Malaria module Flashcards
Ways to measure malaria transmission intensity?
- Suitability maps using GIS
- Entomological inoculation rate
- Parasite measures eg parasite prevalence = rate PR, molecular
- Other community measures eg Hb levels, spleen rates, serological markers
- Symptomatic malaria (threshold ACD vs PCD)
- Severe malaria and mortality eg syndromic definitions, all cause vs specific
What is EIR?
Gold standard measure
Prevalence of infection in vector x vector human contact per unit time
eg Mos infected/Mos caught x Mos caught/’catching events’ x time
Usually thought of as infectious bites per person per year
Provides important ancillary information eg species, blood feeding and resting behaviour
Ways to measure EIR?
Mosquito trapping
- Human landing/biting catch
- light trap catches
- spray catches
- exit traps
Assessment of infectivity
- dissection
- ELISA
- PCR
What are the caveats of using EIR?
- Depends on intensity of sampling and sporozoite rate
- Difficult to capture the heterogeneity of transmission -> most trapping methods are for endophilic vectors
- Considered unreliable if EIR<5 and therefore, suited to measure and monitor transmission at higher levels
What is parasite prevalence?
Widely used
% of people that have a malaria parasite in them
- Suitable for collecting via a variety of approaches eg schools, ANC visits etc
Assess via:
- Microscopy
- RDTs
- PCR/NAAT
Advantages of serology for transmission measurement
Helpful in low levels of transmission or pre-elimination/elimination phases
Detection of hypnozoite carriers in vivax
Can tell you about reduction in exposure by right shift of age and serological prevalence curve
Disadvantages of serology for transmission measurement
No standardised assay
No consensus on what and how many Ags to use
Does not yet tell you about recent infections
Abs saturate at high transmission as everyone positive
Vector control methods for malaria and what they achieve?
Adult control:
- IRS (population level)
- ITNs (personal protection)
robust, standardised, affect density and longevity
Larval control:
- larviciding eg chemical, biological
- biological control
can only do if sites fixed and findable, must be closely adapted to local conditions
Personal protection:
eg nets
Genetic control:
- sterile males
- refractoriness genes
What are the two families of proteins on RBCs that parasites use for invasion?
1) Reticulocyte binding proteins (RBP or RHs)
2) Duffy binding like proteins (DBPs or EBAs)
What antigen does P vivax use to get into cells and how does this affect global populations?
Duffy
Geo: South America and Asia, esp South East
How is P Knowlesi able to jump species?
Possibility that P knowlesi has multiple ways of invading macaque RBCs compared to human cells -> if you put it in lab it will preferentially invade RBCs of macques than humans
P Knowlesi has 3 DBPs
- DBPalpha binds to DARC on both human and macaque cells
How is P Knowlesi mistaken for other plasmodium species?
Microscopy: similar to P malariae
Molecular: some cross reactivity with P vivax
What mutations are associated with artemisin resistance?
pfk13 mutations - reduced susceptibility to artemisin but not complete resistance
- although these might be marker of resistance rather than the causative mechanism
Most people at risk of what type of Malaria?
P vivax
NB: responds less well to vector control
Why is P vivax so widespread?
Sporogony can be completed at lower temperatures hence more widespread
Why is P vivax found less in West Africa?
P vivax selects Duffy positive Ag RBCs only -> most people Duffy negative in W Africa
What is the most common pathology of vivax infections and why?
Anaemia
Due to preference for reticulocytes
Diagnostic features of vivax?
Schuffner’s dots
Enlarged cells
Less merozoites than falciparum
What are P vivax hypnozoites?
Developmentally arrested liver stages that can remain dormant for weeks to months before reactivating causing relapse
–> time to first relapse and frequency of relapses differ among P vivax strains from different geographical areas as hypothesised to be linked to optimal transmission season
- Very small
- Metabolically inactive
- Signals for activation as yet unidentified
Why do P vivax infections not exceed parasitaemias of 1%?
Only 1-3% of all red cells have Duffy Ag
What reticulocytes does P.vivax exclusively invade?
