A Review on Pathophysiology of Malaria: A Overview of Etiology, Life Cycle of Malarial Parasite, Clinical Signs, Diagnosis and Complications

 

Krushna K. Zambare*, Avinash B. Thalkari, Nagesh S. Tour

SBSPM’s B. Pharmacy College, Ambajogai – 431517. Dist. Beed. Maharashtra.

*Corresponding Author E-mail: krushnazambare1@gmail.com

 

ABSTRACT:

Malaria is a mosquito-borne infectious disease targeting humans and other animals. The disease occurs worldwide. It is a life-threatening disease which is transmitted through the bite of an infected female Anopheles mosquito. The causative agent of disease is plasmodium parasite which infects the anopheles mosquito. The bite of this mosquito to humans releases the plasmodium in blood and results in malaria. The disease occurs in anywhere worldwide and affects at any ages and sex. Malaria is endemic in tropical and subtropical regions of world like in Latin Americas, several parts of Asia, China and Africa. The WHO estimates that in 2015 there were 214 million new cases of malaria. About 125 million pregnant women are at risk of infection each year in many parts of Sub-Saharan Africa. Infants and children are frequently affected by malaria. Maternal malaria is connected with around 2 lakh infant deaths yearly. The disease generally occurs to frequent travellers arriving or returning from affected tropical zones. The current review covers the causes, pathogenesis, mode of transmission, symptoms, diagnosis and complications of malaria.

 

KEYWORDS: Malaria, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Anopheles mosquito.

 

 


INTRODUCTION:

Malaria is a life-threatening disease that’s typically transmitted through the bite of an infected female Anopheles mosquito. In another words malaria is a mosquito-borne infectious disease targeting humans and other animals. The disease is caused by infected mosquitoes carry the protozoan parasite belonging to the genus Plasmodium. Bite of this mosquito releases the plasmodium in blood of host through the saliva of a mosquito.

 

The disease occurs in any region of universe and affects at any ages with the susceptibility in both sexes. The disease generally occurs to frequent travellers arriving or returning from affected tropical zones. Malaria is more common in rural areas than in cities.1, 2, 3

 

ETIOLOGY:

Malaria in humans is caused by one-celled parasites of the genus Plasmodium that are transmitted to humans by the bite of female Anopheles mosquitoes. The five protozoan (single-celled) parasites are:

Plasmodium falciparum,

Plasmodium vivax,

Plasmodium ovale,

Plasmodium malariae  

Plasmodium knowlesi.

 

Worldwide appearance of P. vivax is more as compared to other plasmodium species. The P. knowlesi was identified in 2008 as one of the main causative agent of malaria in regions of Asia. During microscopic study due to various similarities in between P. malariae and P. knowlesi are confused during diagnosis leading to wrong diagnosis of causative agent1,4

 

INCUBATION PERIOD:

Incubation period various according to the species of plasmodium which is as follows,

 

Table No. 01. Incubation period of various species of Malaria5

Sr No

Causative agent

Incubation period in days

01

Plasmodium vivax

13 to 15

02

Plasmodium ovale

13 to 15

03

Plasmodium malariae

24 to 30

04

Plasmodium falciparum

7 to 12

 

ROUTE OF TRANSMISSION:

Bite by infected female anopheles:

The infected anopheles mosquito transmits the disease to the healthy host by bite which releases saliva carrying numerous sporozoites.

 

Blood transfusion:

Infected person may also transmit the disease through blood transfusion.

 

Patients and carriers:

Patients who are infected with the parasite are at higher risk of transmitting the disease to the other person via the bite of anopheles. Also the host who are not showing the active symptoms of malaria but carries the malarial parasite in blood are also able to transmit the disease.6

 

LIFE CYCLE OF MALARIAL PARASITE:

·       There are two host for the malerial parasite plasmodium one is Human and another is female Anopheles mosquitoes.

·       Two types of reproduction phases appear in the life cycle of the parasite Asexual reproduction in humans as intermediate host and Asexual reproduction in female Anopheles mosquitoes as final host.

·       Plasmodium parasites are spread by the bite of infected female Anopheles mosquitoes, which feed on human blood in order to nurture their own eggs.

·       While taking its meal (usually between dusk and dawn), an infected female Anopheles mosquito injects immature forms of the Plasmodium parasite, called sporozoites, into the humans bloodstream.

·       Plasmodium sporozoites are of two types tachysporozoites which induce primary attack and bradysporozoites result in relapse.

