MALARIA

Yuankai Wu

Department of infectious diseases

The Third Affiliated Hospital

Sun Yat-Sen Universicty

Malaria • a vector-borne disease caused by single

celled parasites, the Plasmodium protozoa, and transmitted by female Anopheles mosquitoes.

• Characterized by malarial paroxysm of chills, fever and sweats.

Still an enormous pubic health problem and one of the most common infectious diseases.

History of malaria

• Malaria has infected humans for over 50,000 years.

• first recorded in 2700 BC in China.

• originates from Medieval Italian:

• mala aria — "bad air";

• was formerly called ague or marsh fever due to its association with swamps and marshland

History of malaria• 1880, a French army doctor

first observed parasites in patient’s RBC. the 1907 Nobel Prize for Physiology or Medicine.

• 1898, Britain's Sir Ronald Ross finally proved that malaria is transmitted by mosquito.(1902 Nobel Prize)

Charles Louis Alphonse LaveranMuller ： Swiss chemist, discovered DDT to kill mosquito in 1930’ (1984 Noble)Wagner ： Austrian psychiatrist ， used the high fever of malaria to treat dementia in stage-III syphilis(1927 Nobel)

Malaria• 1. Etiology (life cycle)• 2. Epidemiology• 3. Pathogenesis and pathology• 4. Clinical manifestation• 5. Diagnosis • 6. Differential diagnosis• 7. Therapy• 8. Prevention• 9. Summary

Etiology

• Plasmodium protozoa– P. falciparum (the deadliest);– P. malariae ;– P. ovale ;– P. vivax (the most common);

• Within each species there are variant strains.

Life cycle• Sexual cycle in mosquito

– Gametocyte, gamete, zygote,

ookinete, oocyst, sporoblast,

sporozoite

• Asexual cycle in Human

– Exoerythrocytic stage:

sporozoite, tachysporozoite

(12-20d), bradysporozoite

(hypnozoite) (6-11m),

merozoite, schizont,

– Erythrocytic stage:

ring form, trophozoite,

schizont, gametocyte

Ring form

Trophozoite

Schizonte

Gametocyte

Release merozoites

Merozoite

SporozoiteTachysporozoite

Bradysporozoite

Release merozoites

3-6 generations in RBCs

Fertilization

Epidemiology

• Source of infection

– Patients

– Asymptomatic carriers

Epidemiology

• Route of transmission

– Bite by female anopheles mosquitoes.

– Vertical transmission (placenta)

– Blood transfusion

Epidemiology• Susceptibility

– All susceptible

– Travelers and foreigner

– Children, pregnant women

– Short immunity, without cross immunity.

Epidemiology

• Epidemiological feature

– Seasons: Summer and Autumn (temperature)

– In china, P. vivax is predominant, P. falciparum

second, P. malariae and P. ovale seldem.

– Endemic areas: tropic or sub-tropic area.

Endemic countries of malaria (2003)NOTE: In most of these countries malaria was limited to certain areas

The mortality of malaria in china in 1952-1998

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Pathogenesis

Toxic mediators

Inflammatory responses

Hemolysis

Adhere to blood vessels

hypoglycaemia

Chill, fever, sweat

Anemia

Obstruct blood flow

Splenomegaly hepatomegaly

Phagocytosis renal failure Black water fever

metabolic disturbances

Tissue hypoxia

Impaired microcirculation DIC

Cerebral malaria

Pulmonary edema

Clinical manifestation• Incubation period: • 7~30d (7~12, 13~15, 24~30)• Malaria paroxysm: • chills, fever and sweating.• Periodicity:• every 48h (P. vivax, P. ovale) • every 72h (P. malariae)• every 36-48h (P. falciparum)• Between attacks: • feel fine (P. vivax, ovale or malariae) • or miserable (P. falciparum)

Clinical manifestation —typical attack

• Chilling stage: 20min~1h, feel cold and true shaking chills, accompanied with malaise, headache, vomiting or diarrhea.