CD71+ reticulocytes
Where does P vivax sequester?
98% of biomass of parasite of vivax out of blood
large amount found sequestered in the spleen, other reservoirs possible eg BM
Basic features of P vivax transmission in terms of gametocytes and vector uptake
- P vivax density of gametocytes closely correlated to parasitaemia
- Over a certain threshold most mosquitoes that feed become infected
- Sporogonic development can occur at lower temperatures eg than falciparum, but takes longer -> female mos must live long enough for sporozoites to develop and move to the salivary glands
- process takes a min of 9 days when temp around 30 degrees
Two options for treatment of P vivax hypnozoites
Primaquine
- requires 14 days of treatment
- slow/quick metabolisers eg CYP2D6 can affect mode of action
- big issue with adherence
Tafenoquine
- requires 1 dose
Both cause haemolytic anaemia in G6PD deficiency individuals
pregnant women and infants can’t be treated
= if foetus G6PD deficient, infants no dosing for PQ
Issues with G6PD
<200 genetic variants resulting in range of G6PD activity
Naturally selected for: G6PD protective against cerebral malaria but not severe anaemia
G6PD activity lowest in older RBCs -> these haemolyse first then risk of haemolysis may be lower during malaria episode
Primaquine thought safe if levels >40%, tafenoquine if >70%
Measurement based on enzyme activity so relies on: temperature + RBC mass, issues with measuring activity in heterozygote individuals
Issues for control and elimination of P vivax?
- Improved surveillance
- Improved diagnostic test sensitivity
- Shift from treatment of current infections to radical cure
- Drug resistance
- Relapses
- Delivery systems and strategies through primary health care
- Improved VC, especially targeting early biting and outdoor resting vector species
Types of chemoprevention for malaria
- Chemoprophylaxis
- Intermittent preventive treatment - full therapeutic course to particular population at risk - aiming to prevent morbidity or mortality
- MDA - full therapeutic course to whole population at risk, whether known to be infected or not - aiming to interrupt transmission
Issues with chemoprophylaxis
Cost
Resistance to anti-malarial drugs
Incidence of malaria and anaemia once chemoprophylaxis stopped
Problems of adherence to continuous dosing
Difficult to deliver
Chemoprevention strategies?
Age-targeting?
Seasonal targeting? Marked seasonal variation in transmission in some settings
Physiological targeting eg pregnancy, following admission with severe anaemia?
Common forms of chemoprevention
IPTp
PMC: perennial malaria chemoprevention, targets infants and young children
SMC: seasonal malaria chemoprevention, targets children
IPT in school children =IPTsc
Post-discharge chemoprevention
Women on what drug should not be given sulfadoxine/pyrimethamine as IPTp?
Co-trimoxazole
When should IPTp be given?
Start as early as possible in the second trimester
At least 3 doses of SP during pregnancy, min a month apart
What drugs are given for SMC and when?
The standard regimen recommended by the WHO consists of:
Sulfadoxine-Pyrimethamine (SP) – Single dose (taken on Day 1)
Amodiaquine (AQ) – Three-day regimen (taken on Days 1, 2, and 3)
These drugs are given once per month for 3–4 months during the peak malaria season (usually the rainy season when transmission is highest).
What is IPTsc?
Periodic administration of full therapeutic doses of antimalarial medications to school-aged children (typically aged 5–15 years) in areas with moderate-to-high malaria transmission
Why might IPTsc or malaria measures for school children to be important?
Onwards effects of malaria prevention and severe anaemia prevention on literacy, school retention, cognitive function
Also, help to target infectious reservoir that maintains transmission
Features/consequences of asymptomatic malaria?
Chronic low-grade haemolysis and malaria
Recurrent symptomatic episodes
Impair cognitive function and school performance
Increase risk of systemic bacterial infections
Exacerbate other disease eg in pregnant women results in low birth weight babies
Contribute to ongoing transmission and hinder elimination
When might you use MDA for malaria?
