Malaria infection

Summary
In Western countries, almost all malaria occurs in travellers; therefore, the diagnosis may
be missed if a history of travel is not elicited.

Patients typically present with non-specific symptoms such as fever, chills, sweats,
headache, and myalgia.

Examination of a Giemsa-stained blood film remains the diagnostic test of choice.

Once the diagnosis of malaria is confirmed, treatment should be started urgently, as a

delay may be associated with disease progression and complications.

Management should be undertaken in conjunction with an infectious diseases specialist.

Definition
Malaria is a parasitic infection caused by protozoa of the genus Plasmodium . Five
species are known to infect humans; Plasmodium falciparum is the most life-
threatening. [1] It is naturally transmitted to humans through a bite by an infected
female Anopheles mosquito but may potentially be transmitted by blood transfusion or
organ transplantation. [2] [3] [4] It is widely distributed throughout tropical and subtropical
regions, and the main burden of disease falls on these areas. Travellers account for the
majority of disease in Western countries.

THEORY
Epidemiology
On a global scale, 91 countries were still endemic for malaria in 2016. There were an
estimated 216 million malaria cases worldwide in 2016 resulting in an estimated 445,000
deaths. Approximately 90% of all malaria cases and 91% of all malaria deaths occurred
in sub-Saharan Africa, and the majority of deaths (99%) were due to Plasmodium
falciparum infection. [7]

Approximately 1500 to 2000 cases are reported each year in the US, almost all in
travellers. Transfusion-related transmission and local transmission via mosquitoes have
been reported, although this is rare. [8] There were 1724 cases reported in the US in
2014, the fourth highest annual total since 1973. Of these cases, 17% were classified as
severe and 5 deaths were reported. P falciparum accounted for 66.1% of cases, with
13.3% of cases due to P vivax , 5.2% due to P ovale , and 2.7% due to P malariae . [9] In
the UK, 1618 cases of imported malaria were reported in 2016 (mainly caused by P
falciparum ), 15% higher than 2015. [10] CDC: malaria maps
Since 2000, great effort and investment have been directed into international programs
to control and ultimately eliminate malaria. The World Health Organization aims to reduce
global malaria incidence and mortality rates by 90% by 2030. [11] In 2016, 44 countries
reported fewer than 10,000 cases and some countries have been certified as malaria free.
WHO have identified 21 countries with the potential to eliminate malaria by the year
2020. [7]

Pregnant women and children aged under 5 years remain the most susceptible to disease
in endemic areas. [12]Almost all cases of malaria in non-endemic areas are imported by
people travelling from endemic areas, either as tourists or as migrants visiting friends or
relatives. Each year, 25 million to 30 million people from the US and Europe travel to the
tropics, of whom approximately 10,000 to 30,000 acquire malaria. [13] A UK study has
shown that the preventable burden from Plasmodium falciparum malaria has steadily
declined in the UK. [14]Occasionally, individuals living near airports contract malaria,
either via a local mosquito that has been infected through a blood meal from an infected
traveller, or via an infected mosquito from an aeroplane. Rarely, malaria may be acquired
via infected blood products, with 93 cases reported in the US from 1963 to 1999. [15]

A focal outbreak was reported in Bahia State in Brazil in January 2018. As this is not a
malaria-endemic region, malaria prophylaxis has not been recommended previously;
however, the US Centers for Disease Control and Prevention now recommends that
travellers to the town of Wenceslau Guimarães in Bahia State take antimalarial
prophylaxis. [16]

Aetiology
Malaria is caused by protozoa from the genus Plasmodium and is transmitted to humans
through a bite from one of 40 species of female Anopheles mosquitoes.

Infection may also occur through exposure to infected blood or blood products. [2] [3] [4]

Five Plasmodium species cause human disease: P falciparum , P vivax , P ovale , P

malariae , and P knowlesi . The majority of infections are caused by P falciparum and P
vivax , and P falciparum is responsible for the most severe disease. [1]

The distribution of these species is dependent on ecological and behavioural parameters

affecting the ability of mosquitoes to transmit them. [17] There are few known animal
reservoirs; examples include the chimpanzee forP malariae and the crab-eating macaque
( Macaca fascicularis ) for P knowlesi .