• Hot stage: 2~6h, T usually as high as 41 , tachycardia, hypotension, cough, ℃headache, backache, but normal consciousness.

• Sweating stage: 30min~1h, T falls with diaphoresis, fatigue and weak.

• Common signs: anemia, splenomegaly.

Intermittent fever of P. vivax

℃℃

4040

3939

3838

3737 11 2 3 2 3 44 5 6 7 8 9 10 11 12 13 5 6 7 8 9 10 11 12 13 DaysDays

synchronization

Intermittent fever

Clinical manifestation severe attack

• Cerebral malaria:

– P. falciparum infection, T, antimalarial drugs.

– Obstruction of vessels and hypoglycemia.

– Severe headache, high fever.

– Impairment of consciousness: confusion, obtundation, seizures and coma.

– Neurologic sign: hyper-reflexion and bilateral Babinski’s sign. Focal neurologic finding occurs rarely.

The severtity of clinical manifestations

• Parasitemia– P. falciparum: 1,000,000/ mm3 – P. vivax and P. ovale: ≤25,000/mm3

– P. malariae: ≤10,000/mm3

• Infected RBC– P. falciparum: RBCs of any age. – P. vivax and P. ovale: younger RBCs.– P. malariae: older RBCs.

• Multiply speed– P. falciparum: 36-48h – P. vivax and P. ovale: 48h– P. malariae: 72h

Recrudescence and Relapse• Recrudescence:

– residual plasmodium in the bloodstream.– could be found in all the four species

infection.– 1~4wk after relieved, or repeatedly.

• Relapse: – hypnozoites in the hepatocytes.– only found in P. vivax and P. ovale.– usually 3~6mon after “cured”.

Clinical manifestation special type

• malaria in pregnancy:– main adult risk group.– 80% death of malaria in Africa.– more aggravated: anemia, fever,

hypoglycemia, cerebral malaria, pulmonary edema, puerperal(afte labor) sepsis.

– Low birth weight, prematurity. – Vertical transmission.

Clinical manifestation special type

• Malaria infected by blood transfusion:– Symptoms: the same as malaria transmited by

mosquitoes.– Shorter Incubation stage: 7-10d.

no exoerythrocytic stage– No hypnozoite, no relapse.

• Malaria infected by vertical transmission:– Symptoms: the same– Incubation stage: about 1wk after birth.– No hypnozoite, no relapse.

Complications

• Hemolytic urinemic syndrome (black water fever)

• Pulmonary edema.• Hyperreactive malarial splenomegaly.• Shock, hypotension.• Diarrhoea, jaundice, splenic rupture.• Anemia, hemorrhage, DIC.• Hypoglycaemia, metabolic acidosis.

Complications

• Hemolytic urinemic syndrome– More common in adults, rare in children.– More frequent in patients without immunity

and with high parasitemia and G6PD deficiency after quinine or primaquine.

– Intravascular hemolysis, hemoglobinuria.– Lumbago, dark urine(black water), jaundice,

oliguria, renal failure.

Complications

• Hemolytic urinemia syndrome(black water fever).

• Pulmonary edema.• Hyperreactive malarial splenomegaly.• Shock, hypotension.• Diarrhoea, jaundice, splenic rupture.• Anemia, hemorrhage, DIC.• Hypoglycaemia, metabolic acidosis.

Complications

• Pulmonary edema– Uncommon, even in severe infection. – Patients with hyperparasitemia.– Results from capillary leak rather than

heart failure.– A fatal complication.– Treated with positive-pressure artificial

ventilation.

Complications

• Hemolytic urinemia syndrome(black water fever).

• Pulmonary edema.• Hyperreactive malarial splenomegaly.• Shock, hypotension.• Diarrhoea, jaundice, splenic rupture.• Anemia, hemorrhage, DIC.• Hypoglycaemia, metabolic acidosis.

