MALARIA

INTRODUCTION

Malaria is a mosquito-borne infectious disease of humans and other animals caused by

protists (a type of microorganism) of the genus Plasmodium. It begins with a bite from an
infected female mosquito, which introduces the protists via its saliva into the circulatory
system, and ultimately to the liver where they mature and reproduce. The disease causes
symptoms that typically include fever and headache, which in severe cases can progress to
coma or death. Malaria is widespread in tropical and subtropical regions in a broad band
around the equator, including much of Sub-Saharan Africa, Asia, and the Americas.

The term malaria originates from Medieval Italian: mala aria — "bad air"; the disease was
formerly called ague or marsh fever due to its association with swamps and marshland.
Malaria was once common in most of Europe and North America, where it is no longer
endemic, though imported cases do occur.

Other Plasmodium species cause infections in certain animals. Several mammals, birds and
reptiles have their own form of malaria.

HISTORY

References to the unique periodic fevers of malaria are found throughout recorded history,
beginning in 2700 BC in China. Malaria may have contributed to the decline of the Roman
Empire, and was so pervasive in Rome that it was known as the "Roman fever".

 1820 Quinine first purified from tree bark. For many years prior, the ground bark had
been used to treat malaria.
 1880 Charles Louis Alphonse Laveran first identifies the malaria parasite. He is
awarded the 1907 Nobel Prize for the discovery.
 1898 Sir Ronald Ross demonstrates that mosquitoes transmit malaria. He wins the
1902 Nobel Prize for this work.
 1934 Hans Andersag in Germany discovers the Anti-malarial drug Chloroquine,
which is not widely used until after World War II.
 1939 Paul Hermann Muller in Switzerland tests the insecticide DDT. He wins the
Nobel Prize for this work in 1948.
 1952 Malaria is eliminated in the United States.
 1955 World Health Organization (WHO) launches Global Malaria Eradication
Campaign, which excludes sub-Saharan Africa and is eventually abandoned.
 1957 First documented case of resistance to Chloroquine is reported.
 1976 William Trager and JB Jensen grow parasite in culture for the first time, opening
the way for drug discovery and vaccine research.
 1989 The U.S. Food and Drug Administration approves the use of the anti-malaria
drugMefloquine hydrochloride, registered as Lariam® by Hoffman-LaRoche.
 1992 Malaria vaccine candidate RTS,S, developed by GlaxoSmithKline and the
Walter Reed Army Institute of Research, enters clinical trials.
 1996 Insecticide-treated bednets are proven to reduce overall childhood mortality by
20 percent in large, multi-country African study.
 1998 Roll Back Malaria Partnership (RBM) launched by WHO, UNICEF, UNDP and
World Bank with goal of halving malaria incidence and mortality by 2010.
 WHO adopts home management strategy for malaria whereby trained
community volunteers provide antimalarials in remote African communities.
 2000 The U.N. General Assembly adopts the Millennium Development Goals, setting
a target to halt and begin reversing malaria incidence by 2015.
 2001 WHO prequalifies first fixed-dose Artemisinin combination therapy (ACT), sold
by Novartis as Coartem® and recommends ACT as first-line malaria treatment.
 2002 The Global Fund to Fight AIDS, Tuberculosis and Malaria is established and is
led by UCSF’s Sir Richard Feachem.
 Genome sequencing of Anopheles gambiae (mosquito) and Plasmodium
falciparum (parasite) completed.
 2005 World Health Assembly adopts target of 80 percent worldwide coverage of
insecticide nets and ACTs by 2010.
 2007 UCSF study shows combination malaria therapy effective in treating African
children
 World Malaria Forum convenes in Seattle, hosted by Bill and Melinda Gates
Foundation.
 2008 The Global Health Group at UCSF comes forward with the first high-level
strategy for the eventual achievement of malaria eradication. This strategy has since
been widely adopted.
 United Nations adopt April 25 as World Malaria Day.
 Rectal application of the inexpensive antimalarial drug artesunate proven to
save the lives of young children with severe malaria.
 Representatives of nations around the world meet in New York and endorse
the Global Malaria Action Plan (GMAP), which lays out a vision for reducing
malaria in the short term and eventually eradicating it when new tools become
available.
 2009 Global health experts at UCSF release new guidance on malaria elimination
 2010 UCSF study examines progress in meeting international health goals
 UCSF leads Lancet series on malaria elimination
 UCSF experts outline new strategy to eliminate malaria
 2011 UCSF taps Sepúlveda to lead global health efforts
CAUSE OF MALARIA

