Malaria Flashcards
Malaria Epidemiology
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
Malaria Deaths
Over half of malaria deaths are in four countries: Nigeria, DRC, Niger, Tanzania
Malaria Stalled progress
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
Malaria Pathogenesis
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
Malaria Cerebral malaria
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)
Malaria Severe malaria
- 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
Malaria Severe anaemia
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
Malaria PfEMP1
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
Malaria Pf gametocytes
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
Malaria Hypnozoites
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)
Malaria Prevention efforts (human)
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
Malaria Prevention efforts (mosquito)
IRS Indoor residual spraying Insecticides, LLIN long-lasting insecticide bed nets, sterile genetically-modified mosquitoes
Malaria Prevention efforts (what’s needed)
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
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
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
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)
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.
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
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
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)
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
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
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
Malaria Treatment (uncomplicated)
ACT x3 days ie artemether-lumefantrine (AL). Must do clearance films to make sure genuine clearance
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
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
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
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
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.
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
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)
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
Malaria Travel advice
Sleep under insecticide treated bednet, cover up between dusk and dawn, repellents with 30-50% DEET
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
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
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%
Malaria SEAQUAMAT
SE Asia mortality artesunate 15% quinine 22%
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.
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
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
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)
Malaria Adjuvants
Do not use any of these, they do not work - including dexamethasone, anti-TNFa, IVIg, phenobarbitone, mannitol, NAC etc
