MALARIA

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Malaria is an insect-transmitted parasitic disease characterized by recurrent episodes of fever and anaemia (loss of blood) in some cases caused by the Plasmodium species which is usually transmitted between mammals through the bite of the female Anopheles mosquito. It is a disease condition in human beings whereby there is an abnormally high body temperature and shivering (or cold) which generally affects the activeness of the affected individual. Malaria is one of the world’s deadliest vector-borne diseases that affect tropical regions of the world especially the sub-Saharan African continent where the disease burden is high. Vector-borne diseases are infectious diseases carried by other living organisms including mosquitoes, sand flies, ticks and water snails amongst others; and these diseases thrive predominantly in communities where environmental sanitation and living standards of the people are poor.

Vectors are living organisms that can transmit infectious diseases or infectious disease agents (parasites) between human beings and from animals to humans. A variety of vectors are blood-sucking in nature and this implies that they feed on human or animal blood during which they ingest pathogenic microorganism(s) that they transfer or inject into the body of susceptible human hosts when they feed on their blood. Typical example is the female Anopheles mosquito that feeds on human blood and ingests Plasmodium parasites (the causative agent of malaria) during the blood meal. The mosquito vector (in this case the female Anopheles mosquito) injects the ingested Plasmodium parasite into a new human host during their next blood meal, and this causes malaria in the later individual.

Malaria is by-far one of the world’s biggest killer infectious disease among the various vector-borne diseases in man. Other killer vector-borne diseases includes Onchocerciasis, Schistosomiasis, Yellow fever, Dengue fever, Leishmaniasis and Chagas disease. Malaria to a great extent represents one of the world’s greatest public health problems, and it accounts for a high percentage of morbidity and mortality across the globe especially in subtropical and tropical countries as aforementioned. Historically, the disease is believed to have affected monkey and ape populations in Asia and Africa; from which it was transmitted to human populations. Malaria which was derived from an Italian word that means “Bad or spoiled Air” was first discovered by Charles Laveran (a French army surgeon) in 1880 from the blood of a soldier suffering from the disease.Malaria is a disease condition caused by the bites from infected small flying, biting and sucking insects called mosquito. Particularly, the female Anopheles mosquito (a mosquito species responsible for biting and blood sucking) which feeds only on blood meal of animals (humans inclusive) is the vector that helps to transmit the parasite to humans especially after a successful blood meal. Ronald Ross was the first in 1877 to observe the parasitic forms of Plasmodium in the stomach cells of mosquito. This groundbreaking discovery in the malaria epidemic set the landmark for the definition of the different stages of the malaria disease episode (pre-erythrocytic, erythrocytic and sporogonic cycles) in both the mosquito vector and human host. The parasite responsible for the disease is known to live in the erythrocyte (red blood cells) of infected human hosts that has been previously bitten by the mosquito carrying the Plasmodium parasite.

Malaria is a disease that occurs predominantly in the tropical and subtropical regions of the world (Asia and Africa specifically), and it sometimes causes recurrent infections in millions of children and even adults in this part of the world. Despite global and national control strategies for malaria infection, coupled with the development of novel antimalarial drugs, the disease burden of Plasmodium malarial infection still persist. Plethora of programmes including the Roll back Malaria Initiative of the United Nations have all been geared towards finding a lasting solution to the malaria pandemic, yet total cure for the scourge is still far from reach. Though several effective treatment measures are available for malaria infection, the disease still remains a significant human illness worldwide. Malaria is a major global public health problem, and it is adjudged to be by far one of the most important tropical diseases, causing great pain, suffering and even death to people in the tropic and subtropical regions of the world (Nigeria for example). Other parasitic diseases that are of great concern especially in Africa (which has had its fair share of the malady) according to the Tropical Disease Research (TDR) department of the World Health Organization (WHO) includes: Onchocerciasis, schistosomiasis, filariasis, trypanosomiasis and Leishmania. Together, these diseases (malaria inclusive) affect over 500 million people across the globe. Tropical Africa is endemic with malaria, and the disease according to the World Health Organization (WHO) affects about 350 million people worldwide. Each year over one million of these people die from the disease (according to WHO); and this has made the sickness one of the world’s leading cause of death.

HUMAN PLASMODIUM SPECIES

Malaria in humans is majorly caused by four (4) species of Plasmodium. Plasmodium species are in the Phylum Alveolata, Subphylum Apicomplexa, Class Haematozoa,Order Haemosporida, and Genus Plasmodium. Plasmodium parasite is naturally transmitted to susceptible human hosts from an insect vector called female Anopheles mosquito. The 4 major and well known infectious species of Plasmodium that cause malaria in humans are:

  1. Plasmodium falciparum
  2. Plasmodium vivax
  3. Plasmodium malariae
  4. Plasmodium ovale

Of these four species, P. falciparum is known to be extremely harmful and most aggressive of them all. P. falciparum it accounts for the main global burden of malaria. The genus Plasmodium is classified as a blood sporozoan. Species of parasites classified as sporozoa (singular: sporozoan)are known to undergo a complex form of life cycle with alternating asexual and sexual reproductive stages that usually occur in two different hosts (a human and an arthropod). Other examples of blood sporozoan includes: Toxoplasma gondii, Isospora belli, and Cryptosporidium.

Plasmodium species can also cause fever-like illnesses in rodents, but the species responsible for malaria in these animals are quite different from those that cause malaria in humans. The rodent malaria parasites are as follows:

  1. Plasmodium yoelii
  2. Plasmodium vinckei
  3. Plasmodium berghei
  4. Plasmodium chabaudi
  5. Plasmodium knowlesi is parasitic in monkeys.  