Complications

• Hyperreactive malarial splenomegaly– Tropical splenomegaly syndrome (TSS).– Seen in older children and adults.– Associated with repeated infection In

hyperendemic area.– Anemia, massive splenomegaly, elevated IgM

levels and malarial antibody.– Usually responds to prolonged treatment with

prophylactic antimalarial drugs.

Complications

• Hemolytic urinemia syndrome(black water fever).

• Pulmonary edema.• Hyperreactive malarial splenomegaly.• Shock, hypotension.• Diarrhoea, splenic rupture.• Hemorrhage, DIC.• Hypoglycaemia, metabolic acidosis.

Diagnosis• Epidemiological history

– Traveled in endemic areas (bitten by a mosquito)

– Blood transfusion or organ transplantion

• Clinical manifestation

– Typical malaria paroxysm

– Intermittent fever, Several small fever spikes

• Pathogenic detection

– Thick and thin film

• Diagnositic therapy in atypical cases

Diagnosis• Pathogenic Investigations

– Microscopic diagnosis

– Quantitative buffy coat(QBC)

– Antigen detection: RDTs

– Serology test: ELISA, IFA

– Molecular diagnosis: PCR

• Other: complete blood count, blood chemical tests of liver

function and renal function.

Diagnosis Microscopic diagnosis

• Blood smear (Gold standard)

– The most preferred, economic, and reliable

– Thick film: sensitive, diagnosis of infection

– Thin film: identification of species

– Giemsa's staining positive

Ring form and Gametocyte of P. falciparum

Diagnosis

• Pathogenic Investigations

– Microscopic diagnosis

– Quantitative buffy coat(QBC)

– Antigen detection: RDTs

– Serology test: ELISA, IFA

– Molecular diagnosis: PCR

– others

Differential diagnosis• Infectious diseases

– Influenza– Sepsis– Typoid, paratypoid fever– Leptosirosis– Dengue fever– Japanese B encephalitis– toxic dysentery– Hemorrhagic fever with

renal failure– Acute intravascular

hemolysis

• Non-infectious diseases

– Lymphoma, leukaemia

– Malignant histocytosis

– Connective tissue

diseases

Prognosis

• Curable if treated in early stage.

• Chronic malaria in hyperendemic areas.

• Kill up to 15%~20% children<5y in Africa.

Treatment• Symptomatic and supportive measures

– Relief of high fever– Intravenous injection to sustain fluid balance– Treatment hypoglycemia– Dehydration in cerebral malaria– Blood transfusion for severe anemia– Hemodialysis when renal failure – ……

• Antimalarial treatments.

Antimalarial Treatment

• Tissue schizonticides (causal prophylaxis)• Pyrimethamine and Primaquine

• Blood schizonticides (terminate attacks)• Chloroquine , Artemisinine, Quinine, Mefloquine,

Halofantrine, Pyrimethamine, Sulfadoxine, Sulfones, Tetracyclines, Doxycycline

• Tissue schizonticides (prevent relapse)• Primaquine, tafenoquine and Pyrimethamine

• Gametocytocides (block transmission)• Primaquine, tafenoquine, Chloroquine, Quinine, Artemisinine

• Sporozoitocides (ablate transmission of mosquito)

• Primaquine and proguanil

Antimalarial strategy

Blood schizonticides

＋

Gametocytocides /

Tissue schizonticides

Chloroquine

Artimesinine, Artesunate

＋ Primaquine

Tafenoquine

Available drugs

• Quinine

– 0.65g tid×7d

– Seldom used now

• The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine.

