Malaria
Definition
Parasitic infection caused by protozoa of the genus Plasmodium
Five species are known to infect humans
Plasmodium falciparum is the most life-threatening
It is naturally transmitted to humans through a bite by an infected female Anopheles mosquito
May potentially be transmitted by blood transfusion or organ transplantation
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
Risk Factors
Travel to endemic area
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
Inadequate or absent chemoprophylaxis
The incidence of Plasmodium falciparum malaria in travellers who do not take prophylactic drugs is highest in West Africa (52 cases/1000 years exposed)
In South America, India, and Pakistan, a low risk of 1 case per 2000-3000 years exposed exists
Chemoprophylaxis significantly reduces mortality rates
Insecticide-treated bed net not used in endemic area
Pyrethroid-treated mosquito nets are recommended for travellers to endemic areas, to reduce risk of mosquito bites
Settled migrants returning from travel to endemic area of origin
Constitutes two-thirds of all imported malaria, with most patients not taking malaria chemoprophylaxis
This may be due to a number of reasons:
if they grew up not taking prophylaxis they may not see it as important or may not consider it
they may take incorrect prophylaxis
they may perceive the risk as low, especially if only visiting a major city
Low host immunity (for severe disease)
People who have little or no immunity (i.e., individuals living in non-endemic areas) are most at risk for disease and developing serious illness
Pregnancy (for severe disease)
Pregnant women infected with P falciparum are susceptible to complications of pregnancy as the parasites sequester in the placenta
In addition, the prevalence of P vivax infection and parasite density increases during pregnancy, due to the reticulocytosis of pregnancy (P vivax exclusively invades reticulocytes)
Age <5 years (for severe disease)
Children <5 years of age are more likely to have infection and complications of malaria
Immunocompromise (for severe disease)
Individuals with comorbidities, including HIV infection, are susceptible to developing severe malaria infection
Older age (for severe disease)
Malaria is potentially fatal if not treated promptly
Life-threatening complications can develop quickly in patients who initially appear well, and even short delays increase morbidity and mortality
This is especially the case in certain risk groups, including older adults
Differential diagnosis
Dengue fever
Abrupt onset of symptoms
Headache and retrobulbar pain that worsens with eye movements is typical
A rash may be present in about half of patients and may be petechial or otherwise haemorrhagic
Respiratory symptoms prominent, (e.g., cough, haemoptysis, dyspnoea, chest pain)
Respiratory examination may reveal focal coarse crackles or consolidation
Hypoxia is common
Signs of pleural effusion may be present (e.g., dullness to percussion, decreased breath sounds over affected area)
Important to consider current epidemiological situation, (e.g., pandemics, epidemics, winter months)
May give history of ill contacts
Short incubation period (1 to 2 days) with abrupt onset
Mild upper respiratory tract symptoms common (e.g., non-productive cough, pharyngitis, coryza)
Wheezing or rhonchi may be audible on auscultation
Enteric fever (typhoid infection)
Most common on Indian subcontinent
Incubation period 1 to 3 weeks
Gradual onset of sustained fever
Rigors uncommon
Abdominal pain and headache common
Relative bradycardia unreliable
May have a blanching erythematous maculopapular rash (rose spots)
Pyogenic infection
Focal symptoms and signs depend on site affected
May also have prominent systemic symptoms with Group A streptococcal (GAS) infection or pyelonephritis
Conjuctival congestion may be helpful if present
Symptoms and signs of meningitis may be present (e.g., headache, neck stiffness, photophobia)
Weil disease is a syndrome of hepatosplenomegaly with jaundice, bleeding diatheses, and renal failure
Clinical syndrome usually caused by Epstein Barr virus (EBV)
Characterised by fever, pharyngitis, and lymphadenopathy in older children and young adults
History of unprotected sexual contact or sexually acquired infection
Lymphadenopathy and widespread erythematous rash
Preceding history of dysentery in fewer than 50% of patients
More common in young males
Right upper quadrant pain, possibly referred to the right shoulder
Tender hepatomegaly and right pleural effusion present
African trypanosomiasis (sleeping sickness)
History of a tsetse fly bite
Detection of a chancre at the site of the bite, and enlarged lymph nodes
There may be a patchy erythematous rash
May have a history of a tick bite or of spending time on safari
Headache is prominent
May have an eschar or rash
Acquired by inhalation of aerosolised bacteria or, rarely, microaspiration of contaminated drinking water
Presentation includes respiratory symptoms such as cough (may not be productive) and SOB, fever, chills, and chest pain
Other symptoms include headache, nausea, vomiting, abdominal pain, or diarrhoea
Recent travel to endemic area, exposure to TB-infected person
Epidemiology
On a global scale, 109 countries were endemic for malaria in 2008, accounting for over 40% of the world's population
Among 3.3 billion people at risk, there were an estimated 247 million malaria cases in 2006, resulting in nearly a million deaths, mostly of children <5 years of age
More than 70% of cases occur in sub-Saharan Africa and 25% in southeast Asia
Pregnant women and children <5 years of age are most susceptible to disease in endemic areas
Almost all cases in non-endemic areas are imported by people travelling from endemic areas, either as travellers 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
A UK study has shown that the preventable burden from Plasmodium falciparum malaria has steadily increased in the UK, although P vivax burden has decreased
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
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
Five Plasmodium species cause human disease:
