Download lecture_11_Jan 29_2015 malaria1

Each year, more than eleven million children die from the effects of disease
and inadequate nutrition. In some countries, more than one in five children die
before they reach their fifth birthday, and many of those who do survive are
unable to grow and develop to their full potential.
Seven out of 10 of childhood deaths in developing countries can be attributed
to just five main causes, or often to a combination of them:
pneumonia, diarrhea, measles, malaria and malnutrition. Around the
world, three out of every four children seen by health services are suffering
from at least one of these conditions.
Infectious diseases are the leading killer of young people in developing countries:
These deaths occur primarily among the poorest people because they do not have
access to the drugs and commodities necessary for prevention or cure.
Approximately half of infectious disease mortality can be attributed to just three
diseases – HIV/AIDS, TB and malaria.
These three diseases cause over 500 million illnesses and more than 5 million
deaths each year.
None of these diseases has an effective vaccine to prevent infection in children
and adults.
Africa's GDP would be up to $100 billion greater if malaria had been eliminated
years ago.
Malaria - TB - HIV/AIDS
Many low income countries have shown
that, by using available tools both widely
and wisely, TB deaths can be reduced
five-fold, HIV infection rates can also be
reduced by 80% and malaria death rates
can be halved.
But, when a country has a healthcare
budget of less than, for example, $50 per
capita, the costs of the tools needed to
fight TB, malaria and HIV are prohibitive.
Many of the world's poor people live in
countries with very low budgets for health
care.
MALARIA
* Cosmopolitan disease in tropical and sub tropical regions of the world
* Most important vector-borne disease
* Romans called it “mala aria”- disease emanating from the swamps
* Caused decline in the Roman empire?
* Caused problems in finishing the Panama Canal- Gorgas
* The causal agent only identified in 1897
* Malaria symptoms and use of insect repellents recorded in Ebers
papyrus (~ 3000 bc)
* Was malaria present in the Americas before the arrival of Columbus?
MALARIA
40% of the world population is at risk for contracting malaria.
It occurs in over 90 countries.
500 million new cases and 2-3 million deaths annually.
Most deaths occur among young children in tropical Africa who are
infected with Plasmodium falciparum.
Problems with vector resistance to insecticides, Plasmodium resistance
to drugs, no vaccine have made malaria an excellent example of a reemerging infectious disease.
How many is 3 million people?
Malaria Cases
Number of deaths / year
Deaths/day
# Jumbo Jets day
3,000,000
8,200
20
2,000,000
5,500
14
A few years ago about 250,000 people died in the S. Asian tsunami. The
equivalent number occurs approximately every 30-50 days for malaria alone- or
every 10-21 days for a combination of malaria, TB, and HIV/AIDS.
Symptoms
Symptoms of malaria include fever and flu-like illness, including
shaking chills, headache, muscle aches, and tiredness. Nausea,
vomiting, and diarrhea may also occur.
Malaria may cause anemia and jaundice (yellow coloring of the skin
and eyes) because of the loss of red blood cells. Infection with one type
of malaria, P. falciparum, if not promptly treated, may cause kidney
failure, seizures, mental confusion, coma, and death.
For most people, symptoms begin 10 days to 4 weeks after infection,
although a person may feel ill as early as 8 days or up to 1 year later.
Two kinds of malaria, P. vivax and P. ovale, can create problems later:
some parasites can rest in the liver for several months to 40 years after a
person is bitten by an infected mosquito, and can cause disease.
Human malaria
There are four species of the genus Plasmodium that commonly infect man,
P.falciparum, P.vivax, P.malariae and P.ovale. The most important of these is
P. falciparum because it can be rapidly fatal and is responsible for the majority of
malaria related deaths.
Plasmodium vivax
benign tertian malaria, vivax malaria
Plasmodium falciparum
malignant tertian malaria, falciparum
malaria
Plasmodium ovale
tertian malaria, ovale malaria
Plasmodium malariae
quartan malaria, malariae malaria
Human malaria vector: Anopheles sp.
Anopheles gambiae
Anopheles albimanus
Anopheles nunez tovari
Anopheles stephensi
Anopheles pseudopunctipennis
Anopheles arabiensis
A merozoite, showing the apical prominence with a
rhoptry, dense granules, and a very indented nucleus.
Section of liver showing a greatly
enlarged parenchymal cell full of
merozoites (see arrow)
Section of brain showing blood
vessels blocked with developing
P. falciparum parasites (see
arrows).
Important differences:
P. vivax can maintain a liver infection, P. falciparum does not
P. falciparum has a single exoerythrocytic cycle
1) Relapse:
reactivation after a relative inactive period
2) Recrudescence: reappearance of parasitemia after therapy
P. vivax has hypnozoites- dormant stages in the liver cellsreactivated later in life.
Transmission
• sporozoites injected
with saliva
• enter circulation
• trapped by liver
Anopheles
Exoerythrocytic Schizogony
•
•
•
•
•
hepatocyte invasion
asexual replication
6-15 days
1000-10,000 merozoites
no overt pathology
Hyponozoite Forms
• some EE forms exhibit delayed
replication (ie, dormant)
• merozoites produced weeks-tomonths after initial infection
• only P. vivax and P. ovale
relapse = hypnozoite
recrudescence = subpatentt
Erythrocytic
Schizogony
• intracellular parasite
undergoes trophic phase
• young trophozoite called
‘ring form’
• ingests host hemoglobin
• cytostome
• food vacuole
• hemozoin (malarial
pigment)
erythrocytic schizogony
• 48 hr in Pf, Pv, Po
• 72 hr in Pm
gametocytes
Gametocytogenesis
• alternative to asexual replication
• induction factors not known
• drug treatment  #'s
• immune response  #'s
• ring  gametocyte
• sexual dimorphism
• microgametocytes
• macrogametocytes
• no pathology
• infective stage for mosquito
• occurs in mosquito gut
• ‘exflagellation’ most
obvious
• exposure to air induces
•  temperature (2-3oC)
•  pH (8-8.3)
• gametoctye activating
factor in mosquito
• xanthurenic acid
Sporogony
• occurs in mosquito (9-21 d)
• fusion of micro- and
macrogametes
• zygote  ookinete (~24 hr)
• ookinete transverses gut
OF THE 1-3 MILLION or more deaths from malaria that occur
worldwide each year, most are in African children under the age of
five. Children in Africa south of the Sahara are vulnerable to
malaria from about four months of age. In areas of intense
transmission, young children may have as many as six episodes of
malaria each year.
Of the more than 500,000 African children who develop
cerebral malaria (a severe form of the disease that affects the
brain) each year, 10-20% die and approximately 7% are left with
permanent neurological damage. Fever, vomiting, headache and flu-like
symptoms may progress rapidly (often within 24 hours) to convulsions, coma,
and death.
Malaria is a major cause of anaemia in many parts of the world.
Chronic anaemia may adversely affect a child’s growth and
intellectual development. Repeated episodes of malaria may lead
to severe, life-threatening anaemia. Blood transfusions may save
lives in these circumstances, but also expose the child to the risk of
HIV and other blood-borne infections.
Preventative Measures
Prevent Insect Bites
Wear long sleeved shirts and long pants in the evening.
Use insect repellents
Select hotels/housing with nets- preferably pemethrin-impregnated bednets
Take effective drugs
Reduce mosquito habitat
Use residual insecticides (DDT??)
Prevention: Sleep under insecticide-treated nets (ITNs). Studies in Africa have
shown that ITNs can reduce deaths among under-fives by up to one-third.
There is an urgent need to ensure that effective and affordable antimalarial drugs
or drug combinations are widely available to all individuals living in malariaendemic areas. Since, in Africa, many people first go to their local store for
antimalarial drugs, shopkeepers are now being trained to supply the appropriate
dose and duration of treatment.
DRUGS
Mefloquine: (Lariam®) take weekly
The most commonly reported minor side effects include nausea, dizziness,
difficulty sleeping, and vivid dreams. Mefloquine has very rarely been reported to
cause serious side effects, such as seizures, hallucinations, and severe anxiety
Doxycycline take daily
Take doxycycline on a full stomach to lessen nausea; Women who use doxycycline
may develop a vaginal yeast infection. Do not give doxycycline to children under
the age of 8; teeth may become permanently stained.
Malarone™ take daily Malarone is a new combination of two drugs (atovaquone
and proguanil) abdominal pain, nausea, vomiting, and headache can occur.
Chloroquine taken weekly nausea and vomiting, headache, dizziness, blurred
vision, and itching
Quinine: obtained from the bark of a tree in Peru
Quinine has been used for more than three centuries and until the 1930's it was the
only effective agent for the treatment of malaria. It is an alkaloid found in the bark of
the Cinchona tree and is the only drug which over a long period of time has
remained largely effective for treating the disease. It is still used for treating severe
falciparum malaria partly but has undesirable side effects.
In Africa in the 1930's and 40's it was known for people to take quinine when they
thought they had "a touch of malaria" and the association of repeated infections with
falciparum malaria and inadequate treatment with quinine, resulted in the
development in some of acute massive intravascular haemolysis and
haemoglobinuria ie. black water fever.
Chloroquine: A very effective 4-amino-quinoline both for treatment and prophylaxis. It
was first used in the 1940s shortly after the Second World War and was effective in
curing all forms of malaria, with few side effects when taken in the dose prescribed
for malaria and it was low in cost. Unfortunately many strains of falciparum malaria
are now resistant to chloroquine and more recently chloroquine resistant vivax
malaria has also been reported.
Stable malaria: continuous transmission year round
Unstable malaria: transmission is seasonal
In stable malaria: tolerance/resistance can be developed
In unstable malaria: tolerance/resistance is often lost
Human malaria: adaptations to the parasite
1) Sickle Cell- single point mutation- abnormal shape of a percentage of RBC
will not allow parasite development
RBC have bumps on surface- stick to capillary walls, loss of
potassium, parasites inside die
Only benefit is to heterozygous individuals:
double dominant are susceptible
double recessive often die from anemia
Example of strong evolutionary pressure to respond to a parasite
2) G-6-Phosphate dehydrogenase deficiency: results in reduced parasitemias
3) Duffy Blood group: double recessive- completely resistant to P. vivax.
parasite cannot find receptors to enter RBC
Found in 80% of W. African black population
Yahoo and Newspaper column
“This weekend, the Pittsburgh Steelers take on the Denver Broncos
in the AFC Wildcard playoff game. But Steelers safety Ryan Clark
will be watching from the sidelines. Last time he played in Denver, he
nearly died. Clark has a sickle cell trait.
In 2007, it still hadn't been diagnosed and flared up when he played
in Denver. Clark ended up having his gall bladder and spleen
removed in addition to losing 30 pounds. This time, he'll be on the
bench”.
According to the National Heart Lung and Blood Institute, more than
two million Americans have sickle cell trait.
Future of malaria management
New drugs
New insecticides
Greater involvement by governments in vector control and monitoring
Habitat manipulation to reduce mosquito populations
Involve people in their own primary health care
Transgenic mosquitoes- resistant to Plasmodium sp.
Vector Populations
Some bite indoors, alight on wall for pre-diuresis, then leave homes
Some bite indoors, fly outside for pre-diuresis
Some only bite outdoors
Which ones are susceptible to DDT sprays on houses?
“For the next five to ten years, until an effective vaccine is developed,
malaria control will largely be dependent on vector control measures
such as improvements in housing construction, source reduction,
impregnated bednets, and residual insecticide treatment”.
Malaria as therapy???
* Syphilis in Europe had asylums filled with syphilitic paretics:
people made crazy, blind, convulsing, by the Treponema pallidum
* T. Pallidum very sensitive to temperature
* in 1917 Von Jauregg treated syphilitic patients with Plasmodium
vivax- allowed 3-4 bouts of fever- treated with quinine
* Institutions using malaria therapy sprouted in Europe and the US,
tens of thousands infected people saved
* Von Jauregg awarded Nobel prize in 1927