A disease transmitted by the bite of an infected Anopheles mosquito

Anopheles fravirostris - primary incriminated vector in the Philippines

Most important of the parasitic diseases of humans

Caused by four species:

Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae

Malaria-free provinces:
Cebu, Bohol, Catanduanes, Aklan, Iloilo, Capiz, Guimaras, Siquijor, Biliran, Leyte Norte and Sur, Northern Samar and Camiguin.

Category A endemic provinces in the Philippines:

Kalinga, Apayao, Mountain Province, Ifugao, Isabela, Cagayan, Quirino, Zambales, Mindoro Occidental, Palawan, Quezon, Misamis oriental, Davao del norte, Davao del sur, Davao oriental, Bukidnon, Compostela valley, Saranggani, Zamboanga del sur, Agusan del sur, Agusan del norte, Surigao del sur, Tawi-tawi, Sulu, Bulusan

P. falciparum Africa, New Guinea and Haiti P. vivax Central America P. malariae found in most endemic areas especially Sub Saharan Africa
Stable transmission constant, year-round infection Unstable transmission low, erratic or focal transmission.

Principal determinants of the epidemiology of malaria: 1. number (density) 2. human-biting habits 3. longevity of the anopheline mosquito vectors

Characteristics Intrahepatic phase duration (days) No. of merozoites released/infected hepatocyte Erythrocytic cycle duration (hours) Red cell preference

P. falcipuarum 5.5 30,000

P. vivax 8 10,000

P. ovale 9 15,000

P. malariae 15 15,000

48 Younger cells (but can invade cells of all ages) Usually only ring forms

48 Reticulocytes and cells up to 2 weeks Irregularly shaped ring forms and trophozoites, schuffners dots Yellow brown yes

50 reticulocytes

72 Older cells

Morphology

Infected RBCs, schuffners dots

Band of rectangular forms of trophozoites

Pigment color Ability to cause relapse

black no

Dark brown yes

Brown- black no

Hemoglobin is consumed and degraded.

RBC membrane is altered becoming more irregular, more antigenic and less deformable. Infected RBCs stick inside from cytoadherence.
Falciparum malaria: cytoadherence, rosetting and agglutination; sequestration occurs

All stages of the parasites development in P. vivax, P. ovale and P. malariae are seen on peripheral smear.

Activates nonspecific defense mechanisms.

AUGMENTED SPLENIC IMMUNOLOGIC AND FILTRATIVE CLEARANCE FUNCTIONS WITH ACCELERATED REMOVAL OF BOTH PARASITIZED & UNIFECTED RBCS MACROPHAGES ARE ACTIVATED WHEN PARASITIZED CELLS ESCAPING SPLENIC REMOVAL ARE DESTROYED.

Sickle cell disease, ovalocytosis, thalassemia and glucose-6-phosphate dehydrogenase deficiency confers protection against death from falciparum malaria.
Due to impaired parasite growth and low oxygen tension

Specific immune responses

PREMUNITION occurs (Exposure to sufficient strains confers protection from high-level parasitemia and disease but not from infection.) Seen among adults and older children living in regions with stable and intense transmission

Immunity is specific for both the species and the strain of infecting malarial parasite
Involves both humoral and cellular immunity Passive transfer of maternal antibody contributes to the relative protection of infants from severe malaria in the first months of life.

Absence of major histocompatibility antigens on the surface of infected RBCs Malaria antigen-specific immune unresponsiveness Enormous strain diversity of malarial parasites
Parasites express variant immunodominant antigens on the erythrocyte surface

Nonspecific initial symptoms

Prominence of headache, fatigue, abdominal discomfort, and muscle aches

Nausea, vomiting, orthostatic hypotension

Classic malarial paroxysms: fever spikes, chills, rigors at regular intervals :

Benign/Ovale tertian malaria P. vivax or ovale Malignant tertian malaria P. falciparum (may not actually be regular) Quartan malaria P. malaria

Tertian every 2 days

Quartan every 3 days

Generalized seizures
Splenomegaly Hepatomegaly Anemia Petechial hemorrhages in the skin or mucous membrane

CEREBRAL MALARIA
Coma ominous feature of falciparum malaria ~20% adult death rates 15% children death rates May be gradual or sudden postictus Diffuse symmetric encephalopathy Pout reflex is common Absent abdominal and cremasteric reflexes

retinal hemorrhages

Retinal opacifications
Papilledema

Cotton wool spots

Decolorization of a retinal vessel

Generalized, repeated convulsions more in children

Neurologic sequelae more in children than adults

HYPOGLYCEMIA
Poor prognosis
Results from:
failure of hepatic gluconeogenesis Increase glucose consumption

Quinine and quinidine are powerful stimulants of pancreatic insulin secretion

Hyperinsulinemic hypoglycemia

ACIDOSIS
Due to accumulation of organic acids Acidotic breathing/respiratory distress poor prognostic sign Plasma concentration of bicarbonate or lactate best biochemical prognosticators Lactic acidosis is due to:
anaerobic glycolysis Hypovolemia Lactate production by parasites Failure of hepatic and renal clearance

