Malaria

CHEN You-Peng, Prof. Dr.

Email: youpeng.chen@163.com
Dept. of Infectious Diseases,
Anopheles gambiae the first College of Clinical
Medicine, Jinan University

April 2nd. 2018

 Chinese history in natural
science and medicine
(TU Youyou 屠呦呦 born 30 Dec. 1930)
• TU Youyou is a Chinese pharmaceutical
chemist. She is best known for
discovering artemisinin (also known
as qinghaosu) and dihydro-artemisinin, used to
treat malaria. Her discovery of artemisinin and
its treatment of malaria is regarded as a
significant breakthrough of tropical medicine in
the 20th century.
• For her work, Tu received the 2011 Lasker
Award in clinical medicine and the 2015 Nobel
Prize in Physiology or Medicine.
 Case report
• A 55-year-old Caucasian man
• He was confused, had shivering and high fever up to 40℃.
• Physical examination:
• revealed a pulse of 150 beats/min and a systolic blood
pressure of 90 mmHg. The skin was dry, but with no
erythema (rashes). Auscultation of the chest revealed
ubiquitous wheezing and normal heart sounds without
presence of murmurs. The abdomen was soft with no
rebound tenderness. The liver was not enlarged and the
spleen was not palpable. Neurological examination
showed no focal neurological signs and no signs
indicative of meningitis.
• As an embassy member in a sub-Saharan African
country, he left Africa one month prior to admission to
our hospital.
Laboratory tests
• His blood analysis revealed a severe
thrombocytopenia, hemoglobin of 84 g/L,
total bilirubin of 59 μmol/L and lactate
dehydrogenase (LDH) of 300 U/L↑,
→indicative of ongoing hemolysis.
• Procalcitonin and C-reactive protein (CRP)
were markedly elevated.
• Lactate was 7.5 mmol/L↑, base excess - 4.5
mmol/L, anion gap 16.6 mEq/L↑ (3 ～ 11
Normal) and pH 7.43.
→indicative of a compensated metabolic
acidosis.
Diagnosis and treatment?
• severe Malaria---
malaria falciparum parasites were
detected by microscopical examination
of a thick blood film
• --- complicated by septic shock
• Therapy
 fluid resuscitation
 quinine
 Contents
• Definition
• Epidemiological data and distribution
• Epidemiology: infectious sources/
transmission routes
• Morphology of plasmodium parasites
• Life cycle of malaria
• Clinical manifestation
• Diagnosis, differential diagnosis and
complications
• Therapy and prevention
 Definition
• “Mal-aria = bad air (Italian)”, Roman fever
• It is a life-threatening protozoal disease caused by
parasites that are transmitted to people through the
bites of infected female Anopheles mosquitoes.
• Caused by one of four and/or more Plasmodium
species
– Plasmodium falciparum
– Plasmodium vivax
– Plasmodium malariae
– Plasmodium ovale
– Plasmodium knowlesi
The simian malaria parasite P. knowlesi is prevalent in macaque monkeys in
Southeast Asian countries. Human infections with this parasite were thought
to be extremely rare until multiple human infections were reported in 2004
from Malaysian Borneo.
 Discovery of Malaria

