65. Species P. vivax, P. ovale P.malariae P. falciparum Periodicity Tertian Tertian Quartan Irregular/tertian Attacks Typical Typical Typical Intermittent irregular Recrudescence Yes Yes Yes Yes Relapse Yes Yes No No Complications Rare Rare Glomerulo-nephritis Nephritic syndrome Cerebral malaria Black water fever
66.
67.
68.
Editor's Notes
Today I am going to introduce the most important parasitic disease—malaria to you. I am sure that you must have known something about it before this lesson, right? Is there anyone want to tell us what he has heard of malaria?
Each year, there are approximately 515 million cases of malaria, killing between one and three million people, which means one people died in every 30 seconds. By killing a lot of people with productivity, this disease costs endemic countries 1.3% of GDP annually. No mention the money used for the prophylaxis and treatment of it. And this also exacerbated the poverty of these areas and consequently worsen the prevalence of malaria.
I want to tell you something about history of malaria, How it was known by human being in the history. Malaria has infected humans for over 50,000 years, and may have been a human pathogen for the entire history of the species. But the typical periodic fevers of malaria were first recorded in 2700 BC in China. The term malaria originates from Medieval Italian : mala aria — " bad air "; and the disease was formerly called ague[ˈeɪgju] or marsh fever due to its association with swamps and marshland. But, our ancestor didn’t find out what malaria exactly was until the nineteenth century.
in 1880. Doctor Charles, who was a French army doctor observed parasites for the first time, inside the red blood cells of people suffering from malaria. He, therefore, proposed that malaria is caused by this protozoan . And for the first time protozoa were identified as causing disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine . However, people still didn’t know how malaria was transmitted from person to another. A lot of scientists did a lot of research on this. Finally, a Britain, Doc. Ross proved that malaria is transmitted by mosquitoes in 1898. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. For this work Ross received the 1902 Nobel Prize for Medicine. There are two scientists received Nobel prize in the research of malaria, and I wish one of you will become the third one.
Here are the contents that I am going to talk about. Today, I will focus on these topics in red color, which are the key points of this disease.
the pathogen of malaria is named plasmodium protozoa. There are Four distinct species: the most deadliest one is P. falciparum , which always induce serious symptoms and have a higher mortality. And the most common infection in china is caused by P. vivax , and there are two species called P. malariae and P. ovale ; Within each species there are variant strains. Each species has a distinctive appearance under the microscope, and each one can cause infection and produces a somewhat different pattern of symptoms. And they can also infect a single individual at the same time, which will make the clinic symptoms untypical. This should be known when you diagnose a patient suffering from some kind of fever. but how this plasmodium complete its infection. To know this, we need to learn about it’s life cycle.
I know that you all have learned the life cycle of plasmodium in parasitology. So I don’t want to spend too much time in this part. You just need to understand how plasmodium generates and infects patients. The whole life cycle of malaria can be divided into two parts, which are sexual cycle and asexual cycle. The sexual cycle refers to the development in the anopheles mosquito. There are several forms of parasite in the mosquitoes, Gametocyte, gamete, zygote, ookinete, oocyst, sporoblast, sporozoite The asexual cycle happens in human body and it consists of erythrocytic stage and exoerthrocytic stage. The parasite pass its exoerthrocytic stage in our liver. In this stage, the parasites has several different appearances under microscope. they are: sporozoite which is the infectious form, in the infection of P. ovale and P. vivax, there two kinds of sporozoites depend to how long it take to develop to the merozoite.. It takes about 12-20d for tachysporozoite and 6-11months for bradysporozoite. The bradysporozoite is also called hypnozoite, which is the reason of relapse of this two kinds of parasite infection. And there no hypnozoite in the cases of P. malarie and P. falciparum, that’s why no relapse happens in patients infected by this two species of malaria. There are 4 kinds of forms in the erythrocytic stage in the RBC. They are ring form, trophozoite, schizont, gametocyte.