 P falciparum is widespread in the tropic regions of Sub-Saharan Africa, certain

areas of Southeast Asia, Oceania, and the Amazon basin of South America. [1]
 P vivax is predominantly found in most of Asia, the Americas, parts of Eastern
Europe, and North Africa. [18]However, more than 80% of cases occur in three
countries (Ethiopia, India, and Pakistan). P vivax has a wider geographical
distribution than P falciparum , as it can develop in the vector at lower
 temperatures and can survive higher altitudes and cooler climates. Like P ovale ,
it has a dormant liver stage and can reactivate, causing a relapse of symptoms.
 P ovale is found primarily in tropical western and central Africa and islands in the
West Pacific. [19]
 P malariae has a distribution similar to P falciparum but a lower
prevalence. [20] [21] [22]
 P knowlesi is found in certain forested areas of Southeast Asia.

An epidemiological investigation using molecular typing techniques found that P simium ,

a species that is closely related to (but distinct from) P vivax , is responsible for
autochthonous malaria infections in people who live near the Atlantic forest regions in Rio
de Janeiro. This parasite was previously thought to be a monkey-specific species. These
infections were previously diagnosed as P vivax infection due to their similar clinical
presentation. [23]

Risk factors for infection include travel to an endemic area, lack of appropriate
chemoprophylaxis, absence of insecticide-treated bed net in an endemic area, and settled
migrants returning from travel to an endemic area of origin. Risk factors for severe
infection include low host immunity (i.e., individuals living in non-endemic areas),
pregnancy, age <5 years, immunocompromise (e.g., underlying HIV infection), and older
age.
[Figure caption and citation for the preceding image starts]:Female (top) and male
(bottom) Anopheles gambiae mosquitoes. The female is in the process of egg-laying on
a sheet of egg paper. A gambiae is the principal vector of malaria in AfricaCenters for
Disease Control and Prevention Image Library/Mary F Adams, MA, MS; used with
permission

Pathophysiology
During a blood meal, an infected female Anopheles mosquito injects 8 to 15 malarial
sporozoites, which rapidly enter hepatocytes. Reproduction by asexual fission (tissue
schizogony) takes place to form a pre-erythrocytic schizont. This part of the life-cycle
produces no symptoms. After a period of time, 30 to 40 thousand merozoites are released
into the bloodstream to penetrate erythrocytes after attaching via receptors. The time
period before merozoites enter the blood is designated the pre-patent period; this is
between 7 and 30 days for Plasmodium falciparum , but may be much longer for P
vivax or P ovale because of the possible development of an inactive hypnozoite stage in
the liver. [24]

Most merozoites undergo blood schizogony to form trophozoites, evolving to schizonts,

which rupture to release new merozoites. These then invade new erythrocytes and the
48-hour (72-hour for P malariae and 24 hour for P knowlesi ) cycle continues, sometimes
resulting in periodicity of fever. The rupture of erythrocytes releases toxins that induce the
release of cytokines from macrophages, resulting in the symptoms of malaria. [25] Some
merozoites mature into larger forms called gametocytes, which reproduce sexually if they
are ingested by a mosquito.

The outcome of infection depends on the infecting species, the patient's age, and the
level of host immunity. [12][25] Severe disease is more commonly seen with P
falciparum , with sequestration (the binding of mature trophozoites to the endothelium of
small blood vessels), rosetting (the formation of clumps of infected and uninfected
erythrocytes), impaired red cell deformability (in infected and uninfected erythrocytes),
cytokine responses, and high levels of parasitaemia (relating to the multiple entry
pathways for P falciparum into erythrocytes), which are all likely to contribute to this high
mortality.
[Figure caption and citation for the preceding image starts]:Illustration of life-cycle of
parasites of the genus Plasmodium, which are causal agents of malariaCenters for
Disease Control and Prevention Image Library/Alexander J da Silva, PhD/Melanie Moser;
used with permission