Malaria- means “bad air”

ETIOLOGY

A protozoan disease caused by sporozoa of genus Plasmodium

Transmitted by a bite of an infected female Anopheles mosquito

Infective stage to man: Sporozoites

4 Spp. of Plasmodium that affect man:1. Plasmodium falciparum found in the 2. Plasmodium vivax Phils. 3. Plasmodium ovale 4. Plasmodium malariae

Almost all deaths are caused by falciparum malaria.

LIFE CYCLE

patterned from Harrison’s

Asexual Pre-Erythrocytic Stage

Asexual Erythrocytic Stage

Sexual Erythrocytic Stage

After being ingested in the blood meal of a

biting female anopheline mosquito, the male and female gametocytes form a zygote in the

insects midgut.

The zygote matures into an ookinete which penetrates the mosquito’s gut wall forming an

oocyst.

The oocyst expands by asexual division until it bursts to liberate myriad motile sporozoites w/c migrate in the hemolymph to the slivary

gland of the mosquito to await inoculation into another human at the next feeding.

Pre-erythrocytic cycle- invasion of RBC

Intra-erythrocytic cycle- Disease manifestation- direct toxic effect in RBC-related waste products that stimulate macrophages to produce pro-inflammatory cytokines

Asexual Cycle/Schizogony- occurs in man; man serves only as the intermediate host- Infective stage to man: sporozoite

Sexual Cycle/Sporogony/Gametogony- occurs in the mosquito; mosquito is the final host of the parasite- Infective stage to mosquito: gametocytes (macrogamete: pertains to female gametocyte; microgamete: male)

EPIDEMIOLOGY

Falciparum and ovale malaria are tropical diseases.

P. falciparum predominates in Africa, New Guinea, and Haiti; P. vivax is more common in Central America;

P. malariae in sub-saharan Africa; P.ovale in Africa

Principal Determinants of Epidemiology in Malaria:

1.) Number (density) – transmission of malaria is directly proportional to the density of the vector.2.) Human-biting habits3.) Longevity of the Anopheline Vectors: to transmit malaria, mosquito must survive >7 days considering that the parasite’s life cycle lasts from 8-30 days.

Sickle Cell disease - can serve as protection from falciparum infection. On low O2 tension, RBCs develop aggregates that are needle-like that will pierce the parasite.

FYa and FYb – genes that express receptors for RBC. When certain people don’t have these genes or are FY-; this can serve as protection from vivax infection.

PATHOGENESIS

How does malaria cause disease? TISSUE HYPOXIA (underlying basis): lowered O2 tension in tissues hypoxia/anoxia of tissues

Cerebral malaria: causes gray discoloration of the white matter due to hemozoin pigment; constricted ventricles due to cerebral edema

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MALARIA

Female Anopheline mosquito inoculates plasmodial sporozoites from its salivary

gland.

Sporozoites are carried rapidly via the bloodstream to the liver, invading hepatic

parenchymal cells.

Swollen infected liver cells eventually burst discharging motile merozoites into the

bloodstream.

In P.vivax and P.ovale infections, the intrahepatic forms do not divide immediately

but remain dormant, as hypnozoites, for 3weeks or longer causing relapses.

Merozoites invade RBC’s and multiply six- to twenty fold every 48-72 hours and become

trophozoites.

Trophozoites enlarge, species-specific chars become evident, pigment becomes visible,

parasite assumes an amoeboid shape consuming nearly all hemoglobin and grown

to occupy most of the RBC as schizont.

Some of the parasites develop into morphologically distinct, longer-lived sexual

forms (gametocytes) that can transmit malaria.

ERYTHROCYTE CHANGES IN MALARIA CAUSING TISSUE HYPOXIA

1. Sequestration- after invading the erythrocytes, the growing malarial parasite progressively consumes and degrades intracellular proteins principally hemoglobin.- the parasite also alters the RBC membrane by

changing its transport properties, exposing cryptic surfaces antigens, and inserting new parasite-derived proteins. 2. Cytoadherence- In P.falciparum infection, membrane protruberances appear on the RBC’s surface; these “knobs” extrude a high molecular weight, antigenically variant, strain specific PfEMP1 (P. falciparum erythrocyte membrane protein 1) that mediates attachment to receptors on venular and capillary endothelium.3. Rosetting- P.falciparum infected RBC’s adhere to non-infected RBC’s forming rosettes or to other parasitized RBC’s causing agglutination.4. Reduced Red Cell Deformability- severe malaria compromises passage of RBC’s through partially obstructed capillaries and venules and shortens RBC survival. - RBC diameter is reduced to 4um (Normal: 6-8um)

Hemoglobinopathies Protecting The Host From Infection by Malarial Parasites

1) Sickle Cell Trait (HbA/S Heterozygotes) have a six-fold reduction in the risk of dying from severe falciparum malaria due to impaired parasite growth at low oxygen tensions and aggregates of needle-like structures that pirces the parasite

2) Alpha Thalassemia in children3) Melanesian Ovalocytosis

-rigid erythrocytes resist merozoite invasion and intraerythrocytic milieu is hostile.