Burden reduction in specific populations -> eg was used in Ebola outbreak for displaced populations or where health systems not functioning normally
Reduction in transmission
Used for mod to high transmission areas eg prevalence>10%
Used for short term -> effect wanes within 1-3 months
if prevalence around 10% then potential for impact via MDA on both burden and transmission -> if higher prevalence then more likely to effect burden, if lower than 10 then more likely to effect transmission
What are the concerns surrounding chemoprevention?
Immediate concerns
* Drug safety (adverse reactions)
* Drug efficacy (current levels of resistance)
* Feasible coverage (logistics, acceptability)
* Cost and affordability
Future concerns
* Selection pressure for resistance
* Sustainability – risk of resurgence (cases etc rise as soon as programmes stopped)
* Loss of immunity – age shift in disease
burden (rebound phenomenon)
Common challenges of chemoprevention?
Added value?
– In context of integrated malaria control
– Complexities (ethics, time, money, site availability) of evaluating value added to existing strategies
Effective delivery systems for scaling up
Large numbers targeted - Safety, Compliance, Acceptability
Asymptomatic population - requires excellent Tolerability
Drug resistance
– Concern about falling efficacy of SP for IPTp, IPTi
– Lack of data on resistance threshold, relationship between curative and preventive efficacy is unclear
Changing epidemiology
– Decreasing intensity of transmission in some settings, decreases cost effectiveness of preventive
treatment
– Change in objective and role: IPT vs MDA, IPT vs screen and treat
Describe the concept of rebound with respect to malaria control
Effective control delays the acquisition of natural immunity
After chemoprevention, a RELATIVE increase in malaria, compared to no intervention
Note the underlying age- pattern of disease and death: benefits will be greatest when children are protected during age of maximum risk
What is the molecular basis of resistance?
Gene mutations leading to AA change and resistance occur once in 100 million cell divisions (standard eukaryotic mutation rate)
In absence of drug pressure => they are unfit and die out
Intensive use of drug selects these rare changes
Levels of drug resistance may increase by sequential mutations -> intensifies level of resistance by gradual, incremental process
Why might have resistance eg to chloroquine emerged in SE Asia so consistently?
Hypothesis: drug pressure higher in areas where transmission intensity is lower, fewer people have acquired immunity so high % infections are symptomatic and those people seek treatment
Sequential replacement of drugs -> inevitable
Could be SE Asian parasite has a high mutation rate?
What do we speak about when we refer to artemisinin resistance?
Delayed parasite clearance
What RDTs exist for malaria diagnosis?
HRP2 *best sensitivity
PfLDH
PgLDH
Pf-aldolase
Main drug used for PMC?
Sulphadoxine-Pyramethamine
Main drugs used for SMC?
SP-amodiaquine
Dihydroartemisinin-piperaquine
What factors influence whether a RDT will be positive?
Parasite density
Storage and transport
Quality
Resistance
What mutations exist for HRP RDT failure?
hrp2 (chr8)
hrp3 (chr13)
When should you consider switching from HRP-RDT to non-HRP-RDT if resistance rising in a given population?
We want HRP2 over the other tests as they are 5% more sensitive, but if resistance 5+% including CI then no longer any benefit so advise to switch
Repeat prevalence survey for resistance at 1-2 years post initial one
Would HRP3 deletion always result in negative HRP3-RDT?
Hrp3 deletion alone does not give negative RDT as dependent on protein expression -> HRP2 protein expression levels are high enough (which is dependent on parasitaemia -> if high enough, then enough HRP2 to make RDT positive)
What are the biggest changes to malaria resistance?
Surveillance
PH systems/structures
What are the concerns for quality assurance of vector control measures?
Amount of insecticide in BNs
Effectiveness of insecticide after repeated washing
Checking manufacturer claims of long-lasting nets
Compliance with IRS
What are the concerns for quality assurance of malaria treatment?
Authentication of medicines/placebo
Pk/pd studies
Metabolite levels during clinical trials
Definition of substandard medications?
Medical products that fail to meet their quality standards or specifications or both
Definition of falsified medications?
Medical products that deliberately/fraudulently misrepresent their identity, composition or source
Definition of unregistered or unlicensed medications?
