PARASITOLOGY LECTURE 13 – Malaria – Dr. CarandangNotes from LectureUSTMED ’07 Sec C – AsM

MALARIA

- “Malaria” (“Paludisme”)- Mal – bad- Aria – air- Palus (marsh)- disease was caused by vaports and mists arising

from swamp

HISTORY

- 5th Century B.C.o Hippocrates – first to describe the clinical

picture of malaria and some complications of the disease

- 1880o Laveran – first described the malarial

parasites in blood films of man (asexual stage of P. falciparum)

Geographic distribution of malaria in the mid-19th century (malarious areas are shaded)

- 1955o W.H.O. adapted the concept of malarial

eradication

Worldwide range of malaria in 1994 (darker shading)

- Malaria free areas (no vector transmission)

o Manila propero Aklano Capizo Guimarao Siquijoro Bilirano Iloiloo Leyte Norteo Leyte Suro Northern Samaro Camiguino Cebuo Leyteo Catanduanes

- Philippine Statisticso DOH 2001

40,543 cases / yr Morbidity rate of 52/100,000

population

ETIOLOGY

In the Philippines, in order of frequencyo Plasmodium falciparum (most frequent)o Plasmodium vivaxo Mixed infection (Pf and Pv)o Plasmodium malariaeo Plasmodium ovale (exclusively rare)

HUMAN MALARIAL PARASITES

PARASITES DISEASEPlasmodium vivax Benign tertian malariaPlasmodium ovale Benign tertian malaria

Plasmodium falciparum Malignant tertian malariaPlasmodium malariae Quartan malaria

MODE OF TRANSMISSION

Through the bite of female anopheles mosquito Directly from one person to another by passage of

blood containing erythrocytic parasite through:o Blood transfusiono Sharing of contaminated syringes and

needleso Mingling of infected maternal blood with

that of infant during birth process (neonatal malaria)

o Transplacental transmission (congenital malaria)

VECTORS OF MALARIA IN THE PHILIPPINES

Principal vector – Anopheles flavirostris minimus Secondary vector

o Anopheles litoraliso Anopheles balabacensiso Anopheles mangyanuso Anopheles maculates

LIFE CYCLE

Mosquito Cycle (Sporogany)

Human Cycle Schizogony

PATHOPHYSIOLOGY

Degree of damage to tissue depends ono Specieso Parasite concentration

TISSUE ANOXIA

Basic pathophysiology changes in malaria

4 MECHANISMS LEADING TO TISSUE ANOXIA Anemia – hemolysis Changes in blood flow Changes in capillary endothelium Histotoxic anoxia

1. Anemia-hemolysis- Intravascular – rupture of infected and non-

infected rbc- Extravascular – phagocytosis of infected and non-

infected rbc by R.E. cells (Kupffer cells in the liver, macrophages in spleen, lungs and bone marrow)

- Bone marrow dysfunction (dyserythropoeisis) – persist for days or weeks following acute malaria

Characteristics of parasitized red cells Decreased deformability Increased adhesion Increased fragility Decreased oxygen transport Antigen release Toxin production

2. Changes in blood flow- Blockage of small blood vessels- Vasomotor changes – vasoconstriction of arterioles

and venules, vasodilation of capillaries

Blockage of small vessels is brought about by: Cytoadherence – mature forms of parasite (P.

falciparum) first roll on and then adhere to the microvascular epithelium

Reduction in deformability of the parasitized erythrocytes due to:

o Reduced membrane fluidityo Increasing sphericityo Enlarging and relatively viscous

intraerythrocytic parasite

Erythrocyte adhesion (rosetting) of infected rbc with two or more uninfected rbc

Rosetting of P. falciparum in vitro

Consequences of Microcirculatory Obstruction

Reduced oxygen and substrate supply leading to anaerobic glycolysis and lactic acidosis

3. Changes in capillary endothelium- Increased permeability cerebral edema,

hypovolemic shock 4. Histotoxic anoxia- Respiration (oxidative phosphorytation of the

mitochondria) is inhibited

PARASITE VIRULENCE FACTORS

Multiplication Capacity- A rapidly expanding biomass of parasites is more

likely to outstrip host defenses- Immunity reduces multiplication and then limits

the size of the parasite biomass Red cell selectivity- Unselective parasite will not be limited by the

availability of suitable red cellso P. vivax prefers young rbco P. malariae prefers old rbco P. falciparum infectes all stages of rbc

Cytoadherence and rosetting abilityo Parasites with both these adhesive

characteristics may be more pathogenico All four Plasmodium species normally

infecting man can induce rosetting but only P. falciparum causes lethal infection

o Only P. falciparum causes cytoadherence and all parasites sequester in vivo

Potential to induce cytokine releaseo Cytokines are responsible for many of the

symptoms and signs of malaria, particularly fever and malaise

Anitigenicityo Parasites that are not recognized by the

host will obviously have a relative growth advantage

Antimalarial drug resistance o In many areas of the tropics, antimalarial

drugs are widely available and self-medication is common

“Toxins” liberated when mature schizont ruptures: Cytokines (TNF) Phospholipid material