C.L. Alphonse Laveran Ronald Ross

 Charles Louis Alphonse Laveran (French army doctor) was the first to notice parasites
in the blood of a patient suffering from malaria in 1880. He was awarded the Nobel Prize in
1907 for this discovery.
 Ronald Ross was the first to demonstrate that a mosquito could transmit a malaria
parasite and malaria parasites can be transmitted from infected patients to mosquitoes in
1897. For the discovery, he was awarded the Nobel Prize in 1902.
 Histories and Epidemiology
• Described in 2700 BC in China
• Widespread in Asia, Africa and South and central
America.
• Estimated 350-500 million cases per year
• In 2008, there were 247 million cases of malaria
and nearly 1 million deaths --- mostly among
children living in Africa.
• A child dies every 45 seconds of Malaria, the
disease accounts for 20% of all childhood deaths in
Africa.
• In 2015, there were 212 million cases of malaria
worldwide.
 Epidemiology
• In 2015, 91 countries and areas had ongoing malaria
transmission.
• Malaria is preventable and curable, and increased efforts
are dramatically reducing the malaria burden in many
places.
• Between 2010 and 2015, malaria incidence among
populations at risk (the rate of new cases) fell by 21%
globally.
• In the same period, malaria mortality rates among
populations at risk fell by 29% globally among all age
groups, and by 35% among children under 5.
• Sub-Saharan Africa carries a disproportionately high share
of the global malaria burden. In 2015, the region was home
to 90% of malaria cases and 92% of malaria deaths.
Fig. Countries endemic for malaria in 2000 and 2016.
Countries with 3 consecutive years of zero indigenous ( 本土的 ) cases are considered
to have eliminated malaria. No country in the WHO European region reported
indigenous cases in 2015, but Tajikistan has not yet had 3 consecutive years of zero
indigenous cases, its last case being reported in July 2014. Source: WHO database.
http://www.who.int/gho/malaria/malaria_008.pdf?ua=1
 Table. Leading Causes of Death in Children
Under Five Years of Age, Estimates for
2000-2003, and 2011
Malaria is the fifth leading causes of death in children under five in the
world in 2011. (Pneumonia, Prematurity, Birth asphyxia, Diarrhoea)
Rank Cause No (thousands per year) % of all deaths
1 Neonatal causes 3,910 37
Acute respiratory
2 infections 2,027 19
3 Diarrheal diseases 1,762 17
4 Malaria 853 8
5 Measles 395 4
6 HIV/AIDS 321 3
7 Injuries 305 3
Other causes 1,022 10
Total 10,596 100 CDC Malaria
Source: World Health Organization (WHO), The World Health Report 2005
http:malaria\The Impact of Malaria, a Leading Cause of Death Worldwide

http://www.who.int/mediacentre/factsheets/fs178/en/
Table. Estimated number of malaria cases (a) and
malaria deaths (b) by WHO region, 2015
Eastern
African America Mediterranean South-East Asia Western Pacific
 Table. Disability Adjusted Life Years and Malaria
DALYs from DALYs from DALYs from
Area Population all deaths (%) malaria deaths malaria/total
(%) (%)

World 6,122,210 1,467,257 42,280 2.9

Africa 655,476 357,884 (24.4) 36,012 (85.2) 10.1
Americas 837,967 145,217 (9.9) 108 (0.2) 0.07
Eastern 493,091 136,221 (9.3) 2,050 (4.8) 1.5
Mediterranean
Europe 874,178 151,223 (10.3) 20 (0.04) 0.01
Southeast Asia 1,559,810 418,844 (28.5) 3,680 (8.7) 0.9
Western Pacific 1,701,689 257,868 (17.6) 409 (1.0) 0.2

• Adapted from the World Health Organization World Health Report, 2002.
• DALYs = Disability Adjusted Life Years
The sum of years of potential life lost due to premature
mortality and the years of productive life lost due to disability.
Table. Epidemiological data, China

Tang LH. Progress in malaria control in China. Chinese Medical Journal 2000,113(1):89-92 review
 Tang LH. Progress in malaria control in China. Chinese Medical Journal 2000,113(1):89-92 review

全国疟疾报告： 2009 年发病人数 14098 例，死亡 10 人； 2010 年发病人数

7389 例，死亡 14 人 ; 2011 年发病人数 4088 例，死亡 30 人； 2012 年 2451
人发病，死亡 15 人； 2013 年 3896 人发病，死亡 20 人 ; 2014 年 2921 发病
，死亡 24 人； 2015 年 3289 发病，死亡 20 人； 2016 年 3189 cases( 发
病 ) ， death ( 死亡 ) 16 例 ; 2017 年 2697 cases ( 发病 ) ， death (http://www.moh.gov.cn
死亡 ) 6 cases.
 Infectious sources