PATHOGENESIS AND LIFE CYCLE OF THE MALARIA PARASITE (PLASMODIUM)

Inside the human body, the Plasmodium parasite attacks the liver cells which are their first spot of call upon invasion. They penetrate into the liver cells and destroy the cells in which they reside (including the red blood cells). Anaemic conditions (i.e. shortage of blood in the human host) may arise since the Plasmodium parasitedestroyssome liver cells and many erythrocytes (red blood cells). This condition can lead to death following the drastic reduction in oxygen supply, hormonal circulation, and nutrient (food) circulation to cells of the body. The Plasmodium parasite is usually picked and ingested by the insect vector during a blood meal in which it ingests viable plasmodial gametocytes that develops in the insect’s gut (Figure 1). This eventually transforms into the infective forms (sporozoites) that appears in the vector’s salivary gland and is passed on to uninfected human host during the insect’s next blood meal. After inoculation by the female anopheles mosquito, the Plasmodium parasites mature first in the liver of the human host  for a period of about one week before it goes on to complete its multiplication in the red blood cell. This continues until it reaches levels that cause fever (a rise in body temperature) and a wide variety of clinical signs and symptoms in the infected host. The spleen is another vital organ which plays an important role in malaria disease because it is known to confer some level of immunity or protection against malaria to the host. The spleen usually enlarges during acute malaria as it helps to remove erythrocytes that have been invaded by Plasmodium parasites. Malaria disease causes a high mortality in asplenic individuals (those whose spleen has been surgically removed); and such individuals stand a high risk of P. falciparum infection because there spleen is no longer there to perform its usual flushing and cleansing action.

Figure 1. Life cycle of Plasmodium. 1. Malaria-infected female Anopheles mosquito inoculates sporozoites into the human host. 2. Sporozoites infect liver cells 3. And mature into schizonts 4. Schizonts rupture and releases merozoites 5. Merozoitesinfect red blood cells. 6. Ring stage trophozoites mature into schizonts, which rupture releasing merozoites. 7. Some parasites differentiate into gametocytes (sexual erythrocytic stage). 8. Gametocytes (microgametocytes and macrogametocytes) are ingested by a female Anopheles mosquito during a blood meal. 9. The microgametocytes (male gametes) penetrate the macrogametocytes (female gametes) to generate zygotes in the mosquito’s stomach (midgut). 10. The zygote transforms to ookinetes (motile and elongated zygotes). 11. Ookinetes invade the midgut wall of the female Anopheles mosquito and develop into oocysts. 12. Oocysts grow, rupture, and releases sporozoites that move to the mosquito’s salivary gland until the next blood meal. The life cycle of malaria is perpetuated when the sporozoites in the salivary gland of the female Anopheles mosquito is transferred to a new human host during a blood meal. CDC

STAGES OF MALARIA PARASITE (PLASMODIUM) INFECTION

  1. Pre-erythrocytic stage: Pre-erythrocytic stage which can also be called the exo-erythrocytic cycle is the first stage of Plasmodium parasite development in humans, and it occurs inside the cells of the liver (hepatocytes). It is the stage of the Plasmodium parasite development that occurs in the liver cells of the human host (outside the red blood cells) immediately after the introduction or inoculation of sporozoites (infective stage of Plasmodium parasite) into the human blood stream after the bite of an infected female Anopheles mosquito. In this stage, the Plasmodium parasite only multiplies in the hepatocytes of the human liver. After a successful blood meal (or bite from a female Anopheles mosquito), sporozoites leaves the salivary gland of the mosquito and find their way to the bloodstream of the human host where they circulate for a little time period before attacking or entering the hepatocytes. The infection of the liver cells (hepatic infection) in humans is usually asymptomatic (i.e. without any fever or cold), and this may last for several days. The sporozoites remain in the hepatocytes for about 10 days for replication and, eventually mature into schizonts. Upon the rupturing of the schizonts in the hepatocytes, thousands of merozoites are released into the human bloodstream. This marks the beginning of the erythrocytic stage (i.e. the invasion of the red blood cells). It is noteworthy that relapsing fever (or recurrent malaria infection) can also occur in humans after successful treatment, when the dormant stage (hypnozoites) of some Plasmodium species (in particular: sporozoites of P. vivax and P. ovale) persist in the liver; and in turn invade the erythrocytes to cause relapsing fever weeks or years later. The merozoites do not return again to the liver cells from the bloodstream after its departure or release from hepatocytes. This implies that malaria infection (P. falciparum infection) can naturally terminate without any therapy in a year except the disease ends in the death of the sufferer. 
  • Erythrocytic stage: Erythrocytic stage is the phase of Plasmodium parasite invasion into the red blood cells (RBCs), and which usually marks the clinical manifestation of the malaria disease. It is the stage where the Plasmodium manifests itself in the bloodstream with several nuclear division and replication. The erythrocytic stage usually has two phases: the asexual stage (where schizogony are formed) and sexual stage (where gametocytes are formed).  The asexual stage is marked by the invasion of the erythrocyte by merozoites after their release from the liver cells. The Plasmodium parasite undergo asexual multiplication in the erythrocytes (this is known as erythrocytic schizogony), and the merozoites mature inside the RBCs from a ring to a mature trophozoite. The ring stage trophozoites then undergo asexual division (schizogony) to form schizonts that ruptures to release more merozoites. The rupturing of schizonts marks the start of malaria symptoms in the human host following the action of the Plasmodium parasite on the host’s cells to release cytokines. This cycle is repeated for approximately 48 hours (for P. falciparum, P. vivax, and P. ovale) or 72 hours (for P. malariae) and parasitaemia continues depending on the infecting Plasmodium parasite. Sexual stage in the human host is usually characterized by the entering of some parasite merozoites into the erythrocytes. These merozoites later differentiate into male gametocytes (microgametocytes) and female gametocytes (macrogametocytes). This marks the beginning of the sexual phase in the human host, but this sexual stage of the Plasmodium development is not completed in humans but in the insect vector. This occurs when the gametocytes (male and female) are picked up and ingested by female Anopheles mosquitoes during a blood meal; and this ingestion allows the insect vector to continue the transmission of the Plasmodium parasite to susceptible human hosts as it sucks and feed on their blood. It is noteworthy that not all merozoites released from RBCs can go on to infect other erythrocytes. The gametocytes (which are offshoots of merozoites) cannot infect the erythrocytes but rather infects only mosquitoes.    
  • Sporogonic stage: The sporogonic phase occurs solely in the female Anopheles mosquito, and it is characterized by the multiplication of the Plasmodium parasite in the midgut (stomach) of the insect vector. This stage in the Plasmodium parasite life cycle begins immediately after the ingestion of the gametocytes by the female anopheles mosquito during a blood meal. Inside the stomach of the mosquito, the male and female gametocytes undergo fertilization (usually meiosis and fusion of both cells) to form a zygote which later transforms into a motile and elongated form called ookinete. The ookinete enters the midgut wall of the mosquito’s stomach where they later develop into oocysts. The Plasmodium parasite usually takes about 10-35 days to develop within the insect vector (and this stage is called sporogony). The oocysts mature and rupture to release plenty of sporozoites which migrate to the salivary glands of the female Anopheles mosquito where they wait to be transmitted to a susceptible human host during a blood meal. The life cycle of the Plasmodium parasite infection (malaria episode) becomes completed when the sporozoites successfully gain entry into the vascular system of a human host during a blood meal.  

GENETICS AND MOLECULAR BASIS OF ERYTHROCYTE INVASION BY PLASMODIUM

Plasmodium parasites are intracellular protozoa that have an intracellular existence within their affected host cells. Their ability to enter and modify the cellular and molecular mechanisms of their host cells is very advantageous to the Plasmodium parasites as this phenomenon gives them an edge to evade the host immune attack. Merozoites, sporozoites and ookinetes are the three characteristic invasive forms of Plasmodium parasites. While merozoites occur at the blood stages of the Plasmodium parasite (erythrocytic and pre-erythrocytic stages inclusive), both the sporozoites and the ookinetes occur at the mosquito stage of the life cycle of Plasmodium species. The intimate host-parasite relationship that exist between Plasmodium parasites and their human hosts allows them to acquire virtually all the nutrients, macromolecules and other biochemicals required for both anabolic and catabolic reactions from their human host. Thus, Plasmodium parasites have a distinct metabolic pathway from that of their human hosts, and as such could be exploited in the design for novel antimalarial drugs to contain the disease (malaria) that they cause.

SIGNS AND SYMPTOMS OF MALARIA

Malaria is usually accompanied with some specific symptoms, and these include: fever that reaches 40oC or more, chills or cold, headache, nausea, fatigue, vomiting, diarrhea, occasional cough, abdominal pain, splenomegaly (enlargement of the spleen), hepatomegaly (enlargement of the liver), jaundice, chest pain, and myalgia (muscle pain).  Loss of appetite and bitterness of the mouth can also be experienced by some patients. Malaria symptoms are usually manifested in a human host following the rupturing of the red blood cells (erythrocytes) to release erythrocyte schizonts. This action triggers immune response in the host which leads to the formation of cytokines and other immune system products that spark up an inflammatory action that usually results to the chills and fever experienced by the individual. It is noteworthy that the clinical manifestation of malaria is ushered in following the invasion of the erythrocyte by the Plasmodium parasite.  

FACTORS THAT AFFECT THE RESULT OF MALARIA DIAGNOSIS

The clinical and laboratory diagnosis of malaria is challenging to health practitioners, physicians and scientists alike owing to some diagnostic complexity associated with the disease. Malaria is a febrile infection that usually presents clinically with signs and symptoms that are significantly related to other feverish infections (of bacterial or viral origin) common in most tropical regions where the disease is widespread. To detect the parasite and administer therapy to the affected patient appropriately, it is vital that scientist take into consideration some of the prevailing factors that affect the reliability of malaria test results. Some of these factors which commonly promote the indiscriminate use of antimalarial drugs (a cause for emergence and spread of resistant Plasmodium strains) and hold back the specificity of identifying and correctly interpreting malaria parasitaemia diagnostic test results include:

  1. Administration of antimalarial drugs based only on clinical diagnosis.
  2. Presence of persisting viable or non-viable Plasmodium parasites in blood.
  3. Drug resistance of some Plasmodium species.
  4. Sequestration of Plasmodium parasites in host tissues.
  5. Movement of people from malaria-endemic regions to non-endemic areas and vice-versa.
  6. Endemicity of some Plasmodium species in some regions (P. falciparum in sub-Saharan Africa).
  7. Signs and symptoms, and diagnosis of malaria infection.
  8. Issues arising from reporting non-malarial febrile infections as malaria in endemic regions (Africa and Asia).

LABORATORY DIAGNOSIS OF MALARIA

Aside, laboratory diagnosis, clinical diagnosis of malaria is often practiced in some quarters to diagnose the disease but this practice is not versatile (though traditional amongst most physicians) due to its non-specificity and the possibility of missing out other febrile non-malarial infections in the process. The diagnosis of malaria in the hospital or laboratory is usually suspected when patients present with febrile conditions. Usually venous blood or capillary blood specimens are obtained from affected patients, and these are examined microscopically in the laboratory. The diagnosis of malaria infection normally begins with the identification of Plasmodium parasites in the blood smears of patients. Thick and thin blood smears are usually made using the Giemsa staining technique. The ring forms of Plasmodium species as well as their trophozoites and gametocytes are often among the key features of the Plasmodium parasite looked for when performing microscopy on blood smears for detection of malaria parasitaemia. The ring forms of Plasmodium species (particularly P. falciparum) are morphologically endowed withcytoplasm and one or two small chromatin dots; and P. falciparum gametocytes usually assumes a crescent or sausage shape when observed under the microscope (Figure 2).

The trophozoites of P. falciparum assumes an amoeboid shape (Figure 3), and they are rarely seen in peripheral blood smears.  While the thin blood smear helps to differentiate the different species of Plasmodium parasites, the thick blood film preparation helps to concentrate the parasite and help to detect mild cases of malaria parasitaemia. Serological techniques which involve the use of rapid diagnostic tests (containing monoclonal antibodies) to detect specific Plasmodium parasite antigens from blood specimens have also been introduced in malaria laboratory diagnosis. Most recently in the diagnosis of malaria parasitaemia is the use of molecular detection techniques including gene amplification methods, polymerase chain reaction (PCR) and nucleic acid probes to detect malaria parasites from blood specimens of patients. However, the Giemsa staining technique involving thick and thin blood films is still being used in most part of the developing nations as the primary diagnostic protocol for malaria parasitaemia. Abnormal liver function tests and an elevated lactate dehydrogenase tests coupled with low haemoglobin levels should also raise suspicion of malaria parasitaemia.  

Figure 2. Gametocytes of P. falciparum (arrows) in thin (A) and thick (B) blood smear. CDC
Figure 3. Ring forms or trophozoites (arrows) of P. falciparum in thick (A) and thin (B) blood smear. CDC

OVERVIEW OF PROTOCOLS USED FOR THE DIAGNOSIS OF MALARIA

  • Microscopy: Microscopy is still the gold standard for the laboratory diagnosis of malaria infection in many parts of the world where the disease occurs. It usually involves the microscopical investigation of peripheral blood smear (PBS) – which can either be a thick smear (for parasite detection) or thin smear (for parasite-species identification). All the four species of Plasmodium i.e. P. falciparum (Figure 4), P. malariae(Figure 5), P. ovale (Figure 6) and P. vivax (Figure 7) that causes malaria in humans appear differently under the microscope when a thick blood smear is made and examined. And these morphological appearances of the Plasmodium species aids in their identification in the laboratory. Microscopic technique though very relevant in the laboratory diagnosis of malaria is laborious, time-consuming and parasite-specie identification at low levels of parasitaemia is very challenging. This method requires well trained personnel for optimum result. Briefly, two types of blood specimens may be required for laboratory detection of malaria parasites using the microscopy technique: capillary blood obtained by fingerstick and venous blood obtained by venipuncture. To obtain capillary blood, clean the middle or ring finger of the patient with 70 % alcohol; allow to dry. Puncture the ball of the finger and wipe away the first drop with a clean cotton wool. For infants, the heel is usually punctured to obtain venous blood. Touch the next drop of blood with the center of a clean glass labeled slide. Venous blood is usually obtained in an EDTA bottle after drawing blood from the patient using a sterile string. For thin blood smear, place a drop of the blood at one end of a clean glass slide, and use another slide to push and spread the blood forward in a smooth and rapid fashion. For thick blood smear, place a drop of blood at the center of a clean glass slide, and use the edge of another slide to spread the blood in a circular fashion while making sure not to make it too thick. Allow the thin and thick blood smears to dry properly before staining. Thin blood smear is fixed with methanol prior to staining but thick blood smear is not fixed before staining.
Figure 4. Illustration of the morphological features of P. falciparum in a thick smear. 1. Small trophozoites. 2. Gametocytes (normal). 3. Slightly distorted gametocyte. 4. Rounded-up gametocyte. 5. Disintegrated gametocyte. 6. Nucleus of leukocyte. 7. Blood platelets. 8. Cellular remains of young erythrocyte. CDC.
Figure 5. Illustration of the morphological features of P. malariae in a thick smear. 1. Small trophozoites. 2. Growing trophozoites. 3. Mature trophozoites. 4, 5, 6. Immature schizonts with varying numbers of divisions of the chromatin. 7. Mature schizonts. 8. Nucleus of leukocyte. 9. Blood platelets. 10. Cellular remains of young erythrocytes. CDC
Figure 6. Illustration of the morphological features of P. ovale in a thick smear. 1. Small trophozoites. 2. Growing trophozoites. 3. Mature trophozoites. 4. Schizonts. 5. Gametocytes. 6. Nucleus of leukocyte. 7. Blood platelets. CDC
Figure 7. Illustration of the morphological features of P. vivax in a thick smear. 1. Amoeboid trophozoites. 2. Schizont- 2 divisions of chromatin. 3. Mature schizonts. 4. Microgametocyte. 5. Blood platelets. 6. Nucleus of neutrophil. 7. Eosinophil. 8. Blood platelets associated with cellular remains of young erythrocytes. CDC    

Note: Allow the fixed thin film to dry before staining. Giemsa stain is usually used for staining blood smears required for detection of Plasmodium parasites, and stained smears are viewed under oil immersion objective lens. In thin smear preparations, the morphological appearances of the components of the Plasmodium species i.e. P. falciparum (Figure 8), P. malariae(Figure 9), P. ovale (Figure 10) and P. vivax (Figure 11) also differ slightly from their appearances in a thick smear preparation. 

Figure 8. Illustration of the morphological appearance of P. falciparum in a thin smear preparation. 1. Normal red cell. 2-18. Trophozoites (Note: image2-10 shows the ring-stage trophozoites). 19-26. Schizonts (Note: image26 is a ruptured schizont). 27, 28. Mature macrogametocytes (female). 29, 30. Mature microgametocytes (male). CDC. 
Figure 9. Illustration of the morphological appearance of P. malariae in a thin smear preparation. 1. Normal red cell. 2-5. Young trophozoites (rings). 6-13. Trophozoites. 14-22. Schizonts. 23. Developing gametocyte. 24. Macrogametocyte (female). 25. Microgametocyte (male). CDC. 
Figure 10. Illustration of the morphological appearance of P. vivax in a thin smear preparation. 1. Normal red cell. 2-6. Young trophozoites (ring stage parasites). 7-18. Trophozoites. 19-27. Schizonts. 28, 29. Macrogametocytes (female). 30. Microgametocyte (male). CDC.
Figure 11. Illustration of the morphological appearance of P. ovale in a thin smear preparation. 1. Normal red cell. 2-5. Young trophozoites (ring). 6-15. Trophozoites. 16-23. Schizonts. 24. Macrogametocytes (female). 25. Microgametocytes (male). CDC.  
  • Rapid diagnostic tests (RDTs): RDTs are immunochromatographic techniques that employ specialized malaria detection test kits for the laboratory diagnosis of malaria infection. They are easy to use and very reliable in the prompt detection of malaria parasites from patient’s specimens. Unlike the microscopic technique, RDTs does not require any specialized training as they can be used based on the manufacturers instruction. RDTs are cost-effective and they were developed to take care of some of the lapses associated with microscopy such as time wastage and inability to detect parasites at low levels of parasitaemia. Some of the commercially available RDTs include ParaSight F, ICT Malaria Pf, and OptiMAL amongst others.
  • Quantitative Buffy Coat (QBC): The QBC technique is a centrifugation method used for the laboratory diagnosis of malaria infection. In this method, blood specimens are centrifuged in specialized tubes (e.g. haematocrit tubes) containing anticoagulant such as EDTA and acridine orange. After centrifugation, the tubes are examined under a fluorescent microscope to detect Plasmodium nuclei or DNA and other parasite components. The acridine orange stains the DNA of the parasite during centrifugation, and it appears as a fluorescing bright-green matter under the fluorescent microscope. The cytoplasm appears as a yellow-orange matter. QBC technique is not versatile in the laboratory detection of malaria infection due to its high cost and inability or poor performance to detect parasite species and numbers.      
  • Serology: Serological tests have also been employed in the laboratory diagnosis of malaria infection. They are mainly based on the detection of specific antibodies produced against the malaria parasite in the blood (serum) of infected individuals. Immunoflourescence antibody testing (IFA) which employs antigen-antibody reactions is one of the versatile methods used in most serological tests.
  • Polymerase Chain Reaction (PCR): PCR is the most sensitive and specific technique for the diagnosis of malaria infection as it can differentiate between mixed infection and actual malaria infection. Unlike other techniques, PCR can detect malarial parasites at very low levels of parasitaemia at the molecular level. However, its usage for the routine diagnosis of malaria in most malaria-endemic regions has been limited by unavailability of specialized trained personnel, high cost of purchase and maintenance, and its mode of operation is more complex than the microscopic technique and other methods used for the laboratory diagnosis of malaria infection.
  • Other tests: Most traditional methods of diagnosing malaria though versatile and inexpensive to perform are usually problematic and challenging. Some of these methods (for example clinical diagnosis) are unreliable while others require a well trained health personnel and equipments which may be lacking in some local communities where the incidence of malaria infection is high. Prompt detection and diagnosis of malaria infection in places where Plasmodium parasite transmission is widespread is vital to the reduction of the morbidity and mortality due to the disease. The challenges associated with some of the traditional methods of diagnosis and detecting malaria parasites in the laboratory and clinical settings have stepped up the need for newer and better detection protocols with high specificity and sensitivity for parasite detection. These newer techniques used for the diagnosis of malaria infection detect malaria parasites from patient’s specimens at the molecular level; and they include: real-time PCR technique, reverse transcription PCR, nested PCR, and DNA microarrays. Though very reliable, specific and sensitive in detecting malaria parasites from patient’s specimen; some of these techniques are not versatile and available for the routine diagnosis of malaria infections in most regions of developing countries where the disease is prevalent. They require specialized trained personnel and high cost of maintenance. Thus, some of these techniques are only practiced or used in reference laboratories for the detection of malaria parasites. ELISA, parasite culture techniques, enzyme immunoassay, flow cytometry, LAMP technique and mass spectrophotometry are other non-molecular techniques which are currently been employed for the prompt detection and diagnosis of malaria infection.      

SOME TERMINOLOGIES USED IN PLASMODIUM INFECTION

  1. Sporozoite: Sporozoite is the infectious form of Plasmodium parasite, which is injected into humans by the bite of female Anopheles mosquitoes.
  2. Merozoite: Merozoite is the form of the Plasmodium parasite that invades the red blood cells immediately after its release from the rupturing of schizonts in the liver cells.
  3. Oocyst: Oocyst is a stage of the Plasmodium parasite which is produced when male and female gametes combine within the mosquito.
  4. Gametes: Gametes are the reproductive elements of the Plasmodium parasite, and it is made up of the male and female forms.
  5. Gametocytes: Gametocytes are the precursors of the sexual forms of Plasmodium parasite, which are released as either male or female gametes within the gut or stomach of the mosquito.
  6. Microgametocytes: Microgametocytes are the male gametes of the Plasmodium parasite.
  7. Macrogametocytes: Macrogametocytes are the female gametes of the Plasmodium parasite.
  8. Haploid: Haploid cells are cells that contain a half set of the entire Plasmodium parasite chromosomes.
  9. Ookinete: Ookinete is the actively moving zygote form of the Plasmodium parasite that enters the stomach of the female Anopheles mosquito to form an oocyst under the outer lining of the mosquitoes’ gut. Ookinete is the zygote that is motile.
  10. Diploid: Diploid cells are cells that contain a full set of the Plasmodium parasitechromosomes.
  11. Zygote: Zygote is the diploid cell formed when the male gamete (microgametocyte) and a female gamete (macrogametocyte) fuse or join together.

FACTORS THAT AFFECT TRANSMISSION OF MALARIA

Environmental factors greatly enhances the spread and transmission of malaria because these climatic factors which are more prone in one part of the world than the other helps the female Anopheles mosquito (that harbours the Plasmodium parasite) to thrive and multiply successfully. The spread of malaria infection in a given population is controlled and affected by certainphysical and biologicalenvironmental factors. These factors either help to increase or reduce the spread and transmission of the disease. These environmental factors which aid or abate the spread and transmission of malaria parasitaemia in a population include climatic factors such as vegetation, rainfall, temperature, and humidity; and biological factors which affect the spread of the parasite.   

  1. Climatic factors: Climatic factors are physical environmental factors that influence the spread and transmission of malaria, and they include vegetation, rainfall, humidity, and temperature. The climate of an area is the average condition of that place over a long time period. The climate of a given geographical area plays significant role in the spread and transmission of malaria. The climatic conditions of a geographical area are always taken into consideration in the epidemiological study of malaria parasitaemia. It gives a clue to the researchers as to why the disease is increasing or abating. Malaria is usually a disease of the tropic and subtropical regions of the world, where the climatic condition is characterized by warmth or hotness. These regions are usually adorned with two seasons which are the dry (harmattan) and wet (rainy) seasons. In other parts of the world (i.e. in the temperate zones), for example, the Antarctic, polar and arctic zones; the weather condition is usually cold and is characterized by four different seasons including: winter, autumn, summer and spring.
  • Vegetation: Vegetation is the sum total of plant species (or fauna) found in a particular area at any given time. The distribution of vegetation in a particular area plays key role in the spread and transmission of malaria. The mosquito that transmits the malaria parasites thrives more in areas with high vegetation because such places serve as hideouts for them to lay their eggs and escape possible destruction from humans. Malaria is prominent in swampy and rainforest areas than in the deserts or savanna because swampy and rainforest areas provide stagnant water and vegetation that supports the life cycle of the mosquitoes. It is noteworthy that mosquito lay their eggs in stagnant water which are common in swampy and rainforest areas. But in the deserts and savanna, which are usually dry, there will be no hideouts for the mosquitoes or stagnant water for them to lay their eggs. Thus, arid areas such as deserts and savanna experience low rates of malaria infection while the rainforests and swampy areas are burdened with high rates of malaria disease due to the relatively high amount of vegetation (including trees) that characterize such habitats. Phytoplanktons are aquatic plants which serve as source of food to the larva of mosquitoes. Some vegetation produces nectar (a sugary substance) which serves as food to male Anopheles mosquitoes. Clearing of vegetation around residential areas can help to reduce the number of mosquitoes in those areas. The removal of trees, grasses, shrubs and other vegetations around residential areas also influences the spread and transmission of malaria since this practice help to eliminate breeding and resting sites of the insect vector that transmits the parasite which causes the diseases.
  • Rainfall: Rainfall is the amount of water that falls in droplets from condensed vapour in the atmosphere. The degree of rainfall coupled with the amount of water in a given area is significant to the rate of spread and transmission of malaria parasites in that geographical location. The insect vector (female Anopheles mosquito) that transmits Plasmodium parasite which causes malaria in humans lays its eggs in water bodies, and this can only be successful in areas that experience high rate of rainfall at any given time. Therefore, there are lesser insect vectors for malaria parasites in the arid zones than in the swampy and rainforests zones where high amount of rainfall provides the required water bodies necessary to flourish the mosquito life cycle. There is massive malaria infection in areas that experience high amount of rainfall compared to desert areas where rainfall is usually very low. Emptying containers that store water and draining of drainages can help to reduce the number of mosquitoes that transmit Plasmodium parasites, because the insect vectors will not find a place to lay their eggs.
  • Temperature: Temperature is the degree of hotness or coldness of a particular environment at any given time. In temperate zones, where the temperature is usually low, there is freezing of water bodies, and this makes it difficult for the mosquito larva and pupa to thrive. Such cold regions make it difficult for adult mosquitoes to be active, and this accounts for the low infestation and low malaria parasitaemia in these zones. Warm and hot regions of the world (tropics and subtropics) are good breeding grounds or habitat for mosquitoes. The water bodies in these zones do not freeze as is the case in temperate zones, and this allows the larva and pupa of the mosquito to survive and produce the adult mosquito which transmits and spread the Plasmodium parasites. The warm environment in the tropic and subtropical zones also allow the mosquito to be active in its breeding and blood sucking activities. High temperatures also favour the development of the different stages of the Plasmodium parasite within the female Anopheles mosquito.
  • Humidity: Humidity is the wetness of the atmosphere of a place at any given time. It increases following increased amount of rainfall in a given geographical area. Humidity also play key role in the spread and transmission of malaria disease in a given geographical zone. Blood sucking female Anopheles mosquitoes are more active in high humidity areas than in relatively low humidity zones. High humidity which creates moist and wet environments also favours the development of the malaria parasite within the body of the insect vector, and also it increases the number of blood sucking mosquitoes in a given area since conditions allows adult mosquitoes to undergo fertilization and lay their eggs. 
  • Biological factors: Biological factors are other factors aside physical (climatic) factors       that influence the spread and transmission of malaria disease within a given geographical         area. Some of the biological factors that affect malaria transmission include:
  • Food availability for the insect vector.
  • Large production of eggs by the insect vector.
  • Availability of long limbs which allows them to settle on the body of human host and suck blood almost unnoticed.
  • Building of damns and lakes which provide stagnant water for insect vector to thrive in their breeding activities.
  • Agricultural activities of man such as building of fish ponds and irrigation which provides stagnant water that allows the insect vector to lay their eggs and continue their life cycle. 

EPIDEMIOLOGY OF MALARIA

Malaria is increasing at a worrying rate compared to the other blood and tissue parasitic infections. According to the World Health Organization (WHO), malaria accounts for one of the most causes of death due to infectious diseases worldwide, and the malady affects an estimated 350 million people around the globe with over a million people dying from the disease yearly. The disease has been in different phases of control, elimination, pre-elimination and prevention of a reintroduction. Some regions have been certified malaria free and have no transmission of the disease for over a decade. But in other regions, especially in Africa, malaria infection is still persistent, and several control and preventive measures for the disease are currently ongoing in order to put the region on the part of some countries that have sustainable localized malaria-free projects, and are fast achieving a pre-elimination and total elimination of the disease in their countries (China, Yemen, Philippines, Solomon Island, Vanuatu and Sudan). Though there still abound several effective therapy, prevention and control measures for malaria infection in Africa and some parts of Asia, the disease still remains an important human infection whose total cure and possible vaccine development is yet to be achieved in order to put the continents on the path of other countries that are already malaria-free.

Epidemiologically, the Plasmodium parasite and its insect vector (female anopheles mosquito) that help in transmitting it to susceptible human host live predominantly in the subtropical and tropical regions of the world (Africa and Asia). The disease has also been reported in southern America where there abound abundant mosquito habitat, while there has been very little of no cases from the North American region. Wet-low lying areas are good breeding sites for the female Anopheles mosquito that helps in transmitting this human dreaded disease. About 40 % of the world’s population lives in malarious countries with about 90 % of malaria infections occurring in the subtropics and tropical parts of the world especially in the sub-Saharan Africa. However, major regions in Asia, Oceania, the Caribbean’s and the Americas (South and Central parts) are also affected by the disease. Also, it has been estimated that the disease kills about one million people annually including children who are under the age of five (5) years.

Malaria is usually limited to the tropical and subtropical countries of the world (as shown in the map above). However, increased globalization coupled with the prevalent global/climatic changes on earth has made the infection to be reported in some non-tropical parts of the world though in limited cases. Malaria has been regarded as a disease of poverty, poor hygiene, sanitation and malnutrition in some quarters; but the primary route or source of the disease is through the bite of an infected female Anopheles mosquito which usually breeds and thrives in dirty environments. Generally, malaria disease is not a disease of temperate regions but rather a disease that is associated with wet low-lying areas (the tropics and subtropical countries) where the female anopheles mosquito that primarily harbours the Plasmodium parasite can breed. Such habitat or environmental conditions (ambient temperatures of about 30oC and very high humidity) provide the best conditions for the insect vector of the parasite to thrive, and this also aids the transmission of the disease too.

Nevertheless, malaria has been reported in some areas such as the USA, UK and even Turkey where both the disease and insect vector was previously cleared. Malaria in such places is usually due to the exposure of non-immune individuals or populations; and when it occurs the malady can be easily controlled unlike in the tropical and subtropical countries where control is still arcane. Also, malaria infection in areas such as the USA which are known to be very low in terms of endemicity of the disease are usually due to imported infections from travelers, soldiers or tourists returning from high endemic areas. The rapid development of resistance by the Plasmodium parasite to some readily available drugs and the breakdown in some control programs has allowed the parasite and the disease to continue in its menace almost unperturbed. Lack of resources in developing nations to contain the situation, poor and slow research and development for a malaria vaccine and possibly total cure, war that have led to the displacement of people from low endemic areas to high endemic areas, malnutrition and environmental changes has further compounded the malaria scourge worldwide. Till date, sub-Saharan Africa (for example Nigeria) still accounts for over 90% of the global malaria cases.

The transmission of malaria can either be:

  • Endemic: This occurs when there is a constant occurrence of malaria cases and transmission within a given population over a successive time period.
  • Epidemic: Malaria becomes epidemic when there is a sharp increase in the incidence of the disease in an endemic area or in a population in which the disease was previously known to occur.
  • Accidental: Accidental malaria infection occurs when the Plasmodium parasite becomes transmitted congenitally from mother to child through the placenta. This type of malaria episode can also occur during blood transfusion or organ transplant. 
  • Imported: Imported malaria occurs when the infection was acquired outside a particular area (usually one that is immune or free from the disease). Imported malaria is usually stimulated following the increased globalization and air travels that allow people to inter-phase between malaria-prone areas and non-endemic malaria populations.

TREATMENT OF MALARIA

The bite of an infected female Anopheles mosquito is required for the transmission of the Plasmodium parasite that causes malaria, thus preventing the bite of this mosquito will help to prevent the acquisition and transmission of the disease. There have been several reported cases of resistance of malaria parasites to some available antimalarial drugs even though artemisinin-based combination therapy (ACT) is still the drug of choice for malaria treatment. However, the treatment of malaria infection usually involves a series of combination therapy that incorporates one antimalarial agent and another as a way of fighting the resistance of the parasite while ensuring a better prognosis in the patient taking the medication. There are usually some variations in the treatment of malaria infection depending on the region where the infection occurred and the prevalent Plasmodium parasite in that geographical area. Thus, there abound certain national guidelines and measures adopted for the effective treatment of the disease depending on the endemicity of the disease in the region. Malaria chemotherapy usually involves the use of Artemisinin-related compounds (artesunate, artemether, and artemisinin), Quinolone-related compounds (mefloquine, chloroquine, primaquine, and quinine), Anti-folates (trimethoprim, pyrimethamine, and proguanil), and certain Antibacterial agents such as macrolides, tetracyclines, and sulphonamides which are used in combination with antimalarial drugs when malaria therapy is anticipated. Chloroquine (which was among the first antimalarial agent), which can be administered either orally or parenterally still remains the preferred drug option for all forms of malaria infection except for certain stages of P. falciparum malaria infection.

Some antimalarial drugs are contraindicated in pregnancy and even in some disease condition (cardiac disorders and disorders of the renal system), thus malaria treatment in pregnant women should be undertaken with caution to prevent fatality in the foetus or mother. Antimalarial agents that functions as folate-antagonists (proguanil) helps to block the synthesis of folate (folic acid) in Plasmodium parasites, which is an important process required by the parasite to thrive. Plasmodium parasites are incapable of utilizing pyrimidines from their human host, thus an obstruction of their innate folate synthesis machinery will automatically result to cell death due to a reduction in pyrimidines and other nitrogenous bases required for synthesis of the organism’s nucleic acid. Artemisinin-related agents are a class of drugs which were originally sourced from a Chinese herbal plant called Artemisia annua(Qinghaosu); and these drugs have been found to be effective to the different forms of malaria infection including multidrug-resistant P. falciparum malaria infection. Quinolone-related compounds (quinine) used for the treatment of malaria infection are alkaloids sourced from the bark of Cinchona tree, and they have been found to be effective against P. falciparum infection. Sulphonamides and other antibacterial agents administered in combination with other antimalarial drugs are used as prophylactics and also for the treatment of P. falciparum malaria infection. These agents usually act as folate-antagonist, as they inhibit the synthesis of folic acid by the Plasmodium parasite.