Medical products that have not undergone evaluation and/or approval by National Medicines Regulatory Authority for the market in which they are marked/distributed or used
Definition of degraded medications?
Leave factory as acceptable quality but degrade due to improper storage
What is the three level testing approach for countries without medicine quality testing?
Level 1: visual/physical inspection
Level 2: screening tests or basic tests as supplied by MiniLab
Level 3: complete pharmacopoeia testing (especially for suspect medicines)
Sampling approaches to quality control/assurance
Convenience: but sampling depends on collectors choice of outlet, poor documentation, prevalence estimates not reliable
Random: aim for representative results that can be replicated, but need to authenticate and update sampling frame increases time and cost of survey
Mystery clients: ie get random people to buy drugs then test them
Overt: additional information collected at min additional cost, risk of sampling bias in samples collected
Benefits of LAMP for malaria
Loop-mediated isothermal amplification of DNA
- simple and rapid, results within 1 hour
Can have high sensitivity depending on method and target gene sequence
could be useful in
- pre-elimination settings
- national surveillance and epidemic detection efforts
- in field antimalarial efficacy monitoring & vaccine trials
- possible utility in detecting placental malaria
What can co-infecting microorganisms do in terms of disease, diagnostics and severity?
- Influence host susceptibility to other infections
- Influence host response
- Cause similar or overlapping symptoms -> diagnostic challenges
- Influence severity of diseases
- Influence risk of developing non-infectious diseases
- Influence treatment response and clinical outcomes
Pathophysiology of placental malaria
Infected RBCs bind CSA (chondroitin sulphate A) via pfEMP1 -> sequestration along intervillous tissue -> inhibition of gas exchange and nutrients
How does multigravity affect immunity to placental malaria? How will changing epidemiology of malaria affect this?
Multi-gravidae will develop var2csa-specific IgG -> anti-adhesion Abs that target CSA-binding parasites
so var2csa = candidate for vaccine development
Better malaria control -> changing epidemiology -> less exposure of pregnant women to develop semi-immunity throughout pregnancies -> makes preventative measures even more important
In what epidemiological settings is malaria in pregnancy worse and why?
Low transmission
- less repeat exposure to parasite -> less immunity
placental malaria is more likely to result in severe maternal anemia, low birth weight, stillbirths, and preterm delivery because the mother’s immune system is not as effective at clearing the infection
Impact of malaria in pregnancy on pregnant women?
Asymptomatic:
Splenomegaly
Parasitaemia
Morbidity:
Anaemia
Febrile illness
CM
Hypoglycaemia
Puerperal sepsis
Mortality:
Severe anaemia
Haemorrhage
Impact of malaria in pregnancy on foetus?
Spontaneous abortion
Stillbirth
Congenital infection
Impact of malaria in pregnancy on newborn?
LBW
Preterm birth
SGA
Febrile illness
Mortality
Methods to combat malaria in pregnancy?
1) Case management
2) ITNs
3) IPTp
Case management of malaria in pregnancy
1st Artemether-lumefantrine
2nd line
Artesunate-amodiaquine
Artesunate-mefloquine
Dihydroartemisinin-piperaquine
When is infant mortality highest with lower BW?
Highest risk of mortality in first week = early neonatal period
(NB: late neonatal is day 7-28, then post-neonatal is after day 28)
Primary objectives of preventative strategies for malaria in pregnancy?
- Increase BW for its life-long benefits
(eg IPTp has been shown to increase BW of babies born to mothers who have had at least 2 doses) - Increase maternal Hb levels
Benefit of SP for Malaria in pregnancy for IPTp rather than DP?
Provides some cross-cover for STIs
What is monitoring?
Routine tracking of key elements of a programme or project’s performance
What is evaluation?
Periodic assessment of the change in targeted results that can be attributed to the programme or project intervention
Types of indicators for monitoring and evaluation
Input eg resources, supplies, staff
Process eg activities like training sessions conducted
Output eg knowledge and services like health worker knowledge
Outcome eg practice, patient adherence
Impact eg health outcome
Use SMART to define indicators
Some challenges for routine data collection for monitoring and evaluation?