Avian malaria
Avian malaria is most notably caused by Plasmodium relictum, a protist that infects birds in
tropical regions. There are several other species of Plasmodium that infect birds, such as-

 Plasmodium anasum
 Plasmodium gallinaceum

But these are of less importance except, in occasional cases, for the poultry industry.
However, in areas where avian malaria is newly introduced, such as the islands of Hawaii, it
can be devastating to birds that have lost resistance over evolutionary time.

In Human
Among the parasites of the genus Plasmodium four species have been identified which can
cause disease in humans:

 Plasmodium falciparum
 Plasmodium vivax
 Plasmodium ovale
 Plasmodium malariae
 Plasmodium knowlesi.

In Monkeys
Fig: Plasmodium falciparum
 Plasmodium cynomolgi bastianelli
 Plasmodium cynomolgi cynomolgi
 Plasmodium brasilianum
 Plasmodium schwetzi
 Plasmodium inui
 Plasmodium simium
 Plasmodium knowlesi

Scientific classification

Domain: Eukaryota
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemosporida
Family: Plasmodiidae
Genus: Plasmodium
Species: P. relictum and others of the genus
TRANSMISSION

Vectors: Plasmodium may exploit several genera of mosquitoes, as vectors and intermediate
hosts

 Culex
 Anopheles,
 Culiceta
 Mansonia and
 Aedes

i. Bites of mosquitoes,
ii. Mechanically by blood transfer as in mass vaccination,
iii. Caponization and injection.

Malaria parasites are transmitted from person to person through Anopheles mosquitoes.
When a mosquito bites, blood containing the parasites is taken into the mosquito's gut. Over a
period of 10 or more days, the parasites undergo a complex development, the mature parasite
eventually coming to reside in the mosquito's salivary glands, ready for transmission to a new
person when it bites again. In the next human host, the parasite first infects the liver,
undergoes rapid replication in this site for at least five days, and then infects red blood cells.
It is in the blood that the parasites causes the most serious symptoms of malaria, including
cerebral malaria initiated by parasitised blood cells blocking blood capillaries in the brain.

Human-to-human transmission of Malaria

As the parasite exists in human red blood cells, malaria can be passed on from one person to
the next through organ transplant, shared use of needles/syringes, and blood transfusion. An
infected mother may also pass malaria on to her baby during delivery (birth) - this is called
'congenital malaria'.

TYPES OF MALARIA

There are five types of Malaria:

 Plasmodium falciparum (P. faliparum) - The most serious form of the disease. It is
most common in Africa, especially sub-Saharan Africa. Current data indicates that
cases are now being reported in areas of the world where this type was thought to
have been eradicated.
 Plasmodium vivax (P. vivax) - Milder form of the disease, generally not fatal.
However, infected animal still need treatment because their untreated progress can
also cause a host of health problems. This type has the widest geographic distribution
globally. About 60% of infections in India are due to P. vivax. This parasite has a
liver stage and can remain in the body for years without causing sickness. If the
patient is not treated, the liver stage may re-activate and cause relapses - malaria
attacks - after months, or even years without symptoms.
  Plasmodium malariae (P. malariae) - Milder form of the disease, generally not fatal.
However, the infected animal still needs treatment because no treatment can also lead
to a host of health problems. This type of parasite has been known to stay in the blood
of some people for several decades.
 Plasmodium ovale (P. ovale) - milder form of the disease, generally not fatal.
However, the infected human still needs to be treated because it may progress and
cause a host of health problems. This parasite has a liver stage and can remain in the
body for years without causing sickness. If the patient is not treated, the liver stage
may re-activate and cause relapses - malaria attacks - after months, or even years
without symptoms.
 Plasmodium knowlesi (P. knowlesi) - causes malaria in macaques but can also infect
humans.

LIFE CYCLE OF PLASMODIUM SPECIES

Life Cycle in Man

A female Anopheline mosquito injects the parasite in the form of ‘Sporozoites’ while taking
the blood meal.