·       P. vivax and P. ovale have both the sporozoites while P. malariae and P. falciparum only tachysporozoites hence there is no relapse in malaria caused by P. malariae and P. falciparum. While P. vivax and P. ovale show relapse which means clinic signs malaria may appear about three to six months or longer after primary attack.

·       The Plasmodium microorganism sporozoites are carried by the blood to the liver where they first infects the cells of the liver and then mature into forms known as schizonts.

·       After the next one to two weeks each schizont multiplies into liver parenchymal cells to thousands of other forms known as merozoites. Merosomes (vesicles filled with merozoites) are released from schizont-infected hepatocytes.

·       The growth of tropozoites in liver cells is termed as exoerythrocytic phase or hepatic or tissue phase.

·       These merozoites released by rupturing the liver cells and are released in the bloodstream where they attack red blood cells.

·       In the red blood cells they grow and multiply in millions. After becoming mature these merozoites destroy the red blood cells and re-enter in the bloodstream.

·       This results in massive hemolysis of the red blood cells. Some merozoites reinfect the red blood cell and reinitiate the cycle in fresh erythrocytes; this stage is termed the asexual blood stage or asexual life cycle of parasite or erythrocytic schizogony.

·       The time interval between invasion of a blood cell and rupture of that cell by the next generation of merozoites occuring approximately by 48 hours for P. vivax and P. ovale while in P. malariae the highest life cycle which is of 72 hours long and P. knowlesi has the shortest life cycle 24 hours, and P. falciparum 36 to 48 hours of life cycle.

·       Due to this life cycle pattern P. vivax and P. ovale has paroxysm attack every other day, P. malariae show has paroxysm attack every three days and P. falciparum paroxysm attack at every 36 to 48

·       At this point, parasites rupture daily from infected blood cells and released into the circulation. Red cell hemolysis leads to acute and chronic anemia.

·       Most of the merozoites reproduce asexually that is, by making the same copies of themselves instead of mixing the genetic material of their parents.

·       The hemolysis and release of merozoites activates the host immune system, resulting in production and release of inflammatory mediators.

·       Mainly cytokines are released as inflammatory markers along with them tumor necrosis factor and interleukins 1 and 6, are also secreted to combat infection by parasite, but these mediators are also responsible for various symptoms of the disease like fever and myalgia (muscle aches).

·       Some of the merozoits may withdraw from asexual life cycle of proliferation that is after invasion to red blood cells and enter to sexual stage of life cycle to form male and female gametocytes a process called gametocytogenesis.

·       These are the cells that can be transmitted to a new mosquito vector if that bites to infected person. The male and female gametocytes will unite only when they enter the gut of another female Anopheles mosquito that bites the infected person.

·       These gametocytes enter the gut of mosquito and further develop into macro-gametes (female) and micro-gametes (male) and form zygote, which then undergo fertilization and development to oocyst. The oocyst after maturity produces embryonic forms called ookinetes.

·       The ookinete then get implanted in the mosquito’s gut, where it mature after 9 to 14 days into zygote, which in turn breakdown and release thousands of sporozoites. The formed sporozoites migrate to the mosquito’s salivary glands and ready to infect the next person in the cycle. 1, 5

 

CLINICAL SIGNS AND SYMPTOMS:

The malarial symptoms generally appear after 2 to 4 weeks after the infection. Malaria is dangerous relapsing disorder due to which some patients may not show symptoms for several months. Common symptoms of malaria include periodic attacks of

·       Firstly there is appearance of chills for around 30 minutes to 1 hour

·       After this stage there is increase in body temperature around over 40°C for 2 to 6 hours with severe headache, myalgia, and skin becomes warm and dry

·       Lastly there is heavy sweating lasting for 30 min to 1 hour during which the temperature drops back to normal.

 

v Anaemia due to the haemolysis of RBCs. Severity of anemia increases if the infected person has parasitemia or G-6-PD deficiency.

v Headache, nausea and vomiting

v Abdominal pain or cramps, diarrhea and bloody stools

v Myalgia, Pallor [pale coloration of skin] due to lysis of erythrocytes,

v Convulsions- commonly seen in young children. Malaria is the leading cause of convulsions with fever in African children

v Splenomegaly (enlargement of the spleen) and hepatomegaly resulted from the marked mononuclear hyperplasia after the rupture of erythrocytes.

v The recurrent attack at 48 hours is called tertian malaria or if is at 72 hours is called quartan malaria.

v The clinical symptoms of malaria appear due to haemolysis of the infected erythrocytes and sticking of RBCs to microvascular endothelium.