Data quality and consistency over time
Completeness
Moving data: from facility to district to national
IT capacity and unsuitable surveillance systems
Fragmentation of data, reporting formats, incentives
Capacity at health facilities to interpret data
work load at health facilities
Bias towards well-funded diseases
Things to think about for evaluation?
What is audience and role of evaluation?
What do you want to measure? Impact vs process evaluation
What are externalities (related to economics)?
Positive or negative ‘spill-over’ benefits or costs arising from consumption or production, incurred by people who did not agree to the action
What is economic evaluation?
Comparison of the additional costs relative to the additional health benefits of one intervention vs a comparator intervention
- NB: a product eg vaccine/tablets is NOT an intervention
An intervention requires action by humans with clear definition of who, what, where, when, why, for how long, how often
eg a systematic and transparent framework to help policy makers get the most benefit from their resources, based on their explicit values and preferences
comparative analysis of alternative courses of action in terms of both their costs and consequences
What is cost effectiveness?
Cost effectiveness: judged on opportunity costs, what else could have been achieved with those same resources
- Often involves comparison against a cost-effectiveness threshold
Equation to compare the incremental costs and effects of an intervention B relative to intervention A?
ICER =
(Cost of intervention B - Cost of intervention A) / (Effect of intervention B - Effect of intervention A)
What type of outputs exist for economic evaluation?
Cost per
- cases treated, houses sprayed etc EG process outcome -> cost analysis
- cases cured, reduction in case incidence EG intermediate health outcome (cost effectiveness analysis)
- deaths averted, life-years gained EG final health outcome (cost effectiveness analysis)
- DALYs averted = cost-utility analysis
Equation for DALYS
YLLs + YLDs
YLLs: years of life lost relative to remaining life expectancy at time of death (mostly relevant for malaria, v little of YLDs)
YLDs: years of life with disability
DALYs: a bad that we seek to avert
What factors are within the concept of cost-effectiveness?
Input prices
Vector biology
Scale
Acceptability, utilisation
Capacity to implement
Epi and dem factors
Tech
Existing infrastructure
Theory of vaccines against sexual stages of malaria?
Female mosquito sucks up human plasma (containing Abs) and malaria gametocytes -> these Abs also transferred to mosquito midgut and can block parasite transmission
Benefit of mosquito stages vaccines?
Examples of how these vaccines might work?
Conservation as not much exposure of these Ags to the immune system
- Abs that prevent fertilisation and further development of zygotes
- Abs that facilitate complement mediated lysis of parasite gametes
What is malaria clinical immunity?
Ability to tolerate considerable parasite burden without obvious clinical symptoms
What is anti-parasite immunity?
Ability to limit parasite growth and maintain parasite density below the threshold for development of clinical disease
Rationale for malaria vaccines targeting blood stage?
Target parasite at most destructive stage
Protection does not necessarily have to block all infection but should reduce blood parasitaemia -> reduce disease severity
Major targets:
- surface Ags
- Ags that are involved in merozoite invasion
eg
Abs that block RBC invasion
Abs that enhance parasite phagocytosis by macrophages eg cytokines and T cells that activate macrophages
Abs that preclude sequestration and binding of infected RBCs to activated endothelium
Rationale behind pre-erythrocytic stages for malaria vaccines? Aim of Abs at this stage?
Multiple immunisations in rodents with irradiated sporozoites showed complete protection (also done in non-human primates then humans)
Abs
- that neutralise sporozoite infectivity/block invasion
- T cells and cytokines that inhibit the development of liver stage parasites
What is RTS,S made up of?
Two proteins RTS, S (contain sequences of circumsporozoite protein) in fusion protein with
What metrics can be used for surveillance?
Incidence: no. new cases/pop time
Positivity rate: number of positive tests/no. people tested (normally facility based)
Prevalence: proportion of the population who are infected, often measured in high risk groups eg young children
Under 5 mortality rate
Seroconversion rate
Entomological innoculation rate (EIR) and/or mosquito density/sporozoite rate