Available drugs• Chloroquine (phosphate)

– Most common used• 1.0 po., 0.5 po.6~8h later on the first day

• 0.5 po. Qd on the second and third day

– Drug resistance (P. falciparum)• Quinine +

Doxycycline/Tetracycline/clindamycin

• Artemisinine or Artesunate

Available drugs

• Artemisinine and Artesunate– Powerful and less resistant

– Artemisinine• 1.0 po., 0.5 po.6~8h later on the first day

• 0.5 po. Qd on the second and third day

– Artesunate• 100mg bid×1d ， 50mg bid×4d

– Cerebral malaria and pregnant patients

Available drugs

• Primaquine (phosphate)

– Most commonly used Gametocide

– Prevent relapse and block transmission

• 7.5mg tid × 8d

– Acute intravascular hemolysis (black water fever)

• Routine G6PD test!!

Cerebral malaria

• Artesunate– 60mg iv. drip, at 0, 4, 24, 48hr

– 50mg bid ×2~3d

• Chloroquine– 16mg/kg→8mg/kg → conscious →po.

• Quinine– 500mg q12h →conscious →po.

Caution

• Repeat the thick and thin blood smear

• Do not use Doxycycline, Primaquine,

Mefloquine, Atovaquone-proguanil in

Pregnant women.

• Routine G6PD test?

Prevention

• Control the source of transmission

• Cut off the route of transmission

• Protection of susceptible population

Prevention Source of transmission

• Cases management

– Cure the patients and carriers

– use gametocides and blood schizonticides simultaneously.

– Chloroquine / artemisinine / artesunate

and primaquine / tafenoquine

Prevention Route of transmission

• Vector control

– Kill anopheles mosquitoes: insecticide spraying

– Avoid multiply of mosquitoes:

• Personal protection

– Mosquito nets

– Repellents

– Long clothes

Prevention Protection of susceptible population

• Active prophylaxis

– Vaccine

• Under development

• Passive prophylaxis

– Chemoprophylxis

• Chloroquine (sensitive, pregnant women or

children)

• Mefloquine, Doxycycline, Pyrimethamine.

summary

• Malaria is a vector-borne parasitic disease caused by plasmodium protozoa

• All the four species plasmodium need anopheles mosquitoes and human to complete it’s life cycle.

• Transmitted by a bite of anopheles mosquito.• Characterized by the malaria paroxysm (chill, high

fever,and sweats)• The thick film and thin film can diagnose a malaria.• Use the blood schizonticides and gametocides

simultaneously to kill the parasite.• Prevention refers to the cases management, vector control,

personal protection, vaccine and chemoprophylaxis.• Malaria is still a enomous public health problem world

wide.

THANK YOU!

Species P. vivax, P. ovale P.malariae P. falciparum

Periodicity Tertian Tertian Quartan Irregular/tertian

Attacks Typical Typical Typical Intermittent irregular

Recrudescence

Yes Yes Yes Yes

Relapse Yes Yes No No

Complications

Rare Rare Glomerulo-nephritis

Nephritic syndrome

Cerebral malariaBlack water fever

Useful Links

• Centers for Disease Control and Prevention： http://www.cdc.gov/ Global Fund to Fight AIDS, TB and Malaria： http://www.who.int/malaria/ Global Health AdvocatesInnovative Vector Control Consortium Lubombo Spatial Development Initiative Malaria Foundation International Malaria Journal Malaria Vaccine Initiative Medical Research Council Medicines for Malaria Venture Multilateral Initiative on Malaria Nature Medicine (Malaria) President's Malaria Initiative Roll Back Malaria Partnership South Africa Department of Health (Malaria) East and Southern African Malaria Control UNICEF World Health Organisation World Bank

Why are malaria cases increasing?

• Drug resistence

• No vaccine

• Wars

Do all mosquitoes transmit malaria?

• No. So far, entomologists have identified over 2000 species of mosquito, but only the Anopheles mosquito actually transmits malaria. In Africa, the major vectors for malaria are An. gambiae sl complex and An. funestus, and there are many members of both groups of mosquito. Most Anopheles mosquitoes do not feed during the day but rather do so at dusk or during the night. An. funestus for example feeds most actively between 2am and 4am.