Malaria DTM&H for brainspace Flashcards
(131 cards)
1
Q
Malaria Lab RBC enlarged
A
Pv Po
2
Q
Malaria Lab Multiple trophozoites
A
Pf
3
Q
Malaria Lab Maurer’s clefts Pf
A
few, unevenly distributed
4
Q
Malaria Lab Schuffner’s dots Pv
A
many, evenly distributed
5
Q
Malaria Lab Fimbriation
A
Po
6
Q
Malaria Lab Lifecycle (exoerythrocytic human)
A
Malaria-infected female Anopheles mosquito inoculates sporozoites into human host dermis during blood meal, sporozoites migrate to blood stream, infect liver cells, mature into schizonts which rupture and release merozoites, Pv & Po have hypnozoites that can persist and cause relapse (sporozoite > schizonts > merozoites)
7
Q
Malaria Lab Life cycle (erythrocytic human)
A
Merozoites infect RBC, ring stage troph mature into schizonts which rupture releasing merozoites, most infect RBC continuing the cycle, some differentiate into sexual stage (gametocytes) esp as the human host becomes unwell (merozoites > troph > schizonts > merozoites OR gametocytes)
8
Q
Malaria Lab Life cycle (mosquito)
A
Female Anopheles takes blood meal from human ingesting female and male gametes, change in temperature inside mosquito -> fertilisation, motile ookinete penetrates midgut epithelium and differentiates into oocyst, sporozoites develop in oocyst, mature oocyst ruptures (2w), releasing motile sporozoites migrate to salivary glands awaiting blood meal. (gametocytes > zygotes > ookinetes > oocyst > sporozoites) Female anopheles must take a blood meal every 2-4 days to reproduce
9
Q
Malaria Lab Counting parasitaemia
A
Percentage of RBC infected (not no. of parasites). Want to count 2000 RBC, on x100 look within field where RBC do not overlap and count eight consecutive fields - count downwards as the density of the field will remain similar. Eg. 9 in 8 fields is 9 in 2000 is 4.5 in 1000, is 0.45 in 100 fields, is 0.45%
10
Q
Malaria Lab Microscopy
A
Brain: haemorrhage (orange areas), vessels that look dark, classic feature is ‘ring haemorrhage’ with capillary in centre - black dots stuck to capillary wall are schizonts - usually peripheral RBC sticking and block the capillaries, Liver tissue looks less tidy than normal liver. Pigment in sinusoidal spaces (within Kuppfer cells) not within hepatocytes. Will not see parasites, just evidence of macrophage clearing up. Liver is engorged
11
Q
Malaria Lab Peripheral blood stages
A
All present for Pv, Po, Pm. Mature troph of Pf tend to be sequestered in deep vessels
12
Q
Malaria Epidemiology
A
Treatable tropical disease, estimated 608,000 deaths and 249 million cases in 2022. Endemic through Mexico, Northern South America, sub-Saharan and southern Africa, South and SE Asia. Lowest income countries are disproportionately the countries where Malaria is seen and deaths occur
13
Q
Malaria Deaths
A
Over half of malaria deaths are in four countries: Nigeria, DRC, Niger, Tanzania
14
Q
Malaria Stalled progress
A
Since 2013/14 progress against preventing malaria diseases have stalled as the money eliminated malaria from the ‘easy’ countries, places where there was intermittent transmission, countries with more political stability and money in their healthcare system, or countries such as Sri Lanka which is an island nation – easier to control the migration into and out of the countries and an easy barrier for mosquitos. Elimination is removing from an area or region, Eradication is completely getting rid of it. Malaria is not a human-specific disease and zoonotic spill over makes eradication almost impossible for Pk which has animal reservoir (macaque monkeys). Progress has stalled due to COVID-related disruptions, health systems challenges, humanitarian crises, limited funding, effects of climate change, insecticide & artemisinin resistance and invasion of Anopheles stephensi
15
Q
Malaria Pathogenesis
A
Symptoms develop once parasitaemia rises above a certain threshold. Threshold depends on underlying immunity (influenced by endemicity, transmission intensity, and the age of the patient) Periodic fever spikes correspond to erythrocytic cycle, and synchronisation of developmental stages (these are rarely observed now). Erythrocytic cycle is the only part of the cycle that causes disease symptoms. Asexual cycle time of different Plasmodium species gives characteristic cycling fevers. 24h Pk, 48h Pf, Pv, Po, 72h Pm
16
Q
Malaria Cerebral malaria
A
Adherence or sequestration of RBC -> inflammation, microvascular obstruction -> hypoxic brain tissue, disruption of BBB -> oedema and haemorrhage, parenchymal and axonal damage. Similar mechanism in placenta with adhesion -> growth restriction (mild) or fetal and maternal demise (severe). CFR 10-40% Clinical features: impaired consciousness, retinopathy (retinal whitening, discolouration of retinal vessels, retinal haemorrhages and papilloedema), convulsions common (can be subclinical), increased ICP (>80% of children,), cerebral oedema (more common in children)
17
Q
Malaria Severe malaria
A
- Haemolysis of infected RBC -> decreased O2 carrying capacity, rosetting of RBC -> bystander haemolysis. 2. Metabolic acidosis (poor prognostic sign) -> impaired vasoregulation, platelet clumping, lactic acidosis, inflammation. 3. Hypoglycaemia due to N&V, fasting, quinine, metabolic acidosis. 4. AKI 5. Bacteraemia (higher risk in children, esp non-typhi Salmonella) 6. Jaundice, DIC and shock - cardiac dysfunction and arrhythmias uncommon