The life cycle of malaria parasites in the human body. A mosquito infects a person,by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, then trophozoites (a feeding stage), then schizonts (a reproduction stage), then back into merozoites. Sexual forms called gametocytes are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle. When mosquito bite a infected person and take a blood meal. The reproductive form of malaria in the host’s blood stream, male and female gametocyte were sucked into the gut of mosquito. The gametocyte develops into gamete. Then the two kinds of gamete fertilize and forms a zygote, which becomes an ookinete. After attaching to the wall of guts, ookinete developes into oocyst. There are thousands of sporoblast in each matured oocyst. And each sporoblast can grow up to the infective form called sporozoite. In the last stage of sexual cycle, the oocyst bursts and releases sporozoites which migrate to the salivary gland of mosquito and can be injected into humam body when the mosquito bit it’s next victim.
This picture just simplify the lifecycle of the parasite. It’s easy to understand.
There are millions of parasites in a patients blood stream, so the patient is the most common source of infection. In hyperendemic area, the repeated infection and uncompleted immuno-clearance make the chronic or asymptomatic carriers. Due to the neglect of therapy and isolation, These carriers may be more important in transmission of malaria.
There are three routes of transmission. The bite of female anopheles mosquitoes is the most important one. In fact, there are more than 380 species of anopheles mosquitoes, but just about 60 species of them can transmit malaria. In some cases, the parasite in mother’s blood can also pass the placenta and infect a baby, which is called vertical transmission. The malaria can also be transmitted by blood transfusion or organ transplantation.
This picture shows the transmission cycle of malaria. The infected anopheles mosquito transmit malaria by taking a blood meal from a person. The parasite reproduce in the human body, passing the exoerythrocytic and erythrocytic stage, and the gametocyte can also be taken up by the second mosquito and transmit malaria to another person in the next bite. If the patient is a pregnant woman, she will take the risk of transmitting malaria to her baby. And if a carrier give a blood or an organ donation, the recipent may be also infected.
All the people are susceptible. The travelers and foreigners of endemic area is more susceptible and usually have a severe attack. In endemic area, the children and pregnant women is the most susceptible population, it is reported that malaria Kills up to 15%~20% children less than 5y old. The cure of a infection just provide a shot immunity, without cross immunity to other species.
In temperate zone, The epidemic seasons of malaria are summer and autum when the mosquito is more active. There are no obviously epidemic seasons in tropic or sub tropic area because of the hot climate.
We can see most of Africa, south and east Asia, central and south America is the highly endemic areas of malaria. Most of this area located around the equator, and underdeveloped countries.
Let’s look at the prevalence of malaria in china. In the 1950’s, about 100 people in every ten thousand died of malaria. After our new government established, we did much on malaria and the mortality decline rapidly from 1970’s and malaria is rarely reported now, except in Hainan province.
How does a plasmodium damage the human body? This slide shows the pathogenesis of this disease. We know that the parasite infect a great number of RBCs. when the infected RBCs rupture, a lot of toxins and inflammatory mediators such as TNF-alfa, Nitric oxide, IL-1,2, interferon-gama, will be released. most of which are endogenic pyrogens, These endogenic pyrogens will induce a series of inflammatory responses and immuno-responses, and result in the most important clinical manifestation –chill, high fever and then sweating, which is called the typical malaria paroxysm. And the other metabolic disturbances such as hypoglycaemia will also happen at this time. It is easy to understand that the rupture of RBCs results in anemia. In fact, there are a lot of factors result in anemia, such as haemolysis(caused by the black water fever), splenomegaly, abnormal erythropoiesis, Folate depletion and so on. Meanwhile, the ruptured RBCs induce hyperactive phagocytosis as well as the proliferation of the neutro-mono-macrocytic system. the spleen or even liver will become larger and larger as infection goes on. We call it splenomegaly and hepatomegaly. Besides, the excessive splenomegaly will result in extravascular hemolysis and aggravate anemia. There is also a very important complication I must talk about---black water fever. The excessive damage of RBC produce too much hemoglobin to be metabolized by spleen and result in hyperhemoglobinemia, which induce the obstruction of renal tubual and kidney impairment.It is also called hemolytic urinemic syndrome. This syndrome can be also caused by some antimalarial drugs. The parasite infection, especially In cases of P. falciparum infection, will make the RBC more easily adhere to the blood vessels and block the blood stream. This is very dangerous. The impaired microcirculation and the tissue hypoxia in vital organ may result in the cerebaral malaria, pulmonary edema or even diffused intravascular coagulation.