4) Duffy Blood Group System (FY a-b-) individuals with this blood group system are protected from having P.vivax infection.

CLINICAL MANIFESTATIONS

first manifestations are non-specific: the lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches, followed by fever.

1. Tertian malaria (fever every third day) for P. vivax and p. ovale

2. Quartan malaria (fever every fourth day) for P. malariae

3. Subtertian malaria, or sometimes called

malignant tertian (fever more often than every third day, and the disease is lethal) for P. falciparum

4. Malignant Tertian malaria for P. falciparum This qualification of malaria is no longer

applicable nowadays.Most characteristic pathologic feature/s:

Anemia (P. falciparum produces greatest degree of anemia) that is microcytic hypochromic type due to direct loss (impaired hematopoiesis) or destruction (by parasite) of RBCs.

Pigmentation of organs (phagocytosis of hemozoin or malarial pigment after the rupture of host cells, macrophages of spleen & bone marrow; Kupffer cells of liver, at termination of asexual cycle) that increases as infection lengthens. Evident grossly in chronic malaria

Liver enlargement due to congestion in acute malaria and increases in size during chronic malaria.

Splenomegaly is evident, first as a result of congestion following cavernous dilatation of sinusoids and then results from increase in macrophage elements in Billroth’s cords. Repeated attacks results to progressively greater enlargement. Palpation of the spleen is characteristic of malaria.

Blackwater fever, especially in P. falciparum infections; characterized by intravascular hemolysis with hemoglobinemia and hemoglobinuria.

1. Cerebral malaria 2. Severe anemia (hematocrit <15%) results from accelerated RBC removal by the

spleen, obligatory RBC destruction, and ineffective erythropoiesis

3. Renal failure (no urine output <400mL in 24 h, or 12mL/kg/24 h after rehydration, or serum creatinine > 3 mg%)

related to RBC sequestration interfering with renal microcirculatory flow and metabolism acute tubular necrosis

4. Pulmonary edema or adult respiratory distress syndrome

5. Hypoglycemia (blood sugar <40 mg%) results from a failure of heptic gluconeogenesis

and increase in consumption of glucose by the host and the parasite

6. Shock (systolic BP<70 mmHg in adults or <50 mmHg in children age 1-5 y)

7. Spontaneous bleeding and disseminated intravascular coagulation

8. Repeated convulsions 9. Acidosis (arterial pH<7.25 or plasma HCO3<15) 10. Macroscopic hemoglobinuria 11. Hyperparasitemia (>5% parasitemia in

nonimmunes) 12. Hepatic dysfunction common manifestation is jaundice13. Hyperpyrexia (T>40 OC)

Microscopy (Gold Standard) -Thick blood film for rapid detection of parasite

-Thin blood film for species identification -Giemsa stain is usedSerological tests a) PfHRP2 (P.falciparum histidine rich protein 2) dipstick or card test b) Plasmodium LDH dipstick or card test Microtube concentration methods with acridine orange testing -examined under Fluorescent Microscopes

Plasmodium falciparum: Early trophozoites-small rings about 1/5th diameter

of RBC, have 2 nuclear chromatin dots that may also lie on opposite side of ring or close together. Marginal or accole forms have rings at margins of RBC that is diagnostic and more common; multiple

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DEFINITION OF SEVERE MALARIA AND COMPLICATED FALCIPARUM MALARIA

METHODS FOR THE DIAGNOSIS OF MALARIA

ring invasion of RBC may also be evident but less common.

Late trophozoites-not found in PBS because P. f. leaves blood circulation when trophozoites are large. When present (in moribund px) they show rings of larger size. Infected erythrocytes show Maurer’s dots (coarse pink staining on RBC).

Schizont-in internal organs but rarely appears in PBS. Parasite filling erythrocytes with no increase in size. With 10-20 merozoites, dark staining malaria pigments and few Maurer’s dots.

Gametocyte-shaped like a sausage (a.k.a crescent) that is diagnostic of the sp., seen in PBS. Males/microgametocytes has larger nucleus and pale blue cytoplasm in w/c blackish-brown pigment of parasite is distributed; females/macrogametocytes has smaller, more compact nucleus and a dark blue cytoplasm with pigment collected together around nucleus.

Vivax/ ovale – with RBC predilection; infects young RBCs

Malariae – infects old/senescent RBCs Falciparum – infects all RBCs

Plasmodium vivax: Early trophozoite-stout rings, 1/3rd the diameter of

RBC. Show 1 chromatin dot. Late trophozoite-irregular and amoeboid with

pseudopodial processes. Larger with fine grains of brown pigment inside. RBC is enlarged and with characteristic red stippling or Schuffner’s dot.

ANG DAMING DOTS.. MERON PA SA SUSUNOD Schizont-same size as normal RBC. Nucleus is

divided into 18-24 merozoites that are arranged in a morula formation (like cluster of grapes). Pigement is collected in a clump in the center of morula. RBC is enlraged and pale and with Schuffner’s dot.

Gametocyte-full-blown if round and occupies most of enlarged RBC. Malaria pigment is scattered throughout the cytoplasm. Differentiation of sex is not easy and these appear in PBS in early infection.

