Lecture 23- Malaria Flashcards Preview

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Malaria definition

- obligate intracellular protozoa of the genus Plasmodium
- natural hosts are human
- produces acute or chronic infection, most commonly characterised by paroxysms of fever, anaemia and splenomegaly
- transmitted by Anopheles mosquitoes


- Classification

- P. Falciparum
- P. Vivax
- P. Ovale
- P. Malaria
- P. Knowlesi



- 100 countries world wide with 2 billion people at risk
- 300-500 million incidence with an annual mortality of 1 million
- P malaria exists in Africa, haiti and the dominican republic
- P vivax and P falciparum are both present in mexico, central and south america, the indian subcontinent, southeast asia and oceania
- P vivax is rare in africa while falciparum is common in africa
- P ovale is found almost exclusively in africa



- genetic factors involving surface proteins of erythrocytes have evolved in human societies by selective pressures
- heterozygous sickle cell trait is protective of P falciparum infection
- the absence of Duffy A and B blood group determinants is protective against P vivax
- cytoadherance and sequestration are the critical parasite-host interactions responsible for severe disease
- P falciparum sequesters in the microcirculation
- disruption of the microcirculation
- probable RBC receptors are ICAM1, CD36, VCAM1



- gametophytes are the infected RBC - infect mosquitoes but do not cause the disease
- manifestations are a consequence asexual forms and their interactions in the blood compartment


Disease may be a consequence of:

- haemolysis of parasites and normal cells
- haemoglobinuria and ARF
- hypoglycaemia secondary to parasite consumption of glucose and/or inadequate hepatic gluconeogenesis
- Acidosis, SIADH, hyponatremia



- density of parasitemia is dependent on the proportion of susceptible erythrocytes
- reticulocutes are rpeferentially infected with Ovale and Vivax
- older erythrocytes are infected in Malariae infestations
- all erythrocytes are susceptible in falciparum infections


Clinical features

- fever in the returned traveller
- prodrome 2-3 days
- paroxysm with rigors
- frequently have headache, myalgia, back pain, fatigue
- GI symptoms or resp symptoms may confuse the picture
- fever, pallor, jaundice, hepatosplenomegaly
- anemia, thrombocytopenia, leukopenia
- hyperbilirubinemia and non-specifically elevated transaminases are frequent
- hyponatremia and hypoglycemia may occur


Clinical features of vivax/ovale

- incubation usually 12-18 days
- terrain malariae: febrile paroxysms are separated by intervals of 48 hr
- replapses usually occur within 6 months
- splenomgaly usually occurs within 2 weeks
- after 5-7 days may develop classing benign tertian periodicity
- good prognosis


Clinical features: malariae malaria

- mildest form of malaria, produces chronic low level parasitemia
- incubation is usually >18 days
- diagnosis may be difficult, requiring multiple blood films
- recrudescence may occur decades later
- Quartan malaria: febrile paroxysms are separated by intervals of 72 hours
- good prognosis


- Clinical features falciparum malaria

- should be considered a medical emergency in non-immune individuals
- incubation shortest: 10-14 days
- paroxysms often irregular
- clinical findings are similar to other forms of malaria byt mroe severe and acute
- more often more severe anemia and multisystem involvement
- prognosis: mortality up to 25% in non-immune individuals


Clinica features of severe/complicated malaria

- parasitemia
- cerebral malaria
- shock
- Pulmonary oedema
- macroscopic hemoglobulinuria
- renal failure: serum creatinine >265 umol/L
- severe anemia
- hypoglycemia
- academia


Clinical features of cerebral malaria

- unrousable coma not attributable to other cause in a patient with falciparum malaria
- mortality 15-25%, neurological sequelea uncommon
- most common severe complication of falciparum malaria in children
- neurological findings are variable: raised ICP, focal gaze abnormalities, seizures
- rapid recovery in survivors


Diagnosis: microscopy

- gold standard
- capillary rich blood, fresh EDTA/heparinised sample
- uses classing stains
- takes an hour


Thick vs thin film

- thick film improves sensitivity by superimposing 202-30 layers. Measures parasite density +/- speciation, essential for low level parasitemia
- thin film: a fixed monolayer to permit speciation by preservation of parasite and RBC morphology


Microscopy advantages

- good sensitivity: up to 50 parasites/up, but often only 500 parasites/up
- speciation possible, detection mixed infection
- quantification routine, essential for assessment of response, prognosis