• Patients with malaria

• Parasites carriers (people infected with

P. species)
 Routes of transmission
• Spread by bite of infected female Anopheles
mosquitoes

• Transmitted in contaminated blood

transfusion and mother to child transmission
via placenta
• Occasionally injection drug users sharing
needles and as a hospital-acquired infection
related to contaminated equipment
 Plasmodium falciparum

Trophozoite
滋养体

Ring stage

Schizont 裂殖体
 Plasmodium vivax

Ring stage
Trophozoite
Schizont
Gametocyte
 Plasmodium ovale

Ring
Trophozoite
Schizont
Gametocyte
 Plasmodium malariae

Ring stage
Trophozoite
Schizont
Gametocyte
 Plasmodium falciparum
• Most dangerous form of malaria
– Risk of cerebral malaria, renal failure, acute
respiratory distress syndrome, and severe anemia
• Prompt treatment is essential
• Untreated infection in a non-immune person
would likely be fatal
• Once person is treated and cured, there is no
risk of relapse (but he/she can get infected
again)
– P. falciparum has no dormant liver stage
(hypnozoite)
 P. vivax and P. ovale
间日疟原虫，卵形疟原虫

• Less likely to be life threatening than P.

falciparum

• Symptoms (especially fever) can still be

dramatic

• Different drugs are used to treat blood and liver

stage parasites
(A dormant stage parasites-hypnozoites)
Schema of the Life Cycle
of Malaria Human Liver Stages

Mosquito Stages
Sporozoites Exo-erythrocytic
(hepatic) Cycle
Hypnozoites
Schizonts
Merozoites
Sporogonic
Cycle Human Blood Stages

P. falciparum
Clinical symptom
Erythrocytic
Gametocytes Cycle
P. vivax
P. ovale
P. malariae
Sporozoites 子孢子 infect liver
where they enter cells and
multiply

After 12 to 20 days, cells

rupture and release merozoites
which enter red blood cells.
In RBCs, parasites produce both
asexual forms and gametocytes
which are taken up by mosquito

Periods in RBC:
48h for P. vivax, P. ovale;
36h-48h for P. falciparum;
72h for P. malariae
Sexual reproduction takes place
in mosquito gut
Timing of Malaria life
cycle:
malaria sporozoites
(asexual stage) infect
human after a 10 day
maturation process in
mosquitos
malaria gametocytes
(sexual stage) infect
mosquito after a 21 day
maturation process in
humans
 Clinical Manifestations
Incubation periods
• Vivax malaria (benign tertian):
11-25d (14d)
• Ovale malaria:
11-25d (14d)
• Malariae malaria, quartan malaria:
18-35d (28d)
• Falciparum malaria (malignant):
6-27d (11d)
 Clinical Manifestations
• A cold stage: sensation of cold,
shivering; some minutes to 1-2h
• A hot stage: fever, headaches,
vomiting(emesis); 3-6h
• A sweating stage: 1-5h
6-10h in total.
• Intermittent attack
 the "tertian" parasites every second
day (P. falciparum, P. vivax, and P.
ovale)
 the "quartan" parasite every third day
(P. malariae)
 Clinical Manifestations
Symptoms of Malaria
• Fever

• Other symptoms---
chills, fatigue, weakness, headache,
nausea, vomiting, diarrhea, muscle
aches, dark urine, mental status
changes
• The patients often can have a series
(constellation) of symptoms described
as “flu-like”.
 Physical findings
• Common findings
 Elevated body temperature (fever)
 Perspiration (Sweating)
 Weakness
 Splenomegaly after several attacks
• Additional findings in P.
falciparum malaria
 Jaundice
 Hepatomegaly
 Increased respiratory rate
 Clinical Manifestations

• Species (P. falciparum) specific

– Massive hemolysis

– Infected red blood cells produce

cell surface “knobs” that adhere
to endothelial cells in multiple
organs
Uninfected erythrocyte.
cell surface
“knobs” =
small protrusions

“knobs”
 Malaria Mortality

2 main death causes:

Cerebral malaria
–Damages brain and other
Anemia
–Parasites destroy red blood vital organs
cells –Fatality rate of 15% or
–Associated with increased more
mortality
Manifestation
s
 Relapses
• In P. vivax and P. ovale infections, patients
having recovered from the first episode of
illness may suffer several additional attacks
("relapses") after months or even years
without symptoms.
• Relapses occur because P. vivax and P.
ovale have dormant liver stage parasites
("hypnozoites") that may reactivate.
• Treatment to reduce the chance of such
relapses is available and should follow
treatment of the first attack.
 Human genetic background
and malaria
• Sickle cell anemia 镰状细胞性贫血 protects from malaria
 Diagnosis
• Epidemiological data: travel history or
dwelling
• Clinical manifestations
typical attack, three stages (chills,
fever, diaphoresis), 6-10h
Physical findings
Presumptive treatment
• Laboratory findings: Plasmodium spp.
---confirmed
 Laboratory tests
• Microscopic diagnosis --- Observation
of malaria parasites in blood
Giemsa stain
Morphology indicates species---confirmed
• Antigen or antibodies against malaria
parasites detection
• "Rapid Diagnostic Tests" (RDTs): Various test kits are available to
detect antigens derived from malaria parasites. Such immunologic
("immunochromatographic") tests most often use a dipstick or
cassette format, and provide results in 2-10 minutes.

• Molecular diagnosis (PCR) to confirm

diagnosis
Microscopy
WBC
Infected RBC

Blood smear stained with Giemsa, showing a white blood cell (on left
side) and several red blood cells, two of which are infected with
Plasmodium falciparum (on right side).
 Differential diagnosis

• Typhoid fever
• Sepsis syndrome and BSI
• Leptospirosis 钩端螺旋体病
 Cerebral malaria---
• Bacillary dysentery
• Type B encephalitis
 Complications

• Black-water fever: G6PD- deficiency

• Acute renal failure
• Hypoglycemia
• Pulmonary oedema or ARDS
• Jaudice and/or liver dysfunction
• Hematological finding:
thrombocytopenia, DIC
• Infection: pneunomia
 Treatment
• Quinolone derivatives
– Chloroquine:
 250 mg/tablet, 1st day 4 tablets, 2nd and 3rd days 3 tablets
 Inj. 1.5 g plus 5% glycose solute 250-500 ml at the 1st day,
and then Inj. 0.5 g plus 5% glycose solute 250-500 ml at
the 2nd and 3rd days, iv drip, gd
– Quinine:
 300 mg/tablet, 1-2 tablets, tid. For Chloroquine-resistant
 Inj. 500 mg plus 5% glycose solute 250-500 ml, iv drip,
12h later ones again, For cerebral malaria
– Mefloquine:
 250 mg/tablet, 4-6 tablets po, once, For Chloroquine-
resistant
 40
Treatment
• Qinghaosu (artemisinin, arteannuin 青蒿素 )
Artemisinin is the basis of all the new treatments
that are going ahead.
---herb Artemisia annua
For Chloroquine-resistant and cerebral

Inj. 120 mg at 1st day, 60 mg at 2nd and 3rd days

plus 5% NaHCO3 1 ml dilution, 5% glycose
solute added to 5 ml in total
• Primaquinine phosphate （ for P. vivax or P. oval
伯氨喹啉）

e malaria (hypnozoites) 15mg po qd  2-3 weeks

Klayman DL.Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985 May 31;228(4703):1049-55.
Li Y, Wu YL. How Chinese scientists discovered qinghaosu (artemisinin) and developed its derivatives?
What are the future perspectives? Med Trop (Mars). 1998;58(3 Suppl):9-12. Review.
Drug resistance
 Prevention

• To control infected people or

patients with malaria
• Vector control
Insecticide of mosquitos
Bednets
• Chemoprophylaxis
Drugs
Malaria vaccines
 Mosquito vectors