Pre-Erythrocytic Schizogony

The thread like curved sporozoites with tapering ends, and an elongated nucleus enter the
liver cells and develop into ‘Merozoites’ In P. falciparum pre-erythrocytic Schizogony
completes in 6 days, in P. Ovale, 9 days, in P. Vivax 8 days and in P. Malariae 15 days.

Erythrocytic Schizogony
 The hepatocytes filled with the parasites rupture liberating merozoites that attack red blood
cells. (The blood remains sterile during pre-erythrocytic stage and there are no clinical
manifestations or pathological damage).
 During this stage, (The parasites invade the RBC and undergo the following changes in
form).

Fig: Plasmodium erythrocytic cycle

 Fig: Plasmodium life cycle

In Mosquito
Only the mature sexual forms develop inside the mosquito. From one micro gametocyte
(male gametocyte) 5-8 microgametes are developed in the mid-gut. This is called
‘Exflagellation’.

Sporozoites
 The macrogametocyte (female) gives rise to only one macrogamete.
 Fusion of male and female gametes results in the formation of a ‘Zygote’.
 The Zygote is converted into ‘Ookinete’ which further develops into ‘Oocyst’, inside
the gut cells of mosquito. The oocyst matures and forms a large number of
Sporozoites
 On the 10th day of infection the oocyst ruptures liberating Sporozoites in the body
cavity of mosquito. The sporozoites migrate towards the salivary glands where they
concentrate in the ducts. At this stage the mosquito is able to transmit the infection to
man. A single bite of mosquito is sufficient for this purpose.
Malarial Hepatopathy

Liver dysfunction as a result of malaria is rare and is usually a result of a coexisting liver
condition such as viral hepatitis or chronic liver disease. The syndrome is sometimes called
malarial hepatitis, although inflammation of the liver (hepatitis) does not actually occur.
While traditionally considered a rare occurrence, malarial hepatopathy has seen an increase,
particularly in Southeast Asia and India. Liver compromise in people with malaria correlates
with a greater likelihood of complications and death.

SIGNS AND SYMPTOMS

Incubation period refers to how long it takes from initial infection to the appearance of
symptoms. This generally depends on the type of parasite:

 P. falciparum - 9 to 14 days
 P. vivax - 12 to 18 days
 P. ovale - 12 to 18 days
 P. malariae - 18 to 40 days

However, incubation periods can vary from as little as 7 days, to several months for P. vivax
and P. ovale. If you are taking medication to prevent infection (chemoprophylaxis) the
incubation period is usually longer.

Symptoms in birds

A bird that has symptoms from Plasmodium spp. infection generally has many parasites
multiplying in the circulating blood within a week of the mosquito’s bite. Birds suffer

 Loss of appetite,
 Shanks and the toes are dry and birds have ruffled feathers
 Extreme leg weakness,
 Nervous signs like twisting of the head
 Greenish-yellow or greenish white diarrhea
 Blood circulation to organs may be impaired, and the liver and spleen may be
enlarged, with anemia due to destruction of red blood cells.
 In heavy infections death is common.

In human:
The classic symptom of malaria is paroxysm-a cyclical occurrence of sudden coldness
followed by rigor and then fever and sweating, occurring every two days in P. vivax and
P. ovale infections, and every three days (tertian fever) for P. malariae. P. falciparum
infection can cause recurrent fever every 36–48 hours (quartan fever) or a less pronounced
and almost continuous fever.
The signs and symptoms of malaria typically begin 8–25 days following infection; signs
include

 Decreased consciousness
 Significant weakness such that the person is unable to walk
 Inability to feed
 Two or more convulsions
 Low blood pressure (less than 70 mmHg in adults or 50 mmHg in children)
 Breathing problems
 Circulatory shock
 Kidney failure or hemoglobin in the urine
 Bleeding problems, or hemoglobin less than 5 g/dl
 Pulmonary edema
 Low blood glucose (less than 2.2 mmol/l / 40 mg/dl)
 Acidosis or lactate levels of greater than 5 mmol/l
 A parasite level in the blood of greater than 2%
 Retinal damage, and convulsions. splenomegaly (enlarged spleen), fever without
localizing signs, thrombocytopenia, and hyperbilirubinemia combined with a normal
peripheral blood leukocyte count.

Gross lesions:
 Enlargement and blackish discoloration of the liver and spleen
 Presence of pale and watery heart blood.
 Birds that died prior to 21 days PI had some trace deposits of subcutaneous fat and
were in relatively good flesh with only minor atrophy of the pectoral muscles.
 Emaciated carcass and prominent keels.
 Impression smears from these tissues often reveals schizonts.
 Schizonts are present in several tissues throughout the body.

DIAGNOSIS

Clinical sign and symptom

Laboratory Tests

Malaria is typically diagnosed by the microscopic examination of blood using blood films or
using antigen-based rapid diagnostic tests (RDT).

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. Thin films are similar to usual
blood films and allow species identification because the parasite's appearance is best
preserved in this preparation. Thick films allow the microscopist to screen a larger volume of
blood and are about eleven times more sensitive than the thin film.
From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) as
few as 5 parasites/µL blood. Diagnosis of species can be difficult because the early
trophozoites ("ring form") of all four species look identical and it is never possible to
diagnose species on the basis of a single ring form; species identification is always based on
several trophozoites.

Blood films

Species Appearance Periodicity Liver persistent

Tertian Yes
Plasmodium vivax

Tertian Yes
Plasmodium ovale

Tertian No
Plasmodium falciparum

Quartan No
Plasmodium malariae

Antigen tests
Antigen-based rapid diagnostic tests (RDTs) are often more accurate than blood smears at
predicting the presence of malaria parasites.

For areas where microscopy is not available, or where laboratory staff are not experienced at
malaria diagnosis, there are RDTs that require only a drop of blood.

Immunochromatographic tests have been developed, distributed and field tested. These tests
use finger-stick or venous blood, the completed test takes a total of 15–20 minutes, and the
results are read visually as the presence or absence of colored stripes on the dipstick, so they
are suitable for use in the field. One disadvantage is that dipstick tests are qualitative but not
quantitative – they can determine if parasites are present in the blood, but not how many.

Molecular methods
Molecular methods are available in some clinical laboratories and rapid real-time assays (for
example, QT-NASBA based on the polymerase chain reaction) are being developed with the
hope of being able to deploy them in endemic areas.

PCR (and other molecular methods) is more accurate than microscopy. Levels of parasitemia
are not necessarily correlative with the progression of disease, particularly when the parasite
is able to adhere to blood vessel walls.
PROGNOSIS OF MALARIA

When properly treated, patient with malaria can usually expect a complete recovery.
However, severe malaria can progress extremely rapidly and cause death within hours or
days. In the most severe cases of the disease, fatality rates can reach 20%, even with intensive
care and treatment. Over the longer term, developmental impairments have been documented
in children who have suffered episodes of severe malaria.

Malaria causes widespread anemia during a period of rapid brain development, and also
direct brain damage. This neurologic damage results from cerebral malaria to which children
are more vulnerable. Some survivors of cerebral malaria have an increased risk of
neurological and cognitive deficits, behavioural disorders, and epilepsy. Malaria prophylaxis
was shown to improve cognitive function and school performance in clinical trials when
compared to placebo groups.

MALARIA PREVENTION AND CONTROL

Methods used to prevent the spread of disease, or to protect individuals in areas where
malaria is endemic, include prophylactic drugs, mosquito eradication, and the prevention
of mosquito bites.

Control Avian Malaria

Surface modified amorphous nanoporous silica molecules with hydrophobic as well as
hydrophilic character can be effectively used as therapeutic drug for combating chicken
malaria in poultry industry. The amorphous nanosilica was developed by top-down approach
using volcanic soil derived silica as source material. Amorphous silica has long been used as
feed additive for poultry industry and considered to be safe for human consumption by WHO
and USDA. The basic mechanism of action of these nanosilica molecules is mediated by the
physical absorption of VLDL, serum triglycerides and other serum cholesterol components in
the lipophilic nanopores of nanosilica. This reduces the supply of the host derived
cholesterol, thus limiting the growth of the malaria parasite in vivo.

Vector control
Before DDT, malaria was successfully eradicated or controlled also in several tropical areas
by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of
the larva stages, for example by filling or applying oil to places with standing water. These
methods have seen little application in Africa for more than half a century.

