Galen’s four humor theory of disease
Blood Black bile Yellow bile Phlegm how all diseases come from inside you so it created a huge step backwards as it shifted an outward causality for diseases to an inward = less hygiene etc.
John Snow
London Cholera mapping
Crudelli & Klebs
identify bacillus rods
Alphonse Laveran
stepped away from slide and sees exflagellation stage, cooled blood
George sternburg
can’t duplicate Crudelli & Krebs, same results in rabbits with spit
patrick manson
identifies mosquito vector for worm but only thought they took one blood meal and that dead mosquitos must release microbes in water
ronald ross
can’t prove mosquito water, doesn’t like ecologists; later discovers Anopheles mosquitos and prove mosquitos have malaria
Bignai & grassi
ask malaria victims about what they do to prevent, convinced of mosquito vector; get first credit
robert koch
creates koch’s postulates and describes acquired immunity in malaria
domenico falleroni
collects mosquito eggs and notices 2 different types = 2 different mosquitos
Anopholism without malaria arguments
Malaria cases where there are not Anopheles mosquitos
Rome History
surrounded by pontine marshes and campagna = regular exposure and partial immunity; northern invaders die = malarial moat; houses faced inward. Atroparvus mosquito species keeps invading species out but it’s a good vivax vector and bad falciparum vector. Cut oak forest down, mosquitos from Africa colonize and are good falciparum vectors; adapts to cold winters by moving indoors. Stable transmission is interrupted = loss of immunity = INC falciparum
Scotland History
sailed to Panama; slaughtered by malaria; bankrupted; England paid their debts and not independent anymore
Americas
import slaves with falciparum = INC mortality for whites = INC need for more slaves; Europeans bring malaria to vulnerable Native Americans; Punctipennis mosquito is dominant in New England and prefers animals, bad falciparum vector. People start using mill dams for power = start building dams to make mill ponds to power water wheels. Quadramaculatus mosquito is favored in this condition; war brings soldier with vivax home and lives close to mill dams = malaria spread; association of mill dam ponds with malaria; finally take dams down
Africa
malaria repels European invaders
Spanish
import slaves with falciparum causing spread to Panama
Bantu events
- Before Bantu: cold temps, wandering hunter/gatherers = irregular exposure and low population density; also forest floors have less mosquito habitat
- Sahara desert formed and Bantu moved south to equatorial Africa
- Bantu cut down jungle for farming = no other malaria prey = mosquitos colonize free puddles = anopheles gambiae rise
- Wandering nomads visit a village; not immune = death by malaria
Anopheles gambiae
Feeds almost exclusively on humans, most reliable malaria vector
Which malaria has the longest incubation period?
P. malariae
Which malaria uses duffy antigens to adhere to RBCs
P. vivax
Which malaria infects 80x more than vivax?
P. falciparum
Which malaria is in monkeys
P. knowlesi
One sentence definition for Malaria:
Infection by protozoan parasites (plasmodium) that is transmitted by mosquitos causing fever, anemia and death.
What are the two hosts malaria uses?
Humans and female anopheles mosquitoes
Definitive v Secondary host
Definitive host: host in which parasite reaches maturity and reproduces sexually (mosquitos)
Secondary/intermediate host: host in which the parasite only resides for a short period of time in an immature form (humans)
Describe the sporogenic cycle
Sporogenic cycle: in mosquitos; gametocytes activate in colder temp of mosquito and create ookinete; ookinetes multiply asexually and form oocytes that make 1000s of sporozoites
Describe the exo-erythrocytic cycle
Exo-erythrocytic cycle: in humans, outside RBC; sporozoites injected into humans and travel to liver via bloodstream; migrate through several liver cells before settling the parasitophorous vacuole; each vacuole generates many merozoites that are transported to bloodstream via merosomes ○ Falciparum 5-6 days ○ Vivax 8 days ○ Ovale 9 days ○ Knowlesi 8-9 days Malariae 13 days
Describe the Erythrocytic cycle
Erythrocytic cycle: in humans inside RBC: merozoites recognize RBCs, attach to RBC surface proteins and use membrane to create parasitophorous vacuole. The Merozoites feed on hemoglobin and alter RBC membrane to be more permeable; each merozoite makes 8-12 new ones that infect more RBCs
○ Occurs every 24 hours in knowlesi
○ Every 48 hours in falciparum, vivax and ovale
Every 72 hours in malariae
What else happens to merozoites?
