Malaria

  • A mosquito-borne infectious disease affecting humans and other animals caused by parasitic protozoans belonging to the Plasmodium type: P. Falciparum, Vivax, Ovale, Malariae, Knowlesi

Lifecycle

  • When a mosquito lands on the skin, it attempts to pierce a small blood vessel with its proboscis in order to suck blood. To prevent the blood from coagulating the mosquito first injects some saliva. Besides vasodilating agents this saliva contains anticoagulants. However, the saliva may also contain micro-organisms. When a human is bitten by an Anopheles infected with malaria, parasites (sporozoites) [Gr. sporos = seed] are introduced into the human body. On average 10-20 sporozoites are injected per bite, although this number can be higher, e.g. 100.

  • A certain protein of the parasite, (the circumsporozoite protein, CSP), plays an important role in the penetration of the sporozoite into a liver cell (cf. Mosquirix vaccine). Sporozoites reproduce asexually in liver cells, by schizogony [Gr. schizo = split, divided]. This is called exo-erythrocytic or pre-erythrocytic reproduction. The form of the parasite produced in this way is called a liver schizont. The multinuclear schizont splits into many thousands of small offspring (merozoites) [Gr. meros = part]. Every successful sporozoite can produce some 20,000 merozoites.


  • Mosquito takes a blood meal and injects sporozoite. Enters liver cells (hepatocytes), multiply (asexual) and burst releasing merozoites into the bloodstream, which in turn infect RBCs. Merozoite grow into ring-shaped form, then a larger form (trophozoite), which mature to schizonts which divide several times to produce new merozoites. A small % differentiate to a sexual form (gametocyte) which is picked up by the insect taking a blood meal. Male/female gametes fertilise in mosquito midgut forming a zygote, then ookinete, then oocyst that produce sporozoites which migrate to the salivary gland where they can be injected into the blood of the next host the mosquito bites.

  • Falciparum: infect all RBC sizes

  • Vivax differences: Hypnozoites, merozoites infect immature RBCs (reticulocytes), no sequestration. Contributing factors to more mild disease.

  • Important for eradication: hypnozoite / gametocyte (not cleared by typical antimalarial drugs, requires primaquine)

  • Important for disease: trophozoite/schizont

Epidemiology

  • Gradual decrease trend in imported malaria WW

  • 2017: 219 million cases & 435,000 deaths/yr (mostly <5 years in SSA)

  • 2015: 500 million cases & 1,000,000 deaths/yr

  • Levels of transmission / EIR

  • Biomass

Species

  • Falciparum: Sub-saharan Africa & the tropics

  • Vivax: widespread, esp, Indian subcontinent, S. America. Not in Sub-sarahan Africa (duffy antigen on RBC (duffy - population)

  • Ovale: West/Central Africa

  • Malariae: Africa + patchy tropical/temperate

  • Knowlesi: Borneo

Pathophysiology

Relapse

• return of fever & asexual parasites due to rupture of hepatic hypnozoites

• sleeping hypocrite returns e.g. vivax/ovale

• …. Relapsing; because of hyponozoites.. dormant liver stage

Recrudescence

• Return of fever and asexual parasitaemia without involvement of hypnozoites

• recurrence of a disease after a brief intermission

• (malaria comes back)

Immunity

Acquired immunity to malaria (Kato lec)

  • Anti-disease immunity seems to develop more rapidly than anti-parasitic immunity after malaria (premunition)

  • Total antimalarial/antisporozoite antibodies increase with age in endemic areas

Clinical

  • Malaria triad (reality in travellers): periodic fever (does not necessarily synchronise), anaemia (usually absent), splenomegaly (mild and cannot be detected by physical examination)

  • Likelihood increase: fever, splenomegaly, low platelet count (but also dengue), increased bilirubin

  • Likelihood decrease: cough

Blackwater fever: AKI

Septic shock (algid malaria) - purpura fulminans… consider bacterial co-infection

Diagnosis

  • Clinical

  • Microscopy (visualise parasite): Thick (sensitivity, approx. 100 p/uL))/Thin films: ring forms

Schizont: 18-20 nuclei: pf or ov

  • Antigen detection tests/RDT: qualitative (cannot assess parasitaemia) (approximately 100-200 p/uL)

  • Nucleic acid detection: PCR (1 p/uL, <0.1 (Pf) with nested PCR: gold standard) / LAMP (1-5 p/uL)... PCR "too" sensitive

  • Antibody detection?

Diagnosis pitfalls

  • Availability bias: clinicians tends to come up with common diseases like influenza

  • Base rate neglect: clinicians tend to neglect the high prevalence of malaria in SSA

  • System error: clinicians cannot perform diagnostic tests for malaria

Additional work-up for decreased LOC:

  • Blood glucose

  • CSF

  • Ophthalmoscopy

Treatment

Parasite reduction rate per 48 hour cycle: Artemisinins > blank > SP & quinolines > tetracyclines

Falciparum

  • Uncomplicated: Artemisinin Combined Therapy, Quinine

  • Complicated / Severe malaria suportive

Artesunate more effective than quinine (AQUAMAT / SEQUEMAT trials) as kills young trophozoites but quinine does not)

Vivax

  • ACT or chloroquine

  • Primaquine

Malaria in pregnancy

  • ACT safe in pregnancy (all trimesters), avoid primaquine (cannot rule out G6PD in the fetus)

  • Quinine?

Artemisinin-based combination therapies (ACT)

Rapidly acting artemisinin e.g. artemether (reduces parasites) + longer-acting partner drug (e.g. lumefantrine) to prevent recrudescence and drug resistance:

  • Artemether + lumefantrine (CoArtem)

  • Artesunate + amodiaquine

  • Artesunate + mefloquine

  • Dihydroartemisinin + piperaquine

  • Artesunate + sulfadoxine-pyrimethamine (SP)

Triple ACTs (TACTs) are under investigation to overcome challenge of drug resistance (e.g. artemether + lumefantrine ….)

Malaria chemoprophylaxis

  • Atoraquone-Proguanil (Malarone): 1-2 days before (therefore good for last-minute travel), 7 days after. Well tolerated, but avoid if severe renal impairment. Usually more expensive. Pregnancy: avoid

  • Doxycycline: 1 day before (therefore good for last-minute travel), 4 weeks after. Cheap. Can prevent other infections e.g. Rickettsia, leptospirosis. Avoid in children ≤8 years, prone to candida, photosensitivity, gastritis. Pregnancy: avoid

  • Mefloquine (Larium): 1-2 weeks before, 4 weeks after. Weekly. Disadvantages: mefloquine resistance, psych/seizures/cardiac contraindications. Pregnancy: ok

  • Chloroquine: 1-2 weeks before, 4 weeks after. Weekly, good for longer trips. Cannot use in chloroquine/mefloquine resistant areas. Pregnancy: ok

  • Primaquine: 1-2 days before, 7 days after. Good for vivax (areas with >90% vivax), short trips. Avoid if G6PD deficiency or not tested, gastritis. Pregnancy: avoid

  • Tafenoquine (Arakoda): 3 days before, 1 week after. Good for vivax and falciparum, short trips. Avoid if G6PD deficiency or not tested, psych disorder. Pregnancy: avoid

Prevention for travellers

  • Awareness of risk

  • Bite protection (insect repellants, cover up clothing, mosquito nets)

  • Chemoprophylaxis

  • D is for prompt diagnosis should preventive measures fail

Atorvaquone/proguanil (malarone): liver and blood stages

Doxy/mefloquine cannot kill liver stage therefore use for 4 weeks after

Eradication/control

  • Prevention (individual/population)

  • Treatment (individual/population)

  • Ross-MacDonald / R0 equation

  • m: number of mosquitoes per person (larva control, release sterile male mosquitoes..)

  • a2 (bite twice, human and mosquito): biting rate of mosquitoes (bed nets, repellants, coils)

  • b: susceptibility of mosquitoes (e.g. vaccines, CRISPR/Cas9- mediated gene knockout of Anopheles gambiae FREP1 suppresses malaria parasite infection)


  • MDA e.g. primaquine, chloroquine, fansidar (example of Vanuatu, Akira Kaneko)

Vaccine

Human

  • Pre-erythrocytic "anti-infection" e.g. RTS,S

  • Asexual blood-stage vaccines "anti-disease" conserved antigens

Mosquito

  • Transmission-blocking vaccine "anti-transmission": vaccine generate antibody in human, antibody kill parasite (gametocyte) in the mosquito

Historical aspects

  • Disease described in Nei Ching China (2700 BC)

  • Malaria symptoms described by ancient Egyptians (1550 BC)

  • Hippocrates (460-377 BC) differentiated between different types of malaria fevers

  • 1880 - Laveran

  • 1897 - Ronald Ross

  • 1948 - P.C.C. Garnham & H.E. Shortt

  • Artemisinin: during Vietnam war (meeting called by Chairman Mao and Premier Zhou to find new malaria drugs, May 1967, project "").. (A.Kaneko lec.

  • Malaria in Japan (CUlleton lec). 1945-1961: eradication by use of anti-malarial drugs and anti-mosquito measures (habitat destruction and insecticide use (DDT). Last cases recorded in Okinawa in 1961, eradicated in 1962