Integrated Vector Management (IVM)

Integrated Vector Management (IVM) is a process for managing vector population in a way
to reduce or interrupt transmission of disease. The aim of IVM is to reduce the number of
bites by infected vectors of malaria by control of anophelines mosquitoes; this may include a
large number of measures. Anophelines breed in clean water and it may therefore be possible
to reduce their densities by proper drainage and other environmental measures or by the use
of larvivorous fish Strategy for malaria prevention and control or chemical larvicides. Where
such methods have proven effective, they should be systematically promoted.
However, in most high-risk areas, long-term measures targeting adult mosquitoes are more
generally effective and applicable. Two such methods are now available: IRS and ITNs. As
these methods are costly and based on insecticides, they shall be targeted to high-risk areas,
which must be identified according to prevalence of criteria. The choice between IRS and
ITNs will be based on operational factors, community acceptance and local experience. The
unit of intervention will be the village through microstratification.

Prophylactic drugs
Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic
areas, and their use is usually restricted to short-term visitors and travelers to malarial
regions.

Quinine was used starting in the seventeenth century as a prophylactic against malaria. The
development of more effective alternatives such as quinacrine, chloroquine, and primaquine
in the twentieth century reduced the reliance on quinine. Today, quinine is still used to treat
chloroquine resistant Plasmodium falciparum, as well as severe and cerebral stages of
malaria, but is not generally used for prophylaxis.

Modern drugs used preventively include mefloquine (Lariam), doxycycline (available

generically), and the combination of atovaquone and proguanil hydrochloride (Malarone).

Indoor residual spraying

Indoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of
homes in malaria affected areas. The first and historically the most popular insecticide used
for IRS is DDT. While it was initially used exclusively to combat malaria, its use quickly
spread to agriculture. In time, pest-control, rather than disease-control, came to dominate
DDT use, and this large-scale agricultural use led to the evolution of resistant mosquitoes in
many regions. If the use of DDT was limited agriculturally, DDT may be more effective now
as a method of disease-control. The DDT resistance shown by Anopheles mosquitoes can be
compared to antibiotic resistance shown by bacteria. The overuse of anti-bacterial soaps and
antibiotics have led to antibiotic resistance in bacteria, similar to how overspraying of DDT
on crops have led to DDT resistance in Anopheles mosquitoes. During the 1960s, awareness
of the negative consequences of its indiscriminate use increased ultimately leading to bans on
agricultural applications of DDT in many countries in the 1970s.

Mosquito nets and bedclothes

Mosquito nets help keep mosquitoes away from people, and thus greatly reduce the infection
and transmission of malaria. The nets are not a perfect barrier, so they are often treated with
an insecticide designed to kill the mosquito before it has time to search for a way past the net.

Insecticide-treated nets (ITN) are estimated to be twice as effective as untreated nets, and
offer greater than 70% protection compared with no net. Although ITN are proven to be very
effective against malaria, less than 2% of children in urban areas in Sub-Saharan Africa are
protected by ITNs. Since the Anopheles mosquitoes feed at night, the preferred method is to
hang a large "bed net" above the center of a bed such that it drapes down and covers the bed
completely.

Vaccination
Vaccines for malaria are under development, with no completely effective vaccine yet
available. Presently, there is a huge variety of vaccine candidates on the table.

Pre-erythrocytic vaccines (vaccines that target the parasite before it reaches the blood), in
particular vaccines based on circumsporozoite protein (CSP), make up the largest group of
research for the malaria vaccine. Other vaccine candidates include: those that seek to induce
immunity to the blood stages of the infection; those that seek to avoid more severe
pathologies of malaria by preventing adherence of the parasite to blood venules and placenta;
and transmission-blocking vaccines that would stop the development of the parasite in the
mosquito right after the mosquito has taken a bloodmeal from an infected person. It is hoped
that the sequencing of the P. falciparum genome will provide targets for new drugs or
vaccines.

Other methods
Education in recognizing the symptoms of malaria has reduced the number of cases in some
areas of the East Africa by as much as 20%. Recognizing the disease in the early stages can
also stop the disease from becoming a killer. Education can also inform people to cover over
areas of stagnant, still water e.g. Water Tanks which are ideal breeding grounds for the
parasite and mosquito, thus cutting down the risk of the transmission between people. This is
most put in practice in urban areas where there are large centers of population in a confined
space and transmission would be most likely in these areas.