18
Q
Malaria Severe anaemia
A
Common (esp African children), Hb <50 in children, <70 in adults. Multifactorial (spleen filters infected and damaged uninfected RBCs, intravascular haemolysis, bone marrow suppression, repeated malaria infection), other contributors: HIV, bacterial infections, hookworm, B12/vitA deficiency. The major cause of severe malarial anaemia is loss of uninfected RBCs and suppression of bone marrow (unlike the assumption that it would be the lysis of pRBCs). changes to the plasma membrane of uninfected RBCs during malaria infection targets these cells for destruction in the spleen. Erythropoiesis failure is caused by haemozoin (breakdown product of Hb by parasite), suppressive cytokines, hepcidin and migration inhibitory factor expressed by the parasite
19
Q
Malaria PfEMP1
A
Plasmodium falciparum erythrocyte membrane protein 1 - immune evasion molecule (60 var genes) cytoadhesion and provides target for human immune system. Host immune system mounts response, but parasite regularly switches var genes (process not well understood) but allows the parasite to stay ahead of the immune system
20
Q
Malaria Pf gametocytes
A
Lose sensitivity to antimalaria drugs as they mature. Asymptomatic gametocyte carriers are a significant problem for malaria control and eradication (as are recovering patients) as they are highly infectious to mosquitoes. Sexual dimorphism: 80% F 20% M. Change in temperature in the mosquito triggers fertilisation and development of zygote
21
Q
Malaria Hypnozoites
A
Liver form of Pv Po - stay as dormant stage (not well understood) days to months/years - occasionally releases sporozoites into bloodstream with resurgence of sx. Pv especially causes social disadvantage due to recurrent infections. Treat with Primaquine (toxic and need to test G6PD)
22
Q
Malaria Prevention efforts (human)
A
Vaccinate against surface of sporozoite - could prevent invasion of hepatocytes - need lots of boosters and response not durable. RTS,S approved by WHO in Oct 2021 (targets CSP of Pf, efficacy 36% clinical malaria, 32% severe malaria
23
Q
Malaria Prevention efforts (mosquito)
A
IRS Indoor residual spraying Insecticides, LLIN long-lasting insecticide bed nets, sterile genetically-modified mosquitoes
24
Q
Malaria Prevention efforts (what’s needed)
A
WHO guidelines to address challenges (contain drug resistance, urban malaria control, stop spread of An stephensi), Innovation and accelerate research & development (RTS,S vaccine, LLINs, new types of vector control, new diagnostics and medicines). Strengthen health systems and increased coverage of current malaria control tools. Ensure robust global malaria funding
25
Malaria Resistance
Due to massive replication, there is significant risk for resistance development. ACT not yet failed in SE, but double dose required. Need to use in different combinations and doses to prevent transmission. Chloroquine was mainstay until ~50y ago, resistance emerged in 1950s, spread from Asia to Africa, resistance to artemisinins and partner drugs emerged in SE Asia, now arisen independently in Africa - presents a major threat. Insecticide (pyrethroid) resistance also presents a major concern. Pf lacking HRP2 are evading diagnosis - 20% Africa, 80% SE Asia. WHO recommendation in areas with >5% false negative RDT due to HRP2 gene deletions to use a non-HRP2 based RDT - however, this reduces the choice and quality of the kits available
26
Malaria Pf pathogenesis
1 Erythrocytes infected with mature parasites (trophozoites & schizonts) sequester intravascularly. 2 Sequestration is caused by adherence between endothelial cells and knob-like projections on the RBC membrane (expressing PfEMP1). 3 Infected RBCs also bind to uninfected cells (rosetting) and uninfected cells become less deformable -> microvascular obstruction. 4 Clinical impact of sequestration depends on the organ affected
27
Malaria Antimalarial immunity
In endemic areas, people can be infected with malaria repeatedly - repeated exposure leads to gradual acquisition of immunity (partial and not sterile - never complete). Two types of immunity develop in parallel and decrease the probability of symptomatic malaria 1. anti-parasite (able to control parasite density) 2. anti-disease (able to tolerate higher parasite densities without fever). Age and exposure independently impact on development of immunity (children living in moderate/high transmission settings develop immunity faster as transmission increases). Immunity wanes without continued exposure (important factor to consider for travellers, internationally VFFR, locally (urban to rural, well controlled to higher transmission areas)
28
Malaria R0 and Ross MacDonald equation
R0 = 1 -> stable transmission - each case gives rise to a single further case, total number of cases remains the same. R0>1 -> cases increase until entire population is infected, R)<1 -> cases decline until infection disappears. Ross-MacDonald equation takes into consideration mosquito density (number of female mosquitoes per person), frequency with which each female bites a human (vs animal), survival rate (probability of mosquito surviving a full day after being infected), length of sporogonic (extrinsic cycle), recovery rate in humans.