NONCARDIOGENIC PULMONARY EDEMA

can develop even after antimalarial therapy Can be aggravated by IV fluid administration RENAL IMPAIRMENT
Common with severe falciparum malaria May be related to erythrocyte sequestration Acute tubular necrosis

In areas with unstable transmission, pregnant women are prone to severe infections.
Fetal death is usual in severe malaria. Low birth weight, fetal distress, premature labor, stillbirth

In areas with stable transmission = asymptomatic

P. vivax malaria low birth weight; this effect greater in multigravid than primigravid women

Malaria can be transmitted by blood transfusion, needle-stick injury, sharing of needles by infected injection drug users, or organ transplantation.
Short incubation period because of the absent preerythrocytic stage P. falciparum malaria tends to be severe in drug addicts

TROPICAL SPLENOMEGALY
Hyperreactive malarial splenomegaly Massive splenomegaly Hepatomegaly Marked elevations in serum titers of IgM and malarial antibody Perisplenitis Hepatic sinusoidal lymphocytosis Peripheral B lymphocytosis Can lead to uninhibited B cell production of IgM & formation of cryoglobulins

QUARTAN MALARIAL NEPHROPATHY

Focal or segmental glumerulonephritis with splitting of the capillary basement membrane
Coarse granular pattern with selective proteinuria better prognosis Responds poorly to either antimalarial agents or glucocorticoids

BURKITTS LYMPHOMA AND EPSTEIN BARR VIRUS INFECTION

Due to malaria-related immunosuppression leading to infection with lymphoma viruses

Is a febrile condition with malaria parasites detected in PBF and absence of severe disease and signs of multidrugresistant P. falciparum May be accompanied by severe headache and chills followed by drenching sweat
Fever may be the only presenting sign in young children and infants Neonate signs of neonatal sepsis DDx: dengue

The ability of a parasite strain to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended, but within tolerance of the subject Recrudescence of asexual parasitemia from the 48th hour thereafter No parasite clearance or reduction

Pregnant patients, children below 5 y.o., nonimmune individuals with asexual P. falciparum parasitemia and
1. Hyperparasitemia (>5% parasitized RBC, > 105 asexual parasites per cumm. Peripheral blood smear) 2. Severe anemia 3. Poor urine output 4. Signs of pulmonary edema 5. Seizures

6. Impaired consciousness 7. prostration/weakness 8. metabolic abnormalities (acidosis, hypoglycemia) 9. signs of DIC 10. macroscopic hemoglobinuria 11. jaundice 12. hyperpryrexia Temperature of >40oC

Peripheral blood smears

Both thick and thin smears SHOULD be examined Every 8H for the first 48 hours; every 8 H while on Quinine; daily until films are negative for asexual forms; and then on D7, 14, 21, and 28 Thick film has advantage of concentrating the parasites increasing diagnostic sensitivity Thin film rapid Two conditions for a smear-negative cerebral malaria: 1. Immediately following antimalarial therapy when coma persists beyond parasite clearance 2. Highly synchronous, untreated severe infection where nearly all parasites are sequestered

In severe malaria, poor prognosis is indicated by:

Predominance of more mature P. falciparum parasites (i.e. >20% of parasites with visible pigment) Presence of circulating schizonts in the PBF Presence of phagocytosed malarial pigment in >5% of neutrophils

PfHRP2 dipstick or card test

Rapid, simple, sensitive and specific, antibody-based

Plasmodium LDH dipstick or card test Microtube concentration methods with acridine orange staining Platelet count is usually reduced: ~105/uL Serology (i.e. IFA) is reserved for screening blood donors, epidemiological studies and evaluation of interventions and research

Malaria cannot be diagnosed clinically with accuracy. Treatment should be started on clinical grounds if laboratory confirmation will be delayed.

Repeat blood smears at least 12-24 H x 2 days if first smears are negative If there is any doubt about the resistance status of the infecting organism, it should be considered resistant.
Choice of drugs depends on the likely sensitivity of the infecting parasites.

Artesunate drug of choice Or artemether Or quinine Or quinidine

Artemether and artemoil do not confer survival benefit as artesunate. Quinine is safer than quinidine
Both though can cause hypotension

Uncomplicated Malaria
Chloroquine 10 mg/kg stat ff by 5 mg/kg at 12, 24 and 36 h or by 10 mg/kg at 24h and 5 mg/kg at 48 h.

Or Amodiaquine 10-12 mg/kg qd x 3D

Primaquine 0.25 mg/kg qd x 14d to prevent relapse
Radical treatment for P. vivax or P. ovale infection

Artesunate 4 mg/kg qd x 3days + sulfadoxine (25 mg/kg)/pyrimethamine 1.25 mg/kg) as single dose Or Artesunate 4 mg/kg qd + Amodiaquine 10 mg/kg x 3 days Sensitive to P. falciparum infection

First line
Either artemether-lumefrantrinr or artesunate

Second line
Either artