Malaria (Pathogenesis, Symptoms and Diagnosis), Prevention and treatment of malaria- Medical microbiology

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                  Pathogenesis, Diagnosis, and treatment of Malaria

Malaria :
- A mosquito-borne infectious disease caused by the bite of a mosquito that carries the parasitic protozoa called Plasmodium species
- The disease can be fatal and life-threatening for humans, transmitted to humans through the bite of infected female Anopheles mosquitoes.
- Plasmodium species comes under the parasite group called "Sporozoa"
- Malaria is one of the major zoonotic diseases that cause millions of human deaths each year
- It is a major public health concern, especially in tropical and subtropical regions. More than 75% of deaths occur in the African region of the world, over a million people mostly children die from malaria each year worldwide


Plasmodium species:
- Malaria is a vector-borne infection that is spread through the bite of the mosquito, thus the term given for this type of infection is a 'zoonotic disease'. The infected vector, the mosquito injects the parasite into the bloodstream of humans.
- Malaria in humans is known to cause primarily by four species of Plasmodium, they are Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae and Plasmodium ovale 
- A new species P. knowlesi has also been found to cause malaria in humans
- P. vivax and P. falciparum are the most common, P. falciparum is the most pathogenic of all four
- The parasite is transmitted to humans via the vector female Anopheles mosquito

General characteristics of five species of Plasmodium that causes infection in humans:

P. vivax:
  • Infects reticulocytes, usually, young cells, has 48 hour incubation period
  • Could remain inactive in the liver as hypnozoites
  • Ring formation with the enlarged RBCs
  • Amoeboid shape trophozoites within 10 hours and into mature schizont containing merozoites in RBC's
P. ovale:
  • Infects young cells, has 48 hours of the incubation period
  • Could remain inactive in the liver as hypnozoites
  • Smaller ring than P. vivax with the enlarged RBCs having oval-shaped edges 
  • Less amoeboid trophozoites than P. vivax
  • Mature schizonts has fewer merozoites than that of P. vivax
P. falciparum:
  • Infects young and old cells, has 36 to 48 hour incubation period
  • Different sizes of RBCs develop with multiple rings
  • Formation of crescent-shaped gametocytes 
  • More severe and life-threatening than other Plasmodium species

P. malariae:
-  Infects old cells, has 72 hours of the incubation period
- Normal size RBCs, the formation of thick rings 
- Trophozoites with the band formation and mature schizonts consists of the merozoites  

P. knowlesi:
  • Infects young and old cells, has 24 hours of the incubation period
  • Different sizes of RBCs with multiple rings
  • Trophozoites with the bands and mature schizonts consists of the merozoites
  • Formation of gametocytes
  • More fatal and life-threatening than other Plasmodium species


Pathogenesis:
  • A female Anopheles mosquito with sporozoites in its salivary glands bites a person and transfers the parasite into the blood.
  • Within a few hours, the sporozoites are carried to the liver via the blood
  • The parasite enters the hepatocytes and starts to grow, the process is known as the "pre erythrocytic cycle"
  •  Merozoites are formed in the liver which ultimately invades the RBCs and reticulocytes, thus "erythrocytic cycle" begins
  • Develops into trophozoites, takes up the hemoglobin, and further develops into mature schizont which consists of several merozoites
  • Merozoites are released into the bloodstream invading RBCs, this is known as the "erythrocytic schizogony cycle"
  • Some merozoites can develop into male and female gametocytes after undergoing several generations of the erythrocytic cycle 
  • The incubation period of the Plasmodium spp is usually one to two weeks except for P. malariae from two weeks to six weeks. Although it may be extended from months to years.

Symptoms of malaria:

Fever is common, a person may experience headaches, chills, and muscle pain within a few days after the infection. Here are the types of symptoms shown by the different types of Plasmodium spp.
Malaria symptoms typically include fever, chills, sweating, headache, muscle aches, and fatigue. These symptoms usually occur 10-15 days after being bitten by an infected mosquito. In severe cases, complications can arise, such as cerebral malaria, anemia, kidney failure, and respiratory distress.

P. vivax-
Mild fever within 48 hours of infection, paroxysm, parasitemia may occur resulting in anemia. In rare cases, it may invade the central nervous system(CNS). If untreated infection may last up to 5 to seven years

P. ovale- 
Mild fever within 48-hour infection, mild paroxysm occurs, parasitemia and anemia develop. CNS infection may occur. If untreated the infection may last up to 12 months

P. falciparum- 
Mild continuous fever, severe paroxysm occurs, parasitemia, and severe anemia develops. CNS involvement is very common, if untreated infection may last up to 6 to 18 months

P. malariae- 
Mild to moderate continuous fever, severe paroxysm occurs, parasitemia, mild anemia. CNS involvement is rare, if untreated infection may last up to more than 20 years.