Microscopy disadvantages

- labour intensive and slow
- requires highly trained staff, performance is observer dependent and maintenance of skulls requires constant exposure
- difficulties in morphological diagnosis with prophylaxis and treatment
- sensitivity moderate requiring repeat films
- microscope expensive and limited use in field


P falciparum microscopy characteristic

- normal size RBC
- multiple parasites per RBC
- rings
- banana shaped gametophytes, black pigment in RBC, schizont rare


P Vivax microscopy characteristic

- enlarged RBC
- one parasite per RBS
- trophozoite is usually amoeboid form, often fragmented
- Schuffner granules, often see gametophyte and schizont


P ovale microscopy characteristic

- enlarged oval shape RBC
- one parasite per RBC
- compact and regular trophozoite
- schuffner's granules, often see gametophyte and schizont


- P malariae microscopy characteristic

- normal size RBC
- usually one parasite per RBC
- compact trophozoite
- often see gametocytes and schizont


Diagnosis: Immunochromatographic capture technique (ICT)

- point of care test to use in field
- uses labelled malarial monoclonal Ab in a mobile phase that binds to serum antigens and becomes immobilised by a second antibody capture system to produce a visible line
- Histidine rich protein 2
- parasite specific LDH
- plasmodium aldolase
Present in sexual and asexual phases


ICT stats

- sensitivity and specific you around 80-90% with expert microscopy but discrepancy results when parasite density


Diagnosis: molecular techniques

- targets include conserved regions: 18S rRNA, circumsporozoite gene
- no commercial test, offered as in-house test in reference lab


Advantages of molecular techniques

- sensitivity: 5 parasites/ul
- ability to speciate in difficult morphological cases including mixed infection
- allows subtyping for epidemiological studies and detection of resistance and virulence genes


Molecular techniques disadvantages

- variation between laboratories because of lack of standardisation
- not available for smaller centers, no commercial test
- high cost and expertise required
- not particularly rapid
- not useful for following up as a test of cure because of persistence of organism



- malaria has a highly effective immune avoidance strategy with the property of antigen switching
- this involves the expression of the var gene which produces variants in the PfEMP-1
- PfEMP1 is responsible for cytoadherance and antigenic presentation on erythrocytes
- 2-18% of each malarial proliferation cycle is associated with a switching event
- exposure causes the development of strain specific non-neutralising immunity, with recrudescence corresponding to antigen switching events
- the spleen has a critical role in clearing parasites erythrocyte from the circulation


Malaria vaccination

- acquired immunity in natural population is non-neutralising and protects against disease rather than infection
- immunity is induced after ongoing exposure, and is short lived in the absence of ongoing exposure
- disease burden occurs disproportionately in children
- passive immunity from infused immunoglobulin has been demonstrated
- vaccines targets include recombinant proteins, synthetic peptides, DNA vaccines, inactivated whole parasites



- Pf66: synthetic hybrid peptide polymer with antigens derived from P falciparum linked to CS protein
- CS protein is a dominant pre-erythtrocytic and hepatic antigen expressed prior to the erythrocytic phase and has the potential to prevent disease
- RCT revelead efficacy of 28% new infectin but overall no clinically significant benefit found


Mosquirix: RTS,S vaccine

- based upon CS protein coupled with HBsAg
- Effective vs P falciparum only
- results 5 RCT, revealed modest efficacy


Appropriate therapy requires

- identifying the species of malaria parasite
- estimating the level of parasitemia
- determining the immune status of the patient
- ascertaining the likely geographic origin of the infecting parasite



- chloroquine and amodiquine
- quinine, quinidine
- artemisinin, artemether, artersunate
- mefloquine
- halofantrine
- Dihydrofolate reductase inhibitors
- dihydropteroate syntheses innhibitors
- primaquine
- tetracycline, doxycycline
- atovaquone



- indicated for non immune persons entering malaria-endemic areas
- chemoprophylaxis may also be appropriate for certain high-risk groups living in endemic areas
- most prophylaxis do not prevent infection but aborts or modifies clinical attack
- most suitable for drugs of longer T1/2
- chloroquine phosphare is effective for infection caused by Vivas, ovale, malaria and chloroquine-sensitive strains of falciparum
- chloroquine resistant falciparum: artermether primary choice, doxcycline or the combination of atovaquone, proguanil are alternatives
- administration should be initiated before entering a malarous area and should be continued for 4 weeks after leaving