- Both have endotoxin like activity- Causes symptoms and signs of the paroxysm such

as shivering, cool extremities, headache, chills, fever, malaise, followed by sweating, vasodilation, and defervesence

Nitric oxide(No) may cause many of the pathological features of severe malaria which include hypotension, lactic acidosis, hypoglycemia and coma

Other effects of cytokine:

Placental dysfunction Suppression of erythropoiesis Hepatic dysfunction Inhibition of gluconeogenesis Promote cytoadherence by up regulating the

endothelial expression of some vascular ligands for P. falciparum infected rbc particularly ICAM-I, the principal receptor of cerebral vascular epithelium

Mediators of parasite killing by activating leucocytes and other cells to release nitric oxide generating parasitidal lipid peroxides

BLACKWATER FEVER (G6PD)

Refers to massive intravascular hemolysis and the passage of dark red, brown, or usually black urine

More common in G6Pd deficient patients receiving sulfa containing drugs, quinine, or artemisinin

Occurs in severe falciparum malaria in patients without G6PD deficiency but was given quinine or artermisinin

LIVER DYSFUNCTION

Jaundice is common Decreased in clotting factor synthesis Decreased metabolic clearance of drugs Decreased biliary excretion Failure of gluconeogenesis lactic acidosis and

hypoglycemia

HYPOGLYCEMIA

Associated closely with hyperlactatemia In adults, increased glucose demand

predominates while in children, reduced glucose supply may be more important

Stimulation of pancreatic B cell insulin secretion in quinine treated patients (occurs after the first 24 hours of treatment)

ACIDOSIS

Mainly caused by lactic acid due too Tissue anaerobic glycolysiso Reduced circulating red cell o Reduced oxygen carriageo Increased glycolysis (as part of

hypermetabolic state)o Decreased hepatic and renal lactate

clearanceo Lactate production by malaria parasites

GASTROINTESTINAL DYSFUNCTION

Minor stress ulceration of the stomach and duodenum

Pattern of malabsorption due to reduced splanchnic perfusion (secondary to gut sequestration and visceral vasoconstriction)

PLACENTAL DYSFUNCTION

Pregnancy increases susceptibility to malaria due to suppression of systemic and placental cell-mediated immune response

There is intense sequestration of falciparum infected rbc in the placenta leading to thickened syncitiotrophoblast, abnormal uteroplacental blood flow, and placental insufficiency fetal growth retardation

PULMONARY EDEMA

Results from sudden increase in pulmonary capillary permeabiltiy that is not reflected in other vascular body

Cause of this increase in permeability is not known

RENAL FAILURE

Common manifestation of falciparum malaria in adults

Basic pathology is acute tubular necrosis (mechanism remain unclear)

Sequestration is greatest in the medullary vessels and it is in the medulla where tissue PO2 is lowest and most vulnerable to ischemia and further hypoxia

COAGULOPATHY AND THROMBOCYTOPENIA

There is acclerated coagulation cascade activityo Accelerated fibrinogen turnovero Consumption of antithrombin III, protein

C, and protein So Increased concentrations of plasminogen

activator inhibitor-I and fibrin degradation products

o Thrombocytopenia due to increased splenic clearance (moderate in P. vivax and falciparum, severe in falciparum)

Reasons for bacteria superinfection in severe malaria Broader immune suppression due to:

o Defects in monocytes and neutrophil chemotaxis

o Reduced monocytic phagocytic function

COMA IN CEREBRAL MALARIA

Associated with 15-20% mortality 90% of children and 98% of adults survivors

recover without sequelae Involve neurotransmitter abnormalities and nitric

oxide, which is a potent inhibitor of neurotransmission

DIAGNOSIS

Clinical manifestation History of coming from an endemic area or recent

blood transfusion Demonstration of asexual forms of plasmodia in

thin and thick peripheral blood smears; if negative, repeat as often as necessary depending on the severity of the manifestations; at times, in the bone marrow

PLASMODIUM FALCIPARUM

PLASMODIUM VIVAX

PLASMODIUM OVALE

PLASMODIUM MALARIAE

DIAGNOSIS

Quantitative Buffy Coat (QBC) Para sight F test – a dipstick test for the simple

and rapid diagnosis of P. falciparum Serologic test (IFA) – cannot distinguish between

current and past infection, therefore not helpful in establishing the diagnosis of an acute infection.

RATIONALE AND TECHNIQUE OF MALARIA CONTROL

The right way (above) and the wrong way(below) of using the bed net.

Outdoor control of mosquitoes by sapce spraying in a rural area of Singapore, using Dieldrin and a portable “Swingfog” fogging machine.

Larvivorous fish (Gambusia affinis) widely used for mosquito control in many parts of the world

Larvivorous fish used in some malaria control programmes. These are two species of “annual fish” of the family Cyprinodontidae.

Differentiation of Anopheles, Aedes and Culex mosquitoes at various stages of their development

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