This picture just simplify the lifecycle of the parasite. It’s easy to understand.
This picture just show two infected RBCs. We can clearly see a lot of parasites in the infected cells. And they looks very different from the normal cell. there are 1 million infected red cells in every mili-liter blood in p. falciparum infected patients. How can you imagine that?
The incubation period varies from 7d to one month between different species.Symptoms of malaria include high fever , shivering , arthralgia (joint pain),commonly accompanied with anemia (caused by hemolysis), in some cases with vomiting ,diarrhea, or even hemoglobinuria , retinal damage , convulsions and coma in severe cases. The classic symptom of malaria is called malaria paroxysm, it refers to cyclical occurrence of sudden coldness followed by chills and then high fever and sweating lasting four to six hours, occurring every two days in P. vivax and P. ovale infections, while every three for P. malariae . [36] P. falciparum can have recurrent fever every 36–48 hours or a less pronounced and almost continuous fever. But the patient may feel fine between the acttacks in these three species infection, but feel miserable in p.falciparum infection.
Now we know the malaria proxysm is caused by the mediators relased by the bursted RBC and the parasites. It can be divided into three stage, chilling stage, hot stage, and sweating stage. In chillling stage, the patient feels so cold that he actually shakes to resist the coldness, always accompany with malaise, headache, vomitting or diarrhea. 20-60min later, the patient body tempreature rises up to 41 ℃, tachycardia, hypotension, cough, headache, backache can be found, but normal consciousness, the hot stage lasts for 2-6h. Then T falls usually to normal with heavy sweat, fatigue and weak in half to one hours. The pale of lips or conjunctiva and splenomegaly are commonly found in physical examination.
This is a temperature sheet of a patient infected P. vivax. In the early stage, the temperature just rises to as high as 39-40, but without an obvious periodicity. Several days later, the intermittent fever show a strick periodicity of two days.
Except for typical proxysm, there are several types more severe in clinical practice. The cerebral malaria happens usually in P. falciparum infection,it could also be caused by super high fever or antimalarial drugs. The obstruction of vessels and hypoglycemia were found in these patients and are commonly recoginzed as the important physiological and pathological reasons. The patients may have severe headache, high fever, more important, the Impairment of consciousness such as confusion, obtundation, convulsions and coma. hyper-reflexion and bilateral Babinski’s sign can be inducted. But focal neurologic finding occurs rarely.
The severity and the pattern of clinical manifestation differs between different species infection. Take the P. falciparum for example, P. falciparum can infect any RBCs of any age, the concentration of parasite is very high, and P. falciparum takes less time to multiply in RBC than other species. In other words, P. falciparm can damage more RBC in shorter time. So the clinical manifestation especially anemia are worse than the others.
But the scientists found that some of the patients reappeared malaria paroxysm after symptoms disappeared for weeks or months. After research, they found that there are two situations: recrudescence and relapse. Recrudescence usually happens in 1-4wk after relieved or repeatedly. It caused by the residual plasmodium in the blood stream when the therapy is not powerful enough or course of treatment is not long enough. Recredescence can be found in all types of malaria. The patients usually relapse in 3-6mon or even years after cured and there are no plasmodium in the patient’s bloodstream.In fact, people were still puzzled for this before 1980. although the blood stage and mosquito stages of the malaria life cycle were identified in the 19th and early 20th centuries, it was not until the 1980s that the latent liver form of the parasite was observed. The discovery of this latent form of the parasite finally explained why people could appear to be cured of malaria but still relapse years after the parasite had disappeared from their bloodstreams.