Plasmodium malariae Early trophozoite-large stout ring 1/3rd of diameter

of RBC. Multiple infection of RBC is common. Some parasite may show coarse granular golden-yellow pigment that is characteristic of P.m.

Late trophozoite-more solid looking than corresponding stage of P. vivax. Assumes a characteristic band from across the diameter of the RBC. Band can be wide or narrow but well-defined and is diagnostic for this sp. Pigment is coarser and with golden-yellow and black pigment (Ziemann’s dots). Infected RBC is of normal size.

Schizont-nearly fills the RBC and with 6-12 merozoites that form characteristic rosette in the center where the coarse pigment is collected into dense black clump. RBC still not enlarged.

Gametocyte-round, occupying most infected RBC (not enlarged). Coarse black pigment is scattered throughout. Nucleus and cytoplasm are undivided. Male and female are not easy to differentiate. These appear in PBS early in the infection.

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Plasmodium ovale: Ealry trophozoite-about 2-2.5 um in diameter.

Resembles more closely than that of P. malariae but band is not seen. Pigment granules are coarse and dark brown in color but scanty. Infected RBC shows granules like Schuffer’s dots with violet tinge called James’ dots. Infected RBC slightly enlarged, pale, often oval with fimbriated edges.

Late trophozoites-solid-looking non-ameboid parasites. Pigment is scanty and James’ dots are seen.

Schizont-with 4-12 merozoites (ave. 8) in primary attack, nearly increasing to 12-18 in relapses. Nearly fills RBC, oval in shape. With James’ dots.

Gametocyte-indistinguishable from P. malariae. Round and fills the RBC when mature.

Differential Diagnosis: Babesiosis Hepatitis Influenza Liver abscess Meningitis – absence of neck stiffness and

photophobia in malaria Tuberculosis

Typhoid fever - muscles are not tender in malaria Urinary tract infection Yellow fever

DIFFERENTIAL DIAGNOSIS OF SEVERE FALCIPARUM MALARIA

FeverEnteric fever, brucellosis,

influenzaHyperpyrexia Heat stroke, sepsis

JaundiceViral hepatitis, leptospirosis,

relapsing fevers, yellow fever, drug-induced or toxic

hepatitis

HypoglycemiaSevere septicemia, liver failure, Reye’s syndrome

Acute hemolytic anemia

Drug-induced, due to toxic substances, autoimmune diseases, blood diseases –

e.g. inheritable red cell abnormalities, or G6PD

deficiencyGastrointestinal

symptomsPeptic ulcer, gastroenteritis,

salmonellosis, traveler’s diarrhea

Abnormal bleedingHepatitis failure, poisons, viral hemorrhagic fevers,

leptospirosisConvulsions Febrile confusions, epilepsy,

cerebrovascular accidents

EncephalopathyViral , fungal, bacterial protozoal encephalitis;

eclampsia, toxic substances

COMPLICATIONSHyperthermiaAcute Pulmonary EdemaAcute Renal FailureHepatic DysfunctionHypoglycemiaShock (Algid Malaria)Severe AnemiaMetabolic AcidosisHyperparasitemia

TREATMENT Drug of Choice according to WHO

- Quinine: induces dev’t of resistance by the parasite so it is replaced by a combination of Quinine and Tetra/Doxy/Aminocycline.

Artemesinin combined with Mefloquine: highly effective for P. falciparum Mefloquine: for prophylaxis; taken 4 weeks

before travel Vibromycin(100 mg): can be taken on short

notice

For schizonts Sulfonamides (Folic Acid synth) Chlorguanide, pyrimethamine, colchicine (Folic

Acid Metab) Quinine, Chloroquine, amodiaquine (Nucleic

Acid Metab)For gametocytes

PrimaquinFor Exo-erythrocytic cycles

Chlorguanide, pyrimethamine (Folic Acid Metab)

Primaquin

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DRUGS USED FOR MALARIAL DISEASES

P. falciparum A. Chloroquine- sensitive

B. Chloroquine-resistant but sensitive to sulfadoxine/ pyrimethamine

C. Chloroquine-resistant and resistant to sulfadoxine/ pyrimethamine

D. Multidrug-resistant

Not severeSevere

Not severe

Severe

Not severeSevere

Not severeSevere

Chloroquine (Aralen)PO1

Chloroquine IV3

Sulfadoxine/pyrimethamine PO3

quinine (Quinamm) IV6

quinine PO5

quinine IV6

quinine PO5 plus tetracyclinequinine IV6

artesunate IV10

artemether IM11

Sulfadoxine/pyrimethamine (Fansidar) PO2

Chloroquine IV4

quinine PO5

quinine IM7

Mefloquine (Lariam) PO8

quinidine (Quinalam) IV9

quinine IM7

See 5.1 belowquinine IV9

Quinine IM7

P. vivaxP. ovaleP. malariae

Mixed Infections or SpeciesUnknown

Not severeSevere

Chloroquine PO, 1 followed by PO primaquine 12

Chloroquine PO1

Treat as if P. falciparum, then threat other species as indicated13

Mefloquine PO followed by primaquine PO12

Mefloquine PO8

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