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 patients 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 Laveran MullerSwiss chemist, discovered DDT to kill mosquito in 1930 (1984 Noble) WagnerAustrian psychiatristused 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

Sporozoite
Tachysporozoite Bradysporozoite

Merozoite

Release merozoites

Release merozoites

Fertilization

3-6 generations in RBCs

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

Death (/10,000)

Year

The mortality of malaria in china in 1952-1998

Pathogenesis
Toxic mediators Inflammatory responses
metabolic disturbances Chill, fever, sweat

hypoglycaemia

Anemia Hemolysis

Phagocytosis Adhere to blood vessels

Splenomegaly hepatomegaly Tissue hypoxia Obstruct blood flow

renal failure Black water fever

Cerebral malaria
Pulmonary edema Impaired microcirculation DIC

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

40 39
38 37 1 2 3 4 5 6 7 8 9 10 11 12 13
synchronization

Days

Intermittent fever

 Cerebral malaria:

Clinical manifestation severe attack

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 Babinskis 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
Chloroquine Blood schizonticides

Artimesinine, Artesunate

Gametocytocides / Tissue schizonticides

Primaquine Tafenoquine

Available drugs
Quinine
0.65g tid7d 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 bid1d50mg bid4d

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/kg8mg/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 its 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 Periodicity

P. vivax, P. ovale Tertian

Typical
Yes

P.malariae Quartan
Typical
Yes

P. falciparum Irregular/tertian
Intermittent irregular
Yes

Tertian
Typical
Yes

Attacks
Recrudesce nce Relapse Complicati ons

Yes Rare

Yes Rare

No Glomerulonephritis Nephritic syndrome

No Cerebral malaria Black water fever

Useful Links
Centers for Disease Control and Preventionhttp://www.cdc.gov/ Global Fund to Fight AIDS, TB and Malariahttp://www.who.int/malaria/ Global Health Advocates Innovative 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.