29
Malaria Danger signs <5y
Fever or history of fever in the past 24h OR palmar pallor PLUS one or more of the following: unable to drink or breastfeed, vomiting everything, multiple convulsions, lethargy, unconsciousness, stiff neck, chest indrawing or stridor
30
Malaria Danger signs >5y & adults
Fever or history of fever in the past 24h PLUS one or more of the following: very weak or unable to stand, convulsions, lethargy, unconsciousness, stiff neck, respiratory distress, severe abdominal pain
31
Malaria Definition of severe falciparum malaria
Impaired consciousness (GCS<11, Blantyre <3 children), Prostration (generalised weakness so that the person is unable to sit, stand or walk without assistance), Multiple convulsions (mor than 2 episodes within 24h), Acidosis (base deficit >8 or plasma bicarb <15, or lactate >=5), Hypoglycaemia (BSL <2.2), Severe anaemia (Hb <50 or Hct <=15% in children [<70 and <20% in adults]), Renal impairment (Cr>265 or Ur>20), Jaundice (Bili>50), Pulmonary oedema (radiology or SaO2<92% with RR>30 [+/- indrawing/crepitations]), significant bleeding (recurrent or prolonged bleeding from nose, gums or venipuncture sites, haematemesis, melaena), Shock (sBP<70 children <80 adults, evidence of impaired perfusion) Hyperparsitaemia Pf >10% in endemic region >2% non-endemic)
32
Malaria Key concept
Suspect malaria & order test (if initial negative and no alternative dx, retest in 12-24h). Pf or not, severe or uncomplicated? Malaria is a medical emergency (esp in non-immune), evaluate immediately (consider if any prophylaxis taken), consider other tropical infections (typhoid, hepatitis, dengue, VHF, influenza, COVID, HIV etc) - need at least 3 negative diagnostic tests over 24-48h to rule-out malaria
33
Malaria Diagnosis
Clinical (NO!), Microscopy of thick and thin films, RDT detect HRP2 and pLDH. PCR (generally not available in low resources settings) pLDH may be Pf specific or pan-plasmodium
34
Malaria Microscopy vs RDT
Microscopy low cost, high expertise, requires electricity, slow, sens varies on skill, higher spec, speciate and quantify parasites, becomes negative with cure. RDT high cost, low expertise, no electricity, fast, sens varies on kit, lower spec (more variable), can only speciate Pf vs non-Pf, cannot quantify, and will remain positive for weeks to months following treatment
35
Malaria Treatment (uncomplicated)
ACT x3 days ie artemether-lumefantrine (AL). Must do clearance films to make sure genuine clearance
36
Malaria Recurrent Pf
Recurrent can result from reinfection or recrudescence (treatment failure). Treatment failure may be due to drug resistance, suboptimal dosing, poor adherence or vomiting, substandard medicines. Confirm recurrent with microscopy (not PfHRP2 RDTs). May not be possible to distinguish recrudescence from reinfection in individual patients (without PCR for genotyping). Reinfection very common in high transmission areas
37
Malaria Management of treatment failure
Within 28d - alternative ACT to that given first, After 28d consider as a new infection, treat with first line ACT
38
Malaria Admission
Patients with Pf malaria can deteriorate rapidly, even with appropriate treatment (esp non-immune), recommend admitting all patients with Pf for initial treatment. Closely monitor patients with hyperparasitaemia >2-10%, if there is any doubt about the species, or there is coinfection, treat as Pf malaria until diagnosis is clear
39
Malaria Treatment (pregnancy)
Artemether-lumefantrine in all trimesters, other ACTs T2-3. Mefloquine safe in T2-3 with artemisinin derivative. Quinine increased risk hypoglycaemia in late pregnancy, only if effective alternatives not available. Primaquine and tetracyclines should not be used
40
Malaria Treatment non-Pf
Unsure about species - treat for Pf. If non-Pf in area of chloroquine sens - Rx ACT or CQ, chloroquine resistant Rx ACT.
41
Malaria Pv Po prevent relapse
Primaquine, after checking G6PD status if normal give 0.25mg/kg/d 14d (alternative 0.5mg/kg/d 7d - shorter may improve adherence and thus fewer relapses) Cannot give in pregnant women, infants <6m, breast feeding infants <6m or older infants with unknown G6PD status. Pregnant women get weekly chemoprophylaxis with CQ until delivery and breastfeeding complete, then depending on G6PD, give primaquine. In patients with G6PD deficiency can give primaquine 0.75mg/kg weekly for 8w under close medical supervision for haemolysis
42
Malaria Primaquine to prevent transmission
Primaquine kills mature gametocytes of Pf, in endemic low transmission areas, single dose of primaquine (plus ACT) is recommended to reduce the risk of onward transmission. It is not recommended in no-transmission areas as there is no vector (Anopheles mosquito)
43
Malaria Common management errors
Delayed care-seeking, failure of HCW to consider malaria, belief that chemoprevention prevents all malaria, belief that malaria is unlikely if the patient doesn't remember being bitten by mosquitoes, belief that malaria always has classic fever pattern, failure to recognise non-specific symptoms of malaria, failure to immediately obtain a diagnostic test, failure to repeat diagnostic tests if initially negative, failure to prescribe effective treatment immediately, failure to anticipate or treat complications
44
Malaria Travel advice
Sleep under insecticide treated bednet, cover up between dusk and dawn, repellents with 30-50% DEET
45
Malaria Chemoprophylaxis key concepts
Options are Malarone (AQ), Mefloquine, Doxycycline and Primaquine. Pregnant (give Mefloquine), Children (avoid Doxycycline), Depression (avoid Mefloquine). Start 1-2d prior except Mefloquine 2-3 weeks prior. Continue 7d after returning for Malarone and Primaquine, 4w after returning for Mefloquine and Doxycycline. All are given daily except Mefloquine is weekly
46
Malaria Pathophysiology
After infection, protuberances appear on erythrocyte surface within 12-15h, 'knobs' express PfEMP1 (antigenically variable, strain-specific, adhesive protein), which mediates cytoadherence or attachment of the pRBC to endothelial receptors. pRBCs adhere inside vessels (sequestration) to each other (agglutination) and to non parasitised RBC (rosetting) - in non Pf malaria, significant sequestration does not occur. Most of the major manifestations of severe falciparum malaria are caused by sequestration, microvascular obstruction and organ dysfunction
47
Malaria AQUAMAT
Africa (9 countries) severe malaria - 4 key predictors of poor outcome: base deficit >8, coma, Ur>20, underlying chronic illness. Mortality artesunate 8.5% quinine 10.9%
48
Malaria SEAQUAMAT
SE Asia mortality artesunate 15% quinine 22%
49
Malaria Treatment (complicated)
Artesunate IV at 0, 12, 24h. Once received at least 24h parenteral therapy and can tolerate oral, give further 3d ACT. Main objective is to prevent patient from dying, secondary objectives are prevention of disabilities and recrudescent infection. Death from severe malaria often occurs within hours of admission (therapeutic conc of effective antimalaria must be achieved ASAP), severe malaria is a medical emergency, parenteral artesunate is the treatment of choice for all severe malaria. Artesunate rapidly kills ring-stage parasites which are then taken out of the red cells by the spleen, the infected RBC are then returned to circulation but with a shorter life span, resulting in haemolysis. Delayed haemolysis starting >1 week after treatment of severe malaria with artesunate has been reported in hyperparasitaemic, non immune travellers.
50
Malaria Treatment (pre-referral)
The risk for death from severe malaria is greatest in the first 24h (but often the time between referral and start of IV is long, delaying the start of appropriate antimalarial treatment can increase risk of death). Where complete treatment of severe malaria is not possible, but injections are available, adults and children should be given (single IM artesunate & referred to an appropriate facility, if IM artesunate not available, give IM artemether. Where IM injection of artesunate is not available, children <6 should be given a single rectal dose of artesunate and referred immediately
51
Malaria Antibiotics
All children presenting with severe malaria in areas of intermediate and high malaria transmission should be given broad spectrum antibiotics in addition to anti-malarial drugs
52
Malaria Supportive care
Coma (maintain airway, exclude other causes such as low BSL, meningitis), Convulsions (diazepam & anticonvulsants, check glucose), hypoglycaemia (recognise and treat), severe anaemia (transfuse), pulmonary oedema (O2, diuretics, I&V), renal failure (dialysis, haemofiltration, PD), metabolic acidosis (exclude/treat hypoglycaemia & septicaemia), spontaneous bleeding (transfuse, give vitK), shock (suspect bacterial coinfection & septicaemia). Additional management: 1 fluid therapy 2 blood transfusion 3 exchange transfusion (no consensus on whether it reduces mortality)
53
Malaria Adjuvants
Do not use any of these, they do not work - including dexamethasone, anti-TNFa, IVIg, phenobarbitone, mannitol, NAC etc
54
Malaria Cerebral malaria outcomes
Most children who survive make a full recovery, ~15% left with neurological sequelae. Longterm sequelae uncommon in adults (<3%)
55
Malaria Pregnancy
Pf sequesters in the intervillous space of the placenta. Cytoadherence is mediated by binding to chondroitin sulphate A (CSA). First time mothers lack immunity to CSA-binding parasites and are highly susceptible to parasitaemia and chronic infection. As a result, this group is an important reservoir of infection. Over successive pregnancies women can acquire antibodies against CSA-binding iRBCs and resistance to placental malaria. Women living in endemic areas develop antimalaria immunity from lifelong exposure to Pf parasites, which controls infection. Thus, total parasite biomass may be low and difficult to diagnose during pregnancy, even in the presence of placental infection. Placental malaria associated with IUGR, preterm birth, LBW, SGA, stillbirth. Worse with 1st pregnancy, reduces with subsequent. Not just Pf, all malaria infections are harmful. Pregnant women are more likely to have severe malaria (T2-3, higher mortality ~50%), at risk of pulmonary oedema & hypoglycaemia (low transmission areas/non-immunes), at risk for fetal death and premature labour. Parenteral artesunate is the treatment of choice in all trimesters. Mechanism is sequestration (mechanical) and pro-inflammatory
56
Malaria HIV coinfection
Considerable geographic overlap, evidence that HIV coinfection increases malaria severity (higher parasite densities (in partially immune), risk of severe malaria and death (in less immune), in pregnant women - increased adverse effects of placental malaria. HIV patients at higher risk of adverse events and drug interactions: avoid SP if taking SXT, efavirenz increases AQ exposure & risk of toxicity
57
Malaria Severe Pv
Defined as for Pf but no density threshold. Severe manifestations include severe anaemia, resp distress, AKI. Less commonly cerebral malaria, pancytopaenia, splenic rupture, haemoglobinuria, jaundice, renal failure, shock. Treat as for severe falciparum and give primaquine after recovery
58
Malaria Severe Pk
Defined as for Pf but 2 differences parasite density >100,000/uL and jaundice/parasite density >20,000uL. Associated with high parasite densities. Can present with ARF, shock or resp failure. Treat as for falciparum. Microscopically indistinguishable from Pm but with high parasitaemia and clinical symptoms
59
Malaria Key messages
Severe malaria is a medical emergency (manifests differently in children and adults). Treat early with an effective antimalarial (Artesunate > artemether > quinine - watch for late haemolysis after artesunate), give broad spectrum antibiotics to children, be careful with fluid replacement and transfusion. Treat complications appropriately. No good evidence to support most other treatment
60
Malaria Anopheles stephensi
Capable of transmitting Pf and Pv, unlike other main malaria vectors, it thrives in urban and man-made environments (behaves more like Aedes). Can resist high temperatures thus sustaining malaria transmission in dry seasons. Estimate Pf cases could increase by 50% if no additional interventions are implemented. Usually in Asia, is invading through the horn of Africa. Potential to reverse gains in malaria control - not equipped to handle increased urban malaria burden in Africa, difficult to target the vector with standard control interventions. Interventions in place: increased vector surveillance, increased collaboration between different sectors, bylaws on water storage in urban settings, increase vector control strategies that can target the vector (ie larveciding), ongoing coordination meetings led by WHO
61
Malaria Nosocomial transmission
Big problem due to inpatients with circulating gametocytes - advise to sleep under bed net in hospital
62
Malaria Antenatal prevention
Intermittent preventive treatment is recommended in primigravid pregnant women, accessed through antenatal clinics
63
Malaria Preventive factors
Sickle cell heterozygous have 10% of the risk of death from Pf compared with those who are homozygous, HbC, thalassaemias, G6PD. O blood type also protective - these probably affect cytoadhesion and splenic clearance, but not straightforward. Haemoglobinopathies prevent the parasite from establishing own actin cytoskeleton within the host cell, impair vesicular transport, reduced cytoadherence and distort trafficking of PfEMP1
64
Malaria Inflammatory cytokines
Regulation of inflammatory mediators is key to successful resolution of malaria infections. Low levels are beneficial - activation of macrophages to phagocytose infected RBCs and to release toxic radicals that kill the parasite. However, high levels of cytokines cause pathology and disease - instigate fever, increase expression of adhesion molecules on vascular endothelium (higher levels of parasite and leukocyte sequestration), decrease blood glucose levels, inhibit erythropoiesis, promote tissue damage, promote phagocytosis and killing of uninfected RBCs
65
Malaria RTS,S vaccine
RTS,S Ag consists of sequences of circumsporozoite, needs 4 doses, low efficacy (26-51%) and not durable, WHO have rolled out from Oct 2021
66
Malaria R21 vaccine
R21 fused circumsporozoite protein sequences, needs 3 doses plus booster year later, 66% efficacy
67
Malaria Immunology
Immunity to malaria is acquired following natural infection. The rate of development of immunity depends on the intensity of malaria transmission. Different immune mechanisms operate to decrease parasite prevalence, parasite density and the risk of severe disease and death. Many of the symptoms of malaria are caused by overproduction of inflammatory cytokines. Low levels of these cytokines are required to mediate parasite killing. Malarial immunity involves both antibody-mediated and cell-mediated mechanisms, but these may be directed against different stages of the life cycle and against different antigens. Two modestly efficacious malaria vaccines have been recommended by the WHO
68
Malaria Po
Two subspecies curtisi, wallikeri - highest prevalence in African continent. Clinical: longer latency period, understudied, likely underestimated burden. RDT false negatives are common, molecular diagnosis unreliable
69
Malaria Pm
Neglected and commonly benign. Associated with rare kidney pathologies and fatalities. Frequently low parasitaemias, chronic infection suggests immune evasion. Reports of reduced drug susceptibility
70
Malaria Control Clustering heterogeneity
There are always some houses without infection (closed, further from water sources), some with low transmission. Hot populations 'hot pops' are at risk because of what they do (not where they live) ie agriculture work, seasonal exposures
71
Malaria Control Interventions
1 Prevent the malaria coming out of the mosquito (vaccine targeting sporozoite stage) 2 Chemoprevention - prevent the emergency of parasite from the liver 3 Improved case management 4 Prevent onward transmission through mass drug administration and treat people with primaquine to kill gametocytes (difficult). 5 TBV transmission blocking vaccines, insecticide nets, insecticide residual spraying 6 Stopping the production of mosquitoes
72
Malaria Control Challenges for success
Finances, drug resistance, vector resistance (biochemical, behaviour), diagnostic resistance (HRP2), organisation, climate change - in some places malaria will be too hot to exist and other places will become more susceptible
73
Malaria Control Interrupting transmission using vector control
Reduce vector density (kill, or eliminate breeding sites etc), reduce human-vector contact, reduce the vector's capacity to carry parasite
74
Malaria Control Vector control strategies
LLIN long-lasting insecticidal nets, IRS indoor residual spraying, Larviciding, House screening
75
Malaria Control Insecticide resistance
Evolutionary process leading to decreased sensitivity of a vector population to an insecticide. Resulting from selection pressure due to continuous exposure to an insecticide. Mechanisms: target site, metabolic resistance, behavioural resistance, cuticular resistance/reduced penetration
76
Malaria Control Next generation ITNs and IRS
new insecticides, new modes of action
77
Malaria Control Climate change
Climate change alters temperatures and weather patterns in ways that change vector dynamics and increase the risk of malaria. Warmer temperatures can alter vector survival, abundance and increase the geographical spread of malaria vectors. Extensive rainfalls and floods can create more breeding sites extending malaria transmission seasons. Changes in weather can alter mosquito composition, resulting in higher densities of more efficient vectors. Weather changes can affect human behaviour facilitating habits that expose them to vectors eg sleeping outside in hot weather. Temperature changes accelerate changes in vector behaviour, enabling them to escape traditional vector control interventions. Temperature and humidity changes can affect the efficacy of some vector control products.
78
Malaria Control ITNs
ITNs are a key malaria prevention strategy with ~2.7 billion nets distributed by 2022. ITN access - not reaching those who need them most. Householders do not sleep under nets, not durable (retention <2y), fabric integrity - insecticide durability. Mitigation strategies: improve ITN allocation eg digitalisation, social and behaviour change campaigns, new metrics to track ITN durability and improve quality. ITNs can lose protective efficacy in the 3rd year post-distribution, including new dual AI ITNs
79
Malaria Control Threats to control
Outdoor transmission - increase in vectors biting outdoors reduces efficiency of indoor vector control tools like ITNs and IRS. Natural disasters, conflict situations and demographic changes
80
Malaria Control Expanding vector control toolbox
Bait stations (attractive targeted sugar baits - attract and kill, effective up to 6m, promising for controlling outdoor transmission), spatial repellents (transfluthrin passively emanates using natural airflow), systemic insecticides, genetic manipulation, topical repellents, insecticide treated clothing, housing modification, lethal house lures
81
Malaria Control Key messages
Vector control is an important part in the prevention and control of malaria. It was the foundations of the global reductions in malaria burden. Its impact is threatened today by many factors, insecticide resistance, poor durability of nets, reduced funding to boost coverage, invasive species, climate change, outdoor transmission etc. New promising ITNs and IRS have been developed and are being scaled up across Africa. The vector control toolbox is being expanded to go beyond ITNs and IRS eg spatial repellents, ATSBs, Eaves tubes etc – evidence is being generated. Achieving malaria elimination targets will require an integrated and context specific approach which includes vector control
82
Malaria Chemoprevention definition
Administration of a full therapeutic courses of antimalaria treatment to a population at risk, whether infected or not, at defined time points separated by periods without drug exposure – for people living in endemic areas, goal is to reduce burden
83
Malaria Chemoprophylaxis definition
Administration of an anti-malaria drug to an at risk population in such a way as to achieve protective blood levels over the whole of the period at risk – subtherapeutic doses primarily used by non-immune travellers to malaria endemic areas
84
Malaria IPTp Intermittent preventive treatment in pregnancy
Aim: reduce malaria burden in pregnancy. Intervention: from 2nd trimester SP (sulfadoxine-pyrimethamine) at least one month apart, at least 3 doses
85
Malaria PMC perennial malaria chemoprevention (previously known as intermittent preventive treatment in infants)
Aim: reduce clinical malaria, severe malaria, anaemia and all-cause hospital admission. Intervention: SP or SP+AQ at 10w, 14w, 9m
86
Malaria SMC seasonal malaria chemoprevention (previously known as intermittent preventive treatment in children)
Aim: reduce severe anaemia in areas of highly seasonal transmission. Intervention: SPAQ monthly starting before rainy season, and continuing one month after
87
Malaria IPTsc intermittent preventive treatment in school aged children
Aim: target school aged children aged 5-15. Intervention depends on school terms
88
Malaria PDMC post-discharge malaria chemoprevention
Aim: prevention of malaria following severe anaemia, allows patient to fully recover. Intervention. Outcome: 77% reduction in all-cause mortality, 55% reduction in all-cause readmissions
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Malaria Chemoprevention summary
Chemoprevention target different population at risk in different malaria transmission settings. Recommendations to provide more flexibility to countries to adapt these control strategies to suit their settings and priorities. Generally use non-first or second-line treatments. SP with or without another drug mostly used. Importance to continue to monitor the resistance to the drugs
90
Malaria Vaccine summary
Vaccines very effective - important additional tools in the fight against malaria. Rapid deployment of the vaccines underway with 20+ countries preparing to roll out, careful introduction and finding optimal delivery methods, combination with other interventions, evaluation of these vaccines in other age groups, next generation of vaccines - combination with transmission blocking and blood stage vaccines.
91
Malaria Control Indoor residual spraying challenges
Effective tool recommended for scaling up global malaria control. Coverage abysmal 11%, pyrethroid resistance resulting in reduced efficacy. High operational cost.
92
Malaria Control Case management challenges
Microscopy capacity is low across Africa, lab diagnosis relies on RDT kits, testing rates are still poor - without testing we do not truly know the burden of malaria. Most RDTs detect Plasmodium falciparum histidine-rich protein 2 (HRP-2) - Threats: gene deletions reduce sens of RDTs causing false negatives, RDTs detecting Pf- or pan-LDH provide less sensitive alternatives and are more expensive. Under-testing - despite recommendation for every case of fever to have a malaria RDT, only 54% are being tested 2015-2023 (improved from 30% 2005-2011)
93
Malaria Control ACT challenges
Emergence of artemisinin resistance in SE Asia and now spreading to Africa, poor access to treatment, especially hard to reach communities, patriarchal barriers (mothers need to wait for husband to return for permission to take child to healthcare), delayed treatment, poor quality of care
94
Malaria Control Chemoprevention challenges
IPTp has been implemented at scale for several years, yet coverage is suboptimal, missed opportunities in antenatal clinics, SP resistance now a threat esp East Africa
95
Malaria Control Surveillance challenges
Low capacity for surveillance, weak systems (inadequate supply of tools, limited number of trained personnel, incomplete reporting - private sector reporting still a huge challenge in most countries), systems are weakest where the burden is heaviest, poor notification and response during emergencies (eg humanitarian crises)
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Malaria Control Environment challenges
Malaria receptivity is high in most parts of sub-Saharan Africa given the suitable ecology and climate for vector survival. Climate change disruptions including population displacements and mass movement increase malaria risk. Poor integration of real-time meteorological data into national and sub-national malaria monitoring and surveillance systems prevents mitigation planning. Emergence and re-emergence of novel vectors eg Anopheles stephensi
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Malaria Control Challenges key points
Reaching the 2030 goals of the WHO malaria strategy will require new approaches, new tools nd the better implementation of existing ones. Tailoring existing approaches to prevention, diagnosis an treatment to local contexts. Better and more equitable access to all health services. Strengthening the health systems overall, with a view to achieving universal health coverage. Stepping up both domestic and international investment.
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Malaria Control Panel discussion
Lots of inefficiencies in domestic financial management and global funding often goes unspent because countries are unable to use the funding 'fast enough' Financing in rich countries is prioritised by the effect upon rich countries (ie impact on military). Genetically modified mosquitoes are innovative, but need community engagement as concept rejected at present. Vaccine and chemoprevention only protect the person, vector control has a bigger community effect.
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Malaria Prevention ABCD of preventing malaria
Awareness of risk, Bite prevention, Chemoprophylaxis, Diagnose promptly and treat without delay
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Malaria Prevention Awareness of risk
Place: sub-Saharan Africa, areas of deforestation, rural vs urban, type of accommodation. Time; Longer term travellers, seasonality. Person: VFR, extremes of age, pregnancy, immunosuppressed, comorbidities. Awareness of risk: the clinical features of malaria are non-specific - fever, sweats or chills, malaise (vague discomfort), myalgia (muscle pain, tenderness), headache, diarrhoea, cough. Awareness important for you and the patient
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Malaria Prevention Malarone (Atovaquone-proguanil)
Daily 1 d before 7d after. Consider DDI, renal dosing, fatty meal, cannot crush. Preg/BF T2 onwards. SE neuro, GI, hairloss. Malarone is the default option unless pregnant or CrCl<30. It is expensive.
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Malaria Prevention Doxycycline
Daily 1d before 4w after. Consider DDI, take with food. Preg/BF not after 15/40, SE gastritis, teratogen, bones/teeth, photosensitivity
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Malaria Prevention Mefloquine
Weekly 3w before 4w after. Consider DDI, psych hx, can crush, epilepsy, anticoag, allergy to quinine. Preg/BF safe, SE neuropsych & epilepsy (including 1st degree relatives) - would not use in diving, flying, military, cardiac etc
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Malaria Prevention Tafenoquine
Long half-life 18d, monthly for 6m, causally protective. Consider G6PD. Access is an issue
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Malaria Prevention Pregnancy
Discuss cancelling trip. Increased risk of severe malaria, esp vivax > congenital. Placental sequestration -> difficult/delayed diagnosis. Mefloquine - all trimesters, Doxycycline - if finish 4w post travel by 15w (in practice no), Atovaquone-proguanil - safety data does not suggest any adverse effect but sparse data - take folic acid.
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Malaria Prevention Anticoagulants
Inform MO 2-3w before travel. Warfarin: Mefloquine ok, others may interact. DOAC: Mefloquine may increase risk of bleeding, Atovaquone may reduce anticoagulation
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Malaria Prevention Epilepsy
Choose doxycycline or atovaquone/proguanil
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Malaria Prevention Children
Risk of rapid deterioration, weekly mefloquine easiest >5kg. Atovaquone-proguanil >5kg with milk/yoghurt, Doxycycline >12y
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Malaria Prevention Elderly
Higher risk of dying from malaria, comorbidities, drug-drug interactions, renal impairment
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Malaria Prevention Renal disease
CrCl <30 avoid malarone - can use mefloquine and doxycycline
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Malaria Prevention Liver disease
All metabolised in liver, Severe use doxycycline
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Malaria Prevention MoA
Causal (stop hepatocyte infection) Malarone, Primaquine. Suppressive (kill ring stages - need 30d) doxycycline, mefloquine, chloroquine
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Malaria Prevention Standby emergency self-treatment
Doctors may prescribe SBET in some circumstances such as when the risk of the travellers to get malaria is low (if it is high, consider prophylaxis), the travel destination is remote and medical care may not be available, travellers must be advised and fully understood when and how to use SBET
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Malaria Prevention Vaccination
circumsporozoite protein on parasite surface
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Malaria Prevention Monoclonal antibody
L9LS CSP1 major protein of the sporozoite - only a handful of sporozoites during a single cycle of infection, sporozoites are accessible early in infection, 3-6 months protection. Very expensive, not commercially available.
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Malaria Prevention Summary
The burden of diseases occurs in VFR population. 70% falciparum malaria patients have not taken chemoprophylaxis. Adherence to advice, BPM and medication is the cornerstone of effective prophylaxis. There are a limited number of prophylactic drugs. Early presentation and diagnosis are part of disease prevention. Malaria risks for travellers are changing.
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Malaria Small Group Diagnostics
Blood films: speciation, parasitaemia estimation. RDTs: sensitivity comparable to blood film, don't need to be an expert, semi-speciation
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Malaria Small Group Child assessment
Take ABCDE approach: A airway, B RR & SaO2, C HR BP, D GCS & signs of seizure, E check for other signs of severe malaria
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Malaria Small Group Severe malaria criteria
CNS: coma/convulsions, Lungs: ARDS (adults), Respiratory distress or acidosis (children) Kidney: AKI, Shock, Hypoglycaemia (previously SE of quinine), Severe anaemia (children), Hyperparasitaemia 10% in WHO guidelines (2% in HIC settings)
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Malaria Small Group Blantyre coma score
Motor: 2 localises pain, 1 withdraws from pain, 0 no/abnormal response. Verbal: 2 normal cry, 1 abnormal cry, 0 no cry. Eyes: 1 normal (tracking), 0
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Malaria Small Group ACTs
ACT = Artemisinin Combination Therapy. Two (or maybe now 3) drugs in a single tablet. Main drug = an 'artemisinin' (artemether, artesunate, dihydroartemisinin) with combination drug = there to protect the artemisinin (mefloquine, piperaquine, lumefantrine) - first line drug for immediate treatment of all species of malaria. Artemisinins reduce parasitaemia very rapidly - everyone clears their parasitaemia by day 3. They kill more blood stages of the parasite and is probably why they are more effective. Quinine takes day 4 for 50% clearance, day 7 for complete clearance
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Malaria Small Group Severe malaria features
Schizonts not usually seen in peripheral blood as is usually stuck to a capillary. If capillaries are full and schizonts leaking into blood, there is generally a severe infection. Sequestration, predominantly though to be mediated by PfEMP1 (Pf erythrocyte membrane protein) mediate binding in different parts of the body - if bind in brain -> cerebral malaria, if bind in bone marriw - anaemia, lung -> ARDS (but these are not well understood outside of brain and placenta) Malaria is more severe in first pregnancy, then slowly develop antibodies to the antigen that mediate binding to the placenta (gross simplification). Noone has ever shown that any drug that targets any of the putative mechanisms of cerebral malaria have any adjunctive benefit (and some increase mortality).
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Malaria Small Group Treatment of severe
Artesunate and Ceftriaxone. Artesunate is the mainstay drug (can be given IV or rectally ot IM but absorption not good). This has replaced quinine as the drug of choice. SEAQUAMAT and AQUAMAT demonstrated mortality benefit of artesunate compared with quinine. After initial artesunate switch to an ACT to finish treatment, PLUS careful fluids, strongly consider empiric antibiotics. Bacterial infections - classic association with non-typhoidal Salmonella, in severe disease often given broad spectrum Abx alongside antimalarials
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Malaria Small Group Fluids
FEAST trial shows excess mortality with bolus-based fluids in children. High lactate/lowish BP is pretty common. Much of this is due to sequestration not classical hypotension. Giving fluids therefore doesn't really help. Excess fluids plus endothelial dysfunction = BAD
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Malaria Small Group Haemolysis post-artesunate
1-3 weeks after artesunate, 7-22% incidence. Haemolysis of previously infected RBC. Proportional to parasitaemia. At 2-3 week Hb check if >10%. With quinine it takes several days to work, this gives the spleen time to clear damaged RBC as opposed to artesunate - salvage more cells, but they can haemolyse later. Lose the same amount of blood with artesunate as quinine - but it happens more slowly in quinine.
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Malaria Small Group HRP2 delection
Most RDTs detect an antigen called 'histadine rich protein 2'. This is the P falciparum specific antigen. This has generated considerable selection pressure on P falciparum > deletions of this gene are now emerging globally (ie Eritrea and Peru >20%). WHO says if ?5% should switch, btu unclear what to really do
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Malaria Small Group Treatment failure
Causes: poor compliance, counterfeit drugs, drug resistance, another diagnosis. Delayed parasite clearance common in parts of SE Asia. Associated with pf13k (kelch)mutations. Increasing in Africa. This is a 'reduced effect' rather than a true resistance - the response slows out to the clearance time associated with quinine - the drug still works, but just need to give it for longer. What to do: treat for longer, dihydroartemisinin-piperaquine, watch out for recrudescence, triple artemisinins...
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Malaria Small Group Pregnancy
WHO now recommends ACTs in pregnancy in ALL trimesters.
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Malaria Small Group P vivax
Initial treatment of ALL species is with an ACT. P vivax infection -> hypnozoites in the liver. Without specific treatment these lead to recurrence. Only 2 effective drugs: primaquine and tafenoquine. Both drugs can cause haemolysis. Need to assess G6PD prior to treatment.G6PD is not a single disease, there are different levels, and if you have >30% G6PD activity then primaquine is pretty safe. Tafenoquine is long-acting primaquine - the issue is that in most parts of the world it is difficult to access G6PD level, and at least with short-acting primaquine, if someone starts haemolysing you can stop it. Study looking at clearance in high Pv setting. In those who had primaquine - 10% change of infection, in those with placebo 50% - which shows that the vast majority of vivas in this context are recurrences from liver.
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Malaria Small Group Summary
Management of malaria relies on: assessment of the patient for markers of severe disease, RDTs/blood films for speciation +/- assessment of parasitaemia, ACTs are the first line drug for all individuals and all species with non-severe malaria. Artesunate (+/- antibiotics) is the first line for individuals with severe malaria. Drug resistance is emerging, esp in SE Asia. Pv and Po treatment is also needed for hypnozoites with assessment of G6PD activity. **Remember you do not need to have hyperparasitaemia to have severe malaria - the percentage is just one measure of severity, don't forget the clinical features**
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Revision DM Malaria
Treatment of malaria relies on classifying if the patient has severe/complicated OR uncomplicated malaria. Signs of complicated malaria: CNS coma/convulsions (cerebral malaria), Lungs ARDS, Kidney AKI, Shock, Hypoglycaemia, Severe anaemia, Respiratory distress or acidosis, Hyperparasitaemia. ACT are first line treatment of uncomplicated malaria caused by all species. For complicated malaria SEQUAMAT and AQUAMAT both showed artesunate to be superior to quinine. Severe/complicated malaria is associated with a high rate of bacteraemia in children – normally due to non-typhoidal Salmonella and therefore treatment with a broad spectrum ab is normally recommended. Comment: Approach to question: Will always favour ACT over quinine. Have they got severe? Probably then Artemether > artemether/lumefantrine. Then decide if giving CRO or not – he is very sick and may have more than just malaria. If fever and positive RDT then would give Artemether/lumefantrine (or whatever ACT) and would not need to give antibiotics. Also, do not generally need to give abx to adults unless very sick. When children are sick, it is generally due to gut leakage/translocation.
