Lecture 23- Malaria Flashcards
1
Q
Malaria definition
A
- 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
2
Q
- Classification
A
- P. Falciparum
- P. Vivax
- P. Ovale
- P. Malaria
- P. Knowlesi
3
Q
Epidemiology
A
- 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
4
Q
Pathogenesis
A
- 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
5
Q
PApathophysiology
A
- 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
6
Q
Disease may be a consequence of:
A
- haemolysis of parasites and normal cells
- haemoglobinuria and ARF
- hypoglycaemia secondary to parasite consumption of glucose and/or inadequate hepatic gluconeogenesis
- Acidosis, SIADH, hyponatremia
7
Q
Pathophysiology
A
- 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
8
Q
Clinical features
A
- 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
9
Q
Clinical features of vivax/ovale
A
- 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
10
Q
Clinical features: malariae malaria
A
- 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
11
Q
- Clinical features falciparum malaria
A
- 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
12
Q
Clinica features of severe/complicated malaria
A
- parasitemia
- cerebral malaria
- shock
- Pulmonary oedema
- DIC
- macroscopic hemoglobulinuria
- renal failure: serum creatinine >265 umol/L
- severe anemia
- hypoglycemia
- academia
13
Q
Clinical features of cerebral malaria
A
- 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
14
Q
Diagnosis: microscopy
A
- gold standard
- capillary rich blood, fresh EDTA/heparinised sample
- uses classing stains
- takes an hour
15
Q
Thick vs thin film
A
- 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
16
Q
Microscopy advantages
A
- 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
17
Q
Microscopy disadvantages
A
- 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
18
Q
P falciparum microscopy characteristic
A
- normal size RBC
- multiple parasites per RBC
- rings
- banana shaped gametophytes, black pigment in RBC, schizont rare
19
Q
P Vivax microscopy characteristic
A
- enlarged RBC
- one parasite per RBS
- trophozoite is usually amoeboid form, often fragmented
- Schuffner granules, often see gametophyte and schizont
20
Q
P ovale microscopy characteristic
A
- enlarged oval shape RBC
- one parasite per RBC
- compact and regular trophozoite
- schuffner’s granules, often see gametophyte and schizont
21
Q
- P malariae microscopy characteristic
A
- normal size RBC
- usually one parasite per RBC
- compact trophozoite
- often see gametocytes and schizont
22
Q
Diagnosis: Immunochromatographic capture technique (ICT)
A
- 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
23
Q
ICT stats
A
- sensitivity and specific you around 80-90% with expert microscopy but discrepancy results when parasite density
24
Q
Diagnosis: molecular techniques
A
- targets include conserved regions: 18S rRNA, circumsporozoite gene
- no commercial test, offered as in-house test in reference lab
25
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
26
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
27
MALARIA IMMUNOLOGY
- 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
28
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
29
Vaccine
- 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
30
Mosquirix: RTS,S vaccine
- based upon CS protein coupled with HBsAg
- Effective vs P falciparum only
- results 5 RCT, revealed modest efficacy
31
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
32
TREATMENT
- chloroquine and amodiquine
- quinine, quinidine
- artemisinin, artemether, artersunate
- mefloquine
- halofantrine
- Dihydrofolate reductase inhibitors
- dihydropteroate syntheses innhibitors
- primaquine
- tetracycline, doxycycline
- atovaquone
33
Chemoprophylaxis
- 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