Some merozoites develop gametocytes that lie dormant in bloodstream
which malarial stage is responsible for recurring malaria?
Hypnozoites
Which malarial stage would you block with a vaccine to prevent infection?
Sporozoites
Sustained fever
temperature does not fluctuate more than 1 degree/24 hours; graph shows 2/3 at constant temp then decrease
Remittent fever
fluctuation of 2 degrees per hour; graph shows consistent and almost equal spikes and dips
Intermittent fever
normal temp except for a few hours per day; graph has random spikes and dips
Relapsing
high temp more than 3x in 6 months, at least a week apart, lasting a few hours to a few weeks. Fevers separated by symptom-free intervals; graph shows long period of high fever, long period of low fever, repeat
Fever
elevated body temp regulated by hypothalamus. Damage can occur directly to cells, locally as inflammation or systemic as gut bacterial translocation
Falciparum fever
tertian
Vivax/Ovale fever
tertian
Malariae fever
quartan
Knowlesi fever
quotidian
What are pyrogens and examples of exogenous and endogenous?
Pyrogens: heat producing substances
Exogenous like staph aureus toxin. Endogenous like cytokines
How does your body generate heat or reduce heat loss?
Shiver to produce heat
Shunting of peripheral blood to core to reduce heat loss
Vasoconstriction to reduce heat loss
How do we know malaria exerted evolutionary pressures?
We made adaptations to survive it
Which malaria is most ancenstral?
P. malariae
Which malaria is most modern?
P. falciparum
List blood adaptations and if they affect RBC function
Ovalocytosis: oval shaped RBC
Hemoglobin E: deforms Hb and slows vivax in body
RBC without duffy antigens: does not affect RBC function
Thalassaemia: deforms Hb and slows vivax
Sickle cell: reduces cell invasion = high survival rate from falciparum
How long does it take for you to lose acquired immunity
> 6 months = lost resistance
Innate v Acquired immunity
Innate: sickle cell trait against falciparum
Acquired: continuous exposure
Incubation periods
Faciparum: 9-14 days Vivax: 12-18 days - uses duffy antigens Ovale: 12-18 days Malariae: 18-40 days - oldest model, longest incubation Knowlesi: 11-12 days
What is premunition?
Host response that protects you against high numbers of parasite and illness that does not eliminate infection and is only partially effective
Relapse v Recrudescense
- Relapse: recurrence of infection from activation of hypnozoites - only from vivax and ovale; blood was cleared of malaria
- Recrudescence: infection recurring from persistent blood stages of malaria; symptomatically better but still have parasite in blood - all malaria; usually happens if treatment is incomplete
- in falciparum and malariae, parasites are not completely eliminated after recovery
Thick v Thin slide
Thick film: drop of blood on glass slide to examine larger volume of blood and shows the presence of parasite.
Thin film: drop is spread across the slide and is useful for identification of species
Advantages to malaria RDTs
Quick, no subjective component, no time delay, can do it at bedside
Symptoms of Uncomplicated malaria
Shaking and chills High fever - paroxysmal Excessive sweating Extreme fatigue and sleep May recur at regular intervals Enlarged spleen, liver Jaundice Diarrhea/vomiting Anemia - usually mild Abdominal pain Normal WBC Low platelets No vital organ dysfunction
Symptoms of Severe Malaria
Severe anemia Renal failure Pulmonary edema or ARDS Hypoglycemia Cerebral malaria; coma, seizures, neurologic manifestations Circulatory collapse or shock Enlarged spleen, liver Miscarriage, low birth rates Micro-hemorrhages in eye Death
Neurologic consequences of severe malaria
Delirium: misperception of sensory stimuli; vivid hallucinations
Coma: unresponsiveness & cannot be aroused
Obtundation: less than full alertness
Stupor: deep sleep/unresponsiveness taking a lot to be aroused
Prostration: on the ground and cant get up
Specific consequences: Anemia Edema Hypoglycemia Low birth weight Hypotension
Anemia: liver is slaughtering RBCs
Edema: INC alveolar permeability = fluid loss into lungs
Hypoglycemia: parasite consuming your glucose, not renewing
Low birth weight: due to DEC in nutrition
Hypotension: organs aren’t getting enough blood
Common complications in pregnancy
Loss of blood and clogging of small placental vessels
Anemia INC maternal mortality
Low birth weight due to DEC in nutrition = INC risk infant death
Prematurity
INC risk of severe malaria
Has there been good or bad progress in eliminating malaria?