• Malaria transmitted only by

anopheles mosquitos
• Only females take blood meals
• Different anopheline vectors
have different transmission
efficiency
– Anopheles gambiae highly efficient
anopheles culicifacies much less
efficient
 Malaria control
• Drugs
– Intermittent preventive treatment (IPT)
– Chemoprophylaxis (no longer recommended)
Chemotherapy to reduce infectious period in
humans
Absence of chemotherapy to increase
immunity
• Malaria vaccines-
in phase 3 clinical
trials (RTS, S/AS01)
• Vector control
Insecticide Treated Nets (ITNs)
 Chemoprophylaxis
• Most regimens require weekly or more
frequent dosing
– Chloroquine most commonly used drug

• Usefulness severely limited by:

– Difficulty in delivering intervention
– Poor adherence to regimen
– Side effects of chloroquine (especially
itching)
– Increasing P. falciparum resistance to
chloroquine
Most commonly adopted regimen: two
treatment doses of
sulfadoxine-pyrimethamine(SP, 乙胺嘧啶
6.25mg per tablet):
Non-pregnant: 25 mg, qw
Pregnant women: 3 tablets/treatment,
one second trimester, one third
trimester
Tafenoquine (WR 238605)
Vector control: bednets
Bednets and insecticide-
treated mosquito nets
 Insecticides

• DDT use in south Africa

• Difference between larvicides and

imagicides

• Bednet (Insecticide-treated mosquito

nets) use versus outdoor spraying
Mosquito larvae in water
 Genetic manipulation of
mosquito vector
Nature 417, 452 - 455 (23 May 2002);

Transgenic anopheline mosquitoes impaired in transmission of a

malaria parasite

JUNITSU ITO*†, ANIL GHOSH*†, LUCIANO A. MOREIRA*,

ERNST A. WIMMER‡ & MARCELO JACOBS-LORENA*

* Case Western Reserve University, Department of Genetics, 10900 Euclid

Avenue, Ohio 44106-4955, USA
‡ Lehrstuhl für Genetik, Universität Bayreuth, Universitätsstrasse 30, NW1, D-
95447 Bayreuth, Germany
† These authors contributed equally to this work
 A public antibody lineage that potently
inhibits malaria infection through dual
binding to the circumsporozoite protein
• Immunization with attenuated Plasmodium
falciparum sporozoites (PfSPZs) has been
shown to be protective against malaria.
• It could pave the way for the use of
antibodies in the prophylaxis of P. falciparum
infection and for the development of
improved antibody-based subunit vaccines
against malaria.
Tan J, et al.. Nat Med. 2018 Mar 19. doi: 10.1038/nm.4513. [Epub ahead of print]
 Other issues in malaria

• Complex
emergencies
Climate change

Global warming
 Roll Back Malaria (RBM)
• The goal of Roll Back Malaria, established as
a health initiative by WHO and its partners in
1998, is to halve the world's malaria burden by
2010.
• At the Africa Summit on RBM, April 2000,
Heads of State or senior representatives from
44 malaria-afflicted countries in Africa agreed
to a series of interim goals to be attained by
2005.
• Global program with clear strategies
• Provides framework for action
• Prevention and treatment
 Economic burden of malaria

• Controlling for location, colonialism,

geography
 Prevalence of infection in
mosquitoes and humans

1
Humans
Prevalence

Mosquitoes

0 50
Basic reproductive number
Table. Comparison of P. faciparum
and P. vivax malaria
 Summary

• Definition
• The life cycle of malaria
• Diagnosis and characteristics of
different malarias
• Therapy
• Prevention
 References
Tropical Diseases
What are the future perspectives? Med Trop (Mars). 1998;58(3
Suppl):9-12. Review

WHO. World Malaria Report 2013.

http://www.who.int/malaria/publications/world_malaria_
report_2013/report/en/ (2014-4-12)

Li Y, Wu YL. How Chinese scientists discovered qinghaosu

(artemisinin) and developed its derivatives?

Guidelines for the Prevention and Treatment of Malaria in

South Africa

Books: tropical diseases, clinical medicine, infectious

diseases, tropical medicine and sexually transimitted disease.
WHO: http://www.who.int/malaria/world_malaria_report_2010/en/index.html
Vaccine development and immunity. Nature medicine, 2013.
World Malaria Day: April 25th.

Thank you!