The physiological changes of pregnancy and the pathological changes due to malaria have a co-effect on the course of each other. So the malaria in pregnancy could be more aggravated, and the mortality is higher, consititute 80% deaths of malaria in africa. The symptoms are more severe. Besides, it can also induce a lot of problems of the baby: Low birth weight, prematurity. Can also transmite malaria to next generation.
the other special types are malaria infected by blood transfusion and vertical transmission.. The symptoms are the same as the typical ones. But The incubation stage are shorter, usually about 1wk. And they all have no relapse because of the loss of exoerythrocytic stage and bradysporozoites or hypnozoites.
Malaria has a lot of complications. The most important one is Hemolytic urinemia syndrome , which is also called black water fever. In detail, the black water fever is characterized
Pulmonary edema is not common, even in severe cases. Due to its higher mortality, I want to talk about it here. It always happens in patients with hyperparasitemia, and is caused by pulmonary capillary leak, rather than heart failure. It can be treated with positive-pressure artificial ventilation.
Hyperreactive malarial splenomegaly is also called Tropical splenomegaly syndrome (TSS). It is usually seen in older children and adults and caused by the repeated infection In hyperendemic area. The clinical manifestations contains anemia, massive splenomegaly, elevated IgM levels and malarial antibody. To treat this repeated infection, prolonged course of therapy and prophylactic drugs are requied.
To make a right diagnosis, we have to pay attention to these aspects. The epidemiological history will be very important to the diagnosis, which means that if the patient have ever traveled from the endemic area, such as the tropics, southeast Asia, or america, or had a blood transfusion, this patient will be in a higher risk of malaria infection. And if the patient have typical malaria paroxysm, which is defined as a feeling of extremely cold and chill, then high fever, followed with sweating, the diagnosis will be more reliable. Meantime, I will also remind you that the classic paroxysm could be absent in some patients, especially in the early stage or in the P. falciparum infection. These patients may have several small fever spikes a day. Cause a infected mosquito can be transported to somewhere else from endemic area and infects human in non-endemic area, any patient exhibiting any malaria symptoms should be suspected of plasmodium infection. To identify the diagnosis, some laboratory investigations are necessary. There are lots of methods to certify the malaria infection, such as QBC is a sensitive method. It stain the malaria by the fluorochrome which lights up the parasites. But this method needs the fluorescence microscope, which restrict its application. Rapid diagnostic tests are also immunochromatographic tests that detect malaria-specifc antigens in a finger-prick blood sample. It’s simple, sensitive and could be used in difficult conditions. Serology test include ELISA and IFA by detecting the specific antigen or antibody. But the antibodies are not detectable until 3-4wk after infection, so the method basing the antibodies detecting will be more appropriate in epidemiological investigations. Molecular investigation are mostly based on the PCR technique to detect the malaria DNA. It is more accurate, sensitive and specific for all 4 species of plasmodium. Other:total blood cell counts, blood chemical tests of liver function and renal function.
To identify the diagnosis, some laboratory investigations are necessary. There are lots of methods to certify the malaria infection, such as QBC is a sensitive method. It stain the malaria by the fluorochrome which lights up the parasites. But this method needs the fluorescence microscope, which restrict its application. Rapid diagnostic tests are also immunochromatographic tests that detect malaria-specifc antigens in a finger-prick blood sample. It’s simple, sensitive and could be used in difficult conditions. Serology test include ELISA and IFA by detecting the specific antigen or antibody. But the antibodies are not detectable until 3-4wk after infection, so the method basing the antibodies detecting will be more appropriate in epidemiological investigations. Molecular investigation are mostly based on the PCR technique to detect the malaria DNA. It is more accurate, sensitive and specific for all 4 species of plasmodium. But it has a relatively higer false positivity and requires higher laboratory conditions. Other: total blood cell counts, blood chemical tests of liver function and renal function.
The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of blood films because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. To identify the species of infected plasmodium, Thin films are required because the parasite's appearance is best preserved in this preparation. It is similar to usual blood films .With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis. [67] One negative smear does not exclude the diagnosis of malaria, repeatedly tests every 12-24 hours for 48 to 72h is required to diagnose patients in early stage with a very low parasitemia. Blood smear remains the gold standard for confirmation of malaria. But it depends on the quality of the reagents, quality of the microscope, fresh samples and depends on experience of investigators. So we need some methods to avoid this shortcomes.
Form this thin film, we can found several ring form and a gametocyte of P.falciparum.
To identify the diagnosis, some laboratory investigations are necessary. There are lots of methods to certify the malaria infection, such as QBC is a sensitive method. It stain the malaria by the fluorochrome which lights up the parasites. But this method needs the fluorescence microscope, which restrict its application. Rapid diagnostic tests are also immunochromatographic tests that detect malaria-specifc antigens in a finger-prick blood sample. It’s simple, sensitive and could be used in difficult conditions. Serology test include ELISA and IFA by detecting the specific antigen or antibody. But the antibodies are not detectable until 3-4wk after infection, so the method basing the antibodies detecting will be more appropriate in epidemiological investigations. Molecular investigation are mostly based on the PCR technique to detect the malaria DNA. It is more accurate, sensitive and specific for all 4 species of plasmodium. Other:total blood cell counts, blood chemical tests of liver function and renal function.
The differential diagnosis refers to two parts: the one is infectious diseases, and the other is non-infectious diseases. With the epidemiological history, typical clinical manifestation and blood film or serological test and so on, the differentiation will not be difficult.
If the patients are properly treated in early stage, malaria can be cured completely. But in hyperendemic areas the local residents may be infected repeatedly, recover with partial immunity and result in chroic malaria. The malaria had killed up to 15%~20% children<5y in africa.
A succesful treatment consists of Symptomatic/supportive measures and antimalarial treatment. The Symptomatic/supportive measures refer to the therapy to relive high fever, necessary blood transfusion in patients with anemia, heodialysis when renal failure happens, Intravenous injection to sustain fluid balance and so on. For a infectious disease, most important is the etiological therapy, antimalarial treatment.
There are several kinds of durgs for antimalarial treatment. Each durg has their own target and have different effects. To prevent a infection when you are traveling in endemic area, you should use tissue schizonticides, The pyrimethamine and primaquine can be your choices. In clinical practice, we use blood schizonticides. They kill the parasite in RBCs and reduce the damage of RBC to terminate the malaria attacks. There are a lot of drugs can be chosen, such as Chloroquine , Artemisinine , Quinine, Mefloquine, Halofantrine, Pyrimethamine, Sulfadoxine, Sulfones, Tetracyclines, Doxycycline. By killing the bradysporozoites or hypnozoites in the liver we can prevent relapse of p. ovale and vivax. The primaquine and tafenoquine can do this.At the same time, we should avoid the diagnosed patient became the source of tansmission, we can do this by killing the gemetocyte in the patients. primaquine,Chloroquine, Quinine, Artemisinine. Primaquine and proguanil can also prevent the development of oocyst in the mosquito to ablate transmission of mosquito.
In clinical practice, we usually use two kinds of durgs for treatment of malaria.
The first effective treatment for malaria came from the bark of cinchona tree , which contains quinine . A tincture made of this natural product was used by the inhabitants of Peru to control malaria, and was introduced to Europe during the 1640s, where it was rapidly accepted. However, it was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists
Chloroquine is very cheap and, until recently, was very effective, which made it the antimalarial drug of choice for many years in most parts of the world. However, resistance of Plasmodium falciparum to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous Plasmodium strain in many affected regions of the world.In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as quinine and amodiaquine . [75]
The chloroquine resistant malaria has been found in most endemic area. There are some multi-resistant malaria in south asia.
To cut off the route of transmission, we should control the vector-anopheles mosquitoes. We can kill them by insecticide spraying and avoid the multiply of them by Meanwhile, we must protect ourselves from bitten by anopheles mosquitoes. We can used Mosquito nets, repellents to drive mosquitoes away, and should dress clothes with long sleeves rather than short pants or short-sleeved shirts especially when we are outdoors.
The picture shows the link can be explored to be the targets of vaccine.
![Malaria ,[object Object],[object Object],Still an enormous pubic health problem and one of the most common infectious diseases.](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)