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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
  • Pneumonia
    • 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)
  • Influenza
    • 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
  • Leptospirosis
    • 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
  • Infectious mononucleosis
    • Clinical syndrome usually caused by Epstein Barr virus (EBV)
    • Characterised by fever, pharyngitis, and lymphadenopathy in older children and young adults
  • HIV seroconversion
    • History of unprotected sexual contact or sexually acquired infection
    • Lymphadenopathy and widespread erythematous rash
  • Amoebic liver abscess
    • 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
  • Rickettsial infection
    • May have a history of a tick bite or of spending time on safari
    • Headache is prominent
    • May have an eschar or rash
  • Legionnaires' disease
    • 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
  • Pulmonary tuberculosis
    • 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
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