P falciparum
P vivax
P ovale
P malariae
P knowlesi
The majority of infections are caused by P falciparum and P vivax, and P falciparum is responsible for the most severe disease
The distribution of these species is dependent on ecological and behavioural parameters affecting the ability of mosquitoes to transmit them
There are few known animal reservoirs
Examples include the chimpanzee for P malariae and the crab-eating macaque (Macaca fascicularis) for P knowlesi
Distribution:
P falciparum is widespread in the tropic regions in sub-Saharan Africa, certain areas of southeast Asia, Oceania, and the Amazon basin of South America
P vivax is predominantly found in most of Asia, the Americas, parts of Eastern Europe, and North Africa
P ovale is found primarily in tropical western and central Africa and islands in the West Pacific
P malariae has a distribution similar to P falciparum but a lower prevalence
P knowlesi is found in parts of southeast Asia
Risk factors for infection include:
travel to an endemic area
lack of appropriate chemoprophylaxis
absence of insecticide-treated bed net in an endemic area
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)
older age
Clinical features
Fever or hx of fever
Fever, or history of fever, is universal
Characteristic paroxysms of chills and rigors followed by fever and sweats may be described
Usually associated tachycardia
Patterns of fever are rarely diagnostic at presentation but may develop over time:
Fevers occurring at regular intervals of 48 to 72 hours may be associated with P vivax, P ovale, or P malariae infections
In most patients there is no specific fever pattern
Other features:
headache (common)
weakness (common)
myalgia (common)
arthralgia (common)
pallor (common)
hepatosplenomegaly (common)
jaundice (uncommon)
anorexia (uncommon)
nausea and vomiting (uncommon)
diarrhoea (uncommon)
abdominal pain (uncommon)
altered level of consciousness (uncommon)
seizures (uncommon)
hypotension (uncommon)
anuria/oliguria (uncommon)
influenza-like respiratory symptoms (uncommon)
Pathophysiology
During a blood meal, an infected female Anopheles mosquito injects thousands of 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, thousands of merozoites are released into the blood stream 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 P falciparum
May be much longer for P vivax or P ovale because of the possible development of an inactive hypnozoite stage in the liver
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 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
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
Severe disease is more commonly seen with P falciparum, as it sequesters within small blood vessels, contributing to end-organ damage
Investigations
Giemsa-stained thick and thin blood smears
Detection of asexual or sexual forms of the parasites inside erythrocytes
Rrapid diagnostic tests (RDTs)
Detection of parasite antigen or enzymes
FBC
May show thrombocytopenia, anaemia, variable white cell count
Clotting profile
Prothrombin time may be moderately prolonged
Serum electrolytes, urea and creatinine
Usually normal or mildly impaired
Renal failure may be present in severe infection
Serum LFTs
May show elevated bilirubin or elevated aminotransferases
Serum blood glucose
Hypoglycaemia or hyperglycaemia
Hypoglycaemia is probably cytokine-mediated and may subsequently be due to quinine therapy
Urinalysis
May show trace to moderate protein
Urobilinogen and conjugated bilirubin may be present
Arterial blood gas
May demonstrate metabolic acidosis or lactic acidosis in severe disease
PCR blood for malaria
Detection of parasites at very low levels
Species identification if difficulties on microscopy
Management
a) conservative
Suportive care:
Careful fluid management, often with renal support
Airway protection
Control of seizures
Transfusion of blood products
Hypoglycaemia may be worsened by quinine-induced hyperinsulinaemia, so should be monitored closely
b) medical
Depends on local drug sensitivity
Treatment is different in pregnancy
Chloroquine
Cloroquine resistance is widespread in most regions of the world
Especially for P. falciparum
But there have been no reports of chloroquine resistance in infections acquired in:
Parts of Central America (west of Panama Canal)
Haiti
Dominican Republic
Most of the Middle East
Infections acquired in these regions may be assumed to be chloroquine-sensitive and treated with chloroquine (preferred) or hydroxychloroquine
Combination therapies:
Doxycycline or tetracycline
Preferred to clindamycin, due to the availability of more data
Use of doxycycline or tetracycline should be avoided in children because these drugs are deposited in growing bones and teeth.
Artimisinin combination therapies
Widely recommended as first-line therapy
There is evidence to suggest that they are safe and effective for uncomplicated malaria in endemic areas and in non-immune travellers
However, in many countries they are not licensed or available
Mefloquine
Due to increased rates of neuropsychiatric complications, should be used only if the other options are not available
In addition, due to drug resistance, mefloquine is not recommended for infections acquired in southeast Asia
Primaquine
Acts against hypnozoite forms
G6PD levels should be checked, as haemolysis may occur in patients who are deficient in G6PD
c) surgical
n/a
Prognosis
Approximately 90% of travellers who acquire malaria will not become symptomatic until they return home
Delays in diagnosis and treatment increase malaria-associated morbidity and mortality
Malaria can progress from an asymptomatic state to death in as little as 36 to 48 hours
Mortality from treated malaria in non-immune travellers is predominantly due to Plasmodium falciparum and ranges from 0.4% to 10%
Up to 80% of patients with cerebral malaria will recover with treatment, but mortality is still 15% to 20%
True relapses may occur in up to 15% of cases of P vivax or P ovale if no drug active against the hypnozoite stage is given
Treatment algorithms account for this by including primaquine with chloroquine therapy