PREVENTIVE AND CONTROL MEASURES FOR MALARIA

Malaria should be controlled and prevented in human populations (especially in the subtropics and tropical regions where its dominance is evident) due to the economic and medical consequences and burden of the disease. It is a life-threatening parasitic infection that requires complete cure. Controlling malaria infection will help to reduce the morbidity and mortality due to the disease; improve mans activities; reduce and channel resources spent on malaria treatment for other useful ventures, and most of all, it will ensure a better life and future for the present and future generations of individuals in malaria endemic regions. A reduction in malaria morbidity and mortality especially amongst high-risk groups for example pregnant women, breastfeeding mothers, and children through adequate and sustainable containment of the transmission of the disease through the bite of female Anopheles mosquito is critical in malaria endemic regions. However, the world through its many malaria control and eradication programs such as the Roll Back Malaria (RBM) Programme and the rest are looking at a total eradication of the disease in those parts of the world where malaria still accounts for a high rate of morbidity and mortality amongst high-risk groups. The use of artemisinin-based combination therapy (ACT) in addition to the protection of women with intermittent preventive treatment during pregnancy (IPTp) has helped to reduce the health and economic menace of the disease in African continent. Also, the use of long-lasting insecticide-treated mosquito nets (LLITNs) and indoor residual spraying (IRS) using potent insecticides have also been recommended as preventive and control measures for the disease.

Malaria is a widespread mosquito-borne disease caused by Plasmodium parasite which is transmitted through the bite of an infected mosquito. The disease is among the leading cause of death in the tropic and subtropical parts of the world; and its prevention is dependent upon strict personal hygiene, effective chemotherapy and a holistic public health measures towards the disease. Malaria disease which already has enormous negative impact on humanity should be prevented and controlled as much as possible in order to ensure better health for people in malaria endemic countries. The total prevention and control of malaria in the subtropics and tropical counties of the world is still a mirage. Eradication of both the Plasmodium parasite and its insect vector in these areas has been very much slower. The control and prevention of malaria depends hugely on the total elimination of possible breeding sites of the insect vector (female Anopheles mosquito) and avoidance of long biting contact between human hosts and the insect vector. The resistance of the Plasmodium parasite to readily available antimalarial drugs coupled with the prevailing resistance of the insect vector to insecticides have further compounded the established control measures for the disease in affected parts of the world. Malaria is a vector-borne disease that is transmitted from person to person through the female Anopheles mosquito; thus, protecting people from the insect vector (female Anopheles mosquito) and reducing the number of insect vectors in human populations/environment will go a long way in helping to stop the spread of the disease.

There is still no vaccine against the disease; nevertheless, frantic efforts to develop an effective malaria vaccine are still in progress and very promising. Also, existing malaria control and preventive efforts (including the use of LLITNs, IRS, and IPTp) in malaria endemic regions are beginning to show promising results in some countries, and this has helped to lower the morbidity and mortality associated with the disease in these areas. There are significant variations amongst countries that use LLITNs as a malaria control measure. The reason that may be attributed to the poor distribution or usage of LLITNs in malaria endemic countries in Africa may be connected to paucity of resources to make these nets available for use. In some cases, some people may have it but still do not appreciate the importance of sleeping under the nets, and thus will resort to not using them at all. Whatever maybe the reason for the non-usage of LLITNs by children in some malaria endemic regions of Africa as depicted in the figure below, advocacy and education is a vital tool to convincing these people to the benefit of using these nets as one of the ways to be malaria free. Resources should be channeled towards research and development (R&D) in malaria endemic countries in order to develop novel ways of fighting the disease so that the world’s target of completely eradicating malaria can be achieved.

OTHER PREVENTIVE AND CONTROL MEASURES FOR MALARIA

  1. Ensuring regular and effective insecticide spraying around homes and other mosquito breeding sites in order to destroy the insect vectors.
  2. Constant drainage of swamps and possible destruction or elimination of other breeding sites of the mosquito’s habitats.
  3. Avoiding mosquito bites by wearing long clothes to cover the whole body when in endemic areas, use of long lasting insecticide treated mosquito nets and use of mosquito nettings on doors and windows of houses to prevent the invasion of the insect vector.
  4. Drainage of breeding sites such as gutters to remove surface waters and filling of ponds and pot-holes with sands to prevent breeding of the insect vector.
  5. Use of effective anti-malarial drugs to treat patients during an infection in order to break the life cycle of the Plasmodium parasite.
  6. Proper funding of preventive programs (such as the Roll Back Malaria Initiative of the WHO) in endemic areas couple with the stepping up of research developments of malaria vaccine and a lasting cure or treatment to the malady is also vital to the termination of the disease.
  7. Local research in malaria endemic areas should be strengthened as a way of finding a lasting solution to the malaria endemicity.
  8. People travelling to malaria endemic areas should avoid mosquito bites as much as possible by sleeping under long lasting insecticide treated nets and covering the body properly when outdoor.

FURTHER READING

Chiodini P.L., Moody A.H., Manser D.W (2001). Atlas of medical helminthology and protozoology. 4th ed. Edinburgh: Churchill Livingstone.

Ghosh S (2013). Paniker’s Textbook of Medical Parasitology. Seventh edition. Jaypee Brothers Medical Publishers,

Gillespie S.H and Pearson R.D (2001). Principles and Practice of Clinical Parasitology. John Wiley and Sons Ltd. West Sussex, England.

Gutierrez Y (2000). Diagnostic pathology of parasitic infections with clinical correlations. 2nd ed. New York: Oxford University Press.

John D and Petri W.A Jr (2013). Markell and Voge’s Medical Parasitology. Ninth edition.

Mandell G.L., Bennett J.E and Dolin R (2000). Principles and practice of infectious diseases, 5th edition. New York: Churchill Livingstone. 

Roberts L, Janovy J (Jr) and Nadler S (2012). Foundations of Parasitology. Ninth edition. McGraw-Hill Publishers, USA.

Schneider M.J (2011). Introduction to Public Health. Third edition. Jones and Bartlett Publishers, Sudbury, Massachusetts, USA.

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