P. knowlesi- 
Mild and regular fever, moderate to severe paroxysm, severe anemia may occur. CNS infection is possible, the lasting duration of the infection is not known


Laboratory diagnosis:
Blood samples are used as a standard specimen.
  • Microscopic examination: Blood smears are prepared by placing a drop of blood on a microscope slide, spreading it into a thin film, and allowing it to air dry. The smear is then stained with Giemsa stain, which helps to visualize the parasites under a microscope. Other stains such as Wright-Giemsa and Rapid Field stain are also used. Plasmodium parasites, their life stages (such as rings, trophozoites, schizonts, and gametocytes), and other morphological characteristics can be observed under the microscope.
  • A Finger-stick blood test is recommended where thin and thick blood smears are taken on the glass slides and observed under a microscope. Fluorescent microscopy is also done for the parasite detection
  • Rapid Antigen Test and Antibody tests kits are commercially available. These are also commonly used to quickly diagnose the disease in areas with limited access to microscopy. The test helps in detecting specific malaria antigens in a patient's blood. 
  • Serological tests: IFA, ELISA. Not very helpful in the diagnosis
  • Molecular diagnosis: Nucleic acid amplification test detect the presence of malaria parasites' DNA or RNA in blood samples.
Treatment of Malaria:
  • Drugs- Recommended according to the species of the Plasmodium and the infection type. Chloroquine, mefloquine, quinine, artemisinin, sulfadoxine-pyrimethamine is effective to reduce the symptoms. P. falciparum and P. vivax have become more resistant to these drugs. In serious and severe cases of malaria, the drugs are very less or non-effective
  • Classification of antimalarial drugs- tissue schizonticides, blood schizonticides, gametocytocidal and sporontocidal compounds
  • Recently, in 2021 WHO (World Health Organization) have recommended the first and only licensed vaccine for malaria. RTS, S/AS01, (RTS, S) also known as Mosquirix have shown effective results in the African parts of the world where malaria is prevalent and deaths due to the infection are highest.
The four most important and widely used drugs for the treatment of malaria:
1.Chloroquine and Hydroxychloroquine
2. Quinine
3. Primaquine 
4. Antifolates

1. Chloroquine (4-Aminoquinololines)

Clinical Indication
- Chloroquine is mostly effective against all four types of malaria (except chloroquine-resistant P falciparum) 
- Hydroxychloroquine is the analog of a chloroquine
- Used in the treatment of acute malaria
- Malaria prophylaxis
- Rheumatoid arthritis or systemic lupus erythematosus

Mechanism of Action
- Chloroquine is effective during an intraerythrocytic stage of the parasite.
- The drug concentrates into the parasite-infected erythrocytes and enters the food vacuole of the parasite by an ion-trapping mechanism.

Mechanism of action:
    - intercalation with DNA, inhibition of heme polymerase
    - interaction with Ca++-calmodulin mediated mechanism 
    - inhibit peptide formation and phospholipases leading to parasite death

Absorption, Metabolism, and Excretion 
- Rapidly absorbed from the intestine 
- approximately 50% bound to plasma proteins 
- about 70% of a dose is excreted unchanged in the urine 
- half live is 120 hours

Toxicity (side effects)
- mild headache, visual disturbances, gastrointestinal upsets & pruritus are observed during short term therapy
- After prolonged therapy, retinopathy (bulls-eye macula), lichenoid skin eruption, bleaching of hearing, etc. may be observed

Drug Interaction
- Chloroquine and quinine are antagonistic and should not be used in combination.

2. Quinine (4-aminoquinoline derivatives/ Quinoline derivative)

Clinical Indications 
- Quinine is the main alkaloid of cinchona bark (tree).
- drug of choice in the treatment of an acute attack of falciparum malaria where the parasite is known to be resistant to chloroquine.
- may be given intravenously and then orally when patients start to improve
- Doxycycline or clindamycin may be used as combination therapy with quinine.

Mechanism of action:
- the mechanism for anti-malarial activity remains unclear for quinine.

Absorption, Metabolism, and Excretion
- Quinine is almost completely absorbed in the upper part of the small intestine 
- peaks after 1-3 hours of ingestion 
- half live is approximately 10 hours 
- metabolized in the liver (95%) to inactive hydroxy derivatives
- approximately 5% is excreted in urine as an unchanged drug

Toxicity (side effects)
- Quinine may cause Cinchonism (neural, retinal and auditory toxicity)
- Abdominal pain and diarrhea 
- Rashes, fever, renal failure, hemolytic anemia, thrombocytopenia (too low platelet count in blood), etc.

3. Primaquine/ Primaquine phosphate

Clinical Indication:
- used to eradicate hepatic form of P vivax or P malariea infections after standard chloroquine therapy.
- may be used prophylactically with chloroquine

Mechanism of action:
- inhibits the electron transport chain in mitochondria (structurally similar to coenzyme Q) of parasite

Absorption, Metabolism, and Excretion:
-Primaquine is rapidly absorbed from the gastrointestinal tract
- not bound to tissues
- rapidly metabolized and the metabolites may be pharmacologically active as the parent compound
- peaks after 4 - 6 hours after ingestion
- short half-life and almost completely eliminated from the body by 24 hours

Toxicity (side effects):
- Primaquine have shown to cause lethal hemolysis in individuals with glucose-6-phosphate dehydrogenase deficiency 
- higher dose or prolonged exposure can cause;
  •     gastrointestinal distress nausea
  •     nausea
  •     headache
  •     pruritus (itchy skin)
  •     leukopenia (low WBC- white blood cell)

4. Antifolates (Pyrimethamine)

- inhibit folate metabolism at all stages of parasite life cycles

- serve as a competitive inhibitor of the malarial dihydrofolate reductase

- limited use in malaria prophylaxis due to emergence of resistance

Prevention and Control:
- Protective clothing, full sleeve t-shirts, full length trousers etc. will help to protect exposed skin
- Use of bed nets, insect repellent ointments and topical creams in mosquito prevalent regions
- Use of antimalarial drugs in endemic regions
- Awareness programs in endemic areas focusing on health and hygiene
- Staying inside during evening and night in mosquito prevalent regions
- Clearing the stagnant water areas, which could be the site for the breeding of the mosquitoes

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