 

 

v Amongst the plasmodium species the P. falciparum is causing deadliest form of disease. The P. falciparum infected patient may go from mild symptoms to coma and death unless treated.

v The plasmodium species have variable abilities to infect RBCs which is the important parameter to judge the virulence of plasmodium species. The P.vivax and P. ovale invade young RBC, P. malariae invade old RBC while P. falciparum invade all RBC.

v Also P. falciparum sticks to microvasculature of kidney, brain, liver and lungs leading to damage of vascular endothelium, agglutination of RBCs leading to obstruction of blood flow to various organs.

v  This is the reason for the why P. falciparum is dangerous amongst the other plasmodium species. Hence falciparum infected patients have 10 to 15 times number of parasites per cubic millimetre of blood than patients infected with the other malarial parasites8

 

Fig. No. 01. Symptoms of Malaria8

 

DIAGNOSIS:

Malaria is a multisystem disease. Generally patients experience fever, general aches and pains so it might be misdiagnosed as flu. Sometimes it may be confused with typhoid fever, schistomiasis since both have hepatomegaly. Early and accurate diagnosis of malaria is essential for rapid and effective therapy of disease.

 

1.     Clinical Diagnosis:

It is the tradiational method for the physicians who look for the clinical signs and symptoms of victim. The earliest symptoms of malaria include chills, fever headache, weakness, pruritus, chills, dizziness, abdominal pain, diarrhoea, nausea, vomiting, anorexia, and Myalgia. Physical signs may be confused with other diseases hence clinical diagnosis is challenging test for physicians. Accuracy of malaria diagnosis can be increased by using clinical and parasite finding both at once.

 

 

2.     Microscopic Evaluation:

A.   Microscopic diagnosis using stained thin and thick blood smear:

Plasmodium may be identified using blood smear formed over slide. In this method patient’s blood is spread over the slide and examined under microscope by staining with the Giemsa stain. The thick blood smear technique used for low parasitaemia. Thick blood smear method is used for determining parasite density and checking the patient’s response to treatment.

 

Thin blood smear technique mainly used to check type of plasmodium species infecting the victim. The method mainly shows the morphology of parasite.

 

3.       Rapid diagnostic tests:

The test generally detects the presence of antigens in blood. These tests are very fast and easy to perform. The test may identifies the specific proteins e.g. P. falciparum shows histidine-rich protein II (HRP-II) or lactate dehydrogenase (LDH) or specific and pan-specific antigens (aldolase or panmalaria pLDH).

 

The test uses device that detects antigen of parasite by immunochromatographic assay (colour change in an absorbing nitrocellulose strip) with the help of monoclonal antibodies. The test involves following,

1)       HRP-2 (Histidine Rich Protein-2): It is water soluble protein produced by gametocytes and sporozoites of P. falciparum and is expressed on the membrane of erythrocytes.

2)       Plasmodium aldolase: This is the enzyme released by plasmodium by glycolytic pathway (pan malarial antigen- PMA).

3)       Lactate dehydrogonase (LDH): It is found in patients blood. This enzyme is released by infected red blood cells.

 

The RDT tests are very easy, inexpensive, don’t require electricity and gives result in 10 to 15 minutes. The test may fail in case of low parasitaemia. Due to this reason RDT test must be always followed by microscopic tests to confirm the result.

 

4.       Molecular Diagnosis:

PCR technique is very sensitive and specific for different plasmodium species. The method usually detects parasites nucleis acids. LAMP technique is easy, sensitive, quick and cheaper than PCR. New methods like saponin lysed erythrocytes NAT (nucleic acid amplification technique can also use for diagnosis of malaria.

 

Flow cytometry (FCM): The method mainly detects the presense of hemozoin in blood. The hemozoin is produced when the parasite infects the erythrocytes. Parasites digest the haemoglobin of erythrocyte and crystallize the heme into hemozoin. The phagocytes containing hemozoin when passed through FCM detects it by depolarization of laser light. Hemozoin can also be detected using automated blood cell counters (ACC) which monitors the presence of hemozoin in monocytes.

Mass spectrophotometry also detects presence of specific biomarker which is parasite pigment hemozoin in blood. The technique uses direct ultraviolet laser desorption mass spectrometry (LDMS) for monitoring hemozoin.

 

5.       Serology:

Serological test like immunofluorescence (IFA) or enzyme-linked immunosorbent assay (ELISA) detects presence of antibodies against parasite in patient’s blood.

 

For diagnosis of malaria some newer techniques are also used such as loop-mediated isothermal amplification (LAMP), microarray, latex agglutination assay, cultivation of live malaria parasites and investigating malaria parasites in tissue autopsy e.g. liver, brain, spleen, kidney and lung which can also give reliable test results.2, 9

 

COMPLICATIONS:

·       Acute renal failure:

The malerial parasite causes haemolysis of erythrocytes which leads to the liberation of the haemoglobin inside the vascular system. This haemoglobin may block the glomerulus of kidney leading to necrosis of nephrons. Also it may cause haemoglobinuria. The kidneys become inflamed resulting in polyuria or oliguria.

·       Severe Anaemia:

Usually infected erythrocytes lead to destruction. Also there is increased level of TNF alpha and decreased IL-10. The increased TNF alpha suppresses the bone marrow and causes erythrocyte destruction. The IL-10 has inhibits the TNF alpha activity. This leads to haemolysis and increased production of haptoglobin which is biomarker of haptoglobinaemia commonly found in P. falciparum infection.

·       Blackwater fever:

Passage of dark brown, black or red urine is known as black water fever. The disease is also called as haemoglobinuria which results in acute tubercular necrosis.

·       Cerebral malaria:

The brain is swollen and there are haemorrhages, infracts and herniations. This may be caused by toxic substances released from the parasite which stimulates release of inflammatory mediators such as IL-1, IL-6, IL-8 and TNF alpha. Sometimes there may be obstructive or thrombosis of cerebral vasculature leading to cerebral edema, coma and death. Coma occurs suddenly after convulsions with the signs of delirium, drowsiness, confusion and disorientation.

·       Hypotension and Shock:

In severe malaria the patient develop sudden hypotension leading to shock. Dehydration due to diarrhoea or hypovolaemia may also lead to shock.

·       Pulmonary edema or adult respiratory distress syndrome:

Pulmonary edema may develop due to increased vascular permeability. Sometimes it may results in circulatory collapse called as algid malaria.

·       Metabolic acidosis:

This may results from the renal failure. Generally it is due to lactic acidosis which is increased due to microvascular blockages lading to hypoxia. The hypoxia shifts aerobic glycolysis to anaerobic glycolysis leading to increased production of lactate. Also Lactate is unable to excrete due renal and hepatic failure. This leads to hyperventilation followed by respiratory and circulatory failure.

·       Hypoglycemia:

Anaerobic glycolysis leads to excess utilization of glucose by skeletal muscles. Also hepatic failure leads to decreased gluconeogenesis and glycogenolysis.

·         Other complications include spleenomegaly, hyperpyrexia, hyperparasitaemia, coagulopathy, thrombocytopenia, Jaundice, gastrointestinal dysfunction and premature labour and foetal death in pregnancy.10, 11

 

REFERENCES:

1.      https://www.britannica.com/science/malaria

2.      Noppadon Tangpukdee, Chatnapa Duangdee, Polrat Wilairatanaand Srivicha Krudsood, Malaria Diagnosis: A Brief Review, Korean J Parasitol. 2009; 47(2): 93-102.

3.      Mohammad Sohail et.all, Prevalence of Malaria Infection and Risk Factors Associated with Anaemia among Pregnant Women in Semiurban Community of Hazaribag, Jharkhand, India

4.      https://www.who.int/ith/diseases/malaria/en/

5.      Alan F. Cowman, Julie Healer, Danushka Marapana and Kevin Marsh, Malaria: Biology and Disease, Cell; 2016; 167(20): 610-624

6.      https://www.malariasite.com/transmission/

7.      https://www.malariasite.com/pathophysiology/

8.      https://www.healthline.com/health/malaria#causes

9.      Raghuveer C. V, Mangala Goneppanavar, Laboratory Diagnosis Of Malaria, A Review, Journal of Evolution of Medical and Dental Sciences, 2012; 1(4): 453-462

10.   Dharmeshkumar N Patel, P Pradeep, MM Surti, SB Agarwal Clinical Manifestations of Complicated Malaria – An Overview, JIACM 2003; 4(4): 323-31.

11.   https://www.nhs.uk/conditions/malaria/complications/

 

 

 

Received on 24.06.2019            Modified on 14.07.2019

Accepted on 30.07.2019            © A&V Publications All right reserved

Asian J. Res. Pharm. Sci. 2019; 9(3):226-230.

DOI: 10.5958/2231-5659.2019.00035.3