Good
What are major threats in controlling malaria?
INC travel Plasmodium drug resistance Unstable political/social will INC environmental disturbances Insecticide resistance Cross-border Malaria Poorly trained man power
What makes Vivax difficult to control?
- Unique biology - hypnozoites in the liver
- Asymptomatic in semi-immune populations
- Responds differently to anti-malarials than falciparum
- Poorly funded research
- Mixed infections with falciparum
Outbreak V endemic
Outbreaks: typically involves a village or group of villages
Endemic: entire district or ecotype
3 main categories of disease spread
- Spread by direct contact between susceptibles
- Spread by insect vectors
- Water/soil/food borne
Miasma theory
Miasma: bad smoke or mist that changed the air/atmosphere. Theory that miasmas got worse in hot climates, worse near swamps, stagnant water and decaying things. Draining swamps helped. This lead to sanitary reforms which was good but not causing malaria
Leo Howard & Lewis Hackett
local ecology of malaria, not just one solution
Merozoite
Hypnozoite
Gametocyte
Sporozoite
Merozoite invasive form that attack RBC; generated in vacuoles
Hypnozoite in vivax and ovale, remain dormant in liver
Gametocyte made by merozoites in humans; mosquito take blood meal and they mature in mosquito gut to make ookinetes that make new sporozoites; also survive in human and mosquito
Sporozoite motile infective form; born in mosquito and also live in human
What causes end organ damage?
ischemia
Duffy-Free RBCs
Does not affect RBC function; Vivax can’t find it
Hemoglobin E
Deforms Hb & slows vivax
Hetero: no symptoms
Homo: mild anemia & enlarged spleen
Thalessemia
Deforms Hb & slows vivax
Ovalocytosis
RBC oval shaped and makes invasion difficult; may be asymptomatic, anemic, jaundice or gallstones
Sickle Cell
Homo: death
Hetero: 90% reduction of death
Sickling of RBC = reduce cell invasion
Best vector for falciparum
Anopheles gambiae female
3 phases to intervene epidemic
Phase 1: early detection
- Weekly surveillance at sentinel sites; detection and control within 2 weeks
Phase 2: rapid increase
- Rapid increase in new cases
- Need to track spatial and temporal development; outbreak signature
Use epidemic wave to trace over time and space
Phase 3: Post epidemic period
- Transmission falls to usual low levels
- Short term impacts: economic negatives, behavior changes, devastated populations
- long term impacts: economic, political health resources are low; positive like good political change, improved sanitation and control
Intrinsic v Extrinsic factors that affect burden of disease
Intrinsic factors: human (herd immunity), parasite (virulence), vector (mosquito species complex)
Extrinsic factors: environmental, control, socioeconomic (war, natural disaster, climate)
Malaria dominates where
P. Malariae mostly throughout Africa
P. Vivax Central America, North Africa, Middle East, India, South America, SE Asia
P. Ovalae West Africa
P. Falciparum Africa, Haiti, Papua New Guinea, South America, SE Asia
Knowlesi - SE Asia, mostly around borders
Environmental, human-related and biological factors for predicting malaria
Environmental factors: altitude, temperature, precipitation
Human related factors: land use, livestock, insecticide, socioeconomic status, gender, treatment, access
Biological factors: breeding sites, insecticide resistance, immunity, age
Endemic, epidemic and decadal timescale prediction
Endemic areas: potential prediction of seasonal onset
Epidemic areas: prediction of outbreak
Decadal timescales: potential shift of epidemic areas to higher altitudes
Timeline for Eradication
1 Preparatory phase
2 Attack phase - interrupt transmission: Vector control measures; Surveillance of disease
3 Consolidation phase - not as much efforts as attack phase: Mopping up remaining foci of infections
4 Maintenance Phase; 3 consecutive years without transmission
Elimination v Eradication
Eradication: cessation of malaria parasite transmission and elimination of human reservoir - by extermination of infectious agent
Elimination: reduction to zero incidence of a specific disease in defined area
Control v Extinction
Control: reduction of mortality and disease incidence until no longer a major public health problem
Extinction: no longer exists in nature or lab