria during pregnancy is very dangerous. Women who become infected with Plasmodium parasites during pregnancy are far more likely to develop severe complicated malaria than are non-pregnant women or men who become infected. The reasons for this are many, but a necessary component cause is that both cell-mediated and humoral immunity are much reduced in pregnancy. In addition to the weakened immune system, the biology of the mosquito contributes to the increased disease burden suffered by pregnant women. Pregnant women are more likely to be bitten by mosquitoes in all malaria endemic regions because their higher metabolic rate during pregnancy leads to increased body temperature and increased release of carbon dioxide while breathing. In addition to being at higher risk for mosquito bite, pregnant women are also at higher risk of infection from all Plasmodium species once introduced from the mosquito. Finally, once infected, pregnant women are at higher risk for severe malaria and death relative to their non-pregnant and male peers.

The maternal mortality rate can range between 100 and 1000 per 100,000 live births.

Adverse outcomes of the pregnancies are also higher in malaria infected women because there is active infection of the placenta. The combination of placental infection and the intense host (mother) response to the malaria parasites leads to a high occurrence of fetal loss, low birth weight, pre-term delivery, and perinatal and infant mortality. The attributable risk for low birth weight due to malaria infection ranges between 8% and 14%, 8% and 36% for pre-term delivery, 13% and 70% for fetal growth retardation, and 3% and 8% for infant mortality.

The greatest risk for malaria infection occurs during the 2nd and 3rd trimesters. Dramatic reductions in severe complicated malaria can be achieved if infection in the 2nd and 3rd trimester can be avoided. Even so, the risks are still higher than being malaria free throughout pregnancy

In my next post, we will take a closer look at the epidemiologic and geographic nuances of malaria. We will discuss the marco- and micro-geography that defines the malaria landscapes. This will also conclude the extended series on malaria.


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  2. In this post we learned that children and pregnant women bear the greatest burden of disease when it comes to malaria. In endemic areas parasitemia prevalence among children can be as high as 50%. However, most of these children won’t show any symptoms. Additional reading suggested that this might not be a sure sign of malaria but rather the occurrence concurrent diseases. I am curious if this could really be the case? We also learned that persistent and repeated infection is common and protective immunity following a natural infection takes many years to develop. Once immunity is present people are still susceptible to milder forms. Additionally, P. falciparum usually strikes abruptly in children which means treatment isn’t administered in time. Unfortunately timely treatment is missed even in areas where adequate health care is available.

    1. The abrupt strike of malaria in children in endemic areas is mostly due to the pathogeneses of the disease itself; although a timely treatment such as home treatments administered by mothers have demonstrated the effectiveness in decreasing mortality in children. Pregnant women bear the greatest burden of malaria as well, and it is dangerous and is associated with many adverse outcomes. Since the disease could be asymptomatic and could progress rapidly in general, I am wondering whether there are any timely control measures to protect pregnant women that are comparable to home treatments as seen in children’s cases.

    2. It is interesting that children do not exhibit symptoms until they are in visible respiratory distress or neurologically incapable. It makes administering treatment at the correct time even that much harder. Even in areas where healthcare seems efficient, the proportion of children dying due to malaria is alarmingly high. As we learned in class perhaps teaching mothers or heads of households the proper way to administer at home treatment can curb the mortality rate in children. In regards to pregnant women, WHO recommends antenatal care which can present malaria intervention strategies to women who may not be aware of how much risk they are in being infected with malaria.


  3. Monsurat Odeneye

    In this post we see the burden of the Malaria being fatal especially in children. I find this interesting cause growing up in Nigeria, the first go to medicine/treatment once myself or a child showed symptoms of malaria (often time high fever and sweating) was chloroquine. However, over time and numerous attacks of malaria, I realized I rarely got sick of malaria regardless of my frequent exposure to mosquitoes, guess I grew resistance and my immune system figured a way to accommodate the malaria parasite, (I wonder if it would be the case if I go visit). Also, the post mentioned falciparum malaria which is known to cause rapid death regardless of quick timely intervention, I am curious to know if there is a potential malaria vaccine development in the works and if so, when it will likely be licensed and introduced? I feel the implementation of a vaccine against malaria will provide long-term solution to end the high incidence of morbidity and mortality especially in Sub-Saharan Africa countries.

    1. @ Monsurat I agree with you that given the malaria burden specially child mortality and morbidty related to malaria and the limited success acheived by the global roll back malaria program, the development of Malria vaccine is of paramount importance, However the issue of developing effective antimalarial vaccine is very tasking because the life cycle of the plasmodium is quite complex from the mosquitoes to the human body where it has two stages in the liver and in the blood stream, making the selection of the targeted life cycle stage and the delivery system of the vaccine a daunting challenge, however two malaria vaccines are currently in human trial stage the RTS,S and the PfSPZ Vaccine, the WHO recommended the use of RTS,S this year

    2. @ Monsurat I agree with you that given the malaria burden specially child mortality and morbidty related to malaria and the limited success acheived by the global roll back malaria program, the development of Malria vaccine is of paramount importance, However the issue of developing effective antimalarial vaccine is very tasking because the life cycle of the plasmodium is quite complex from the mosquitoes to the human body where it has two stages in the liver and in the blood stream, making the selection of the targeted life cycle stage and the delivery system of the vaccine a daunting challenge, however two malaria vaccines are currently in human trial stage the RTS,S and the PfSPZ Vaccine, the WHO recommended the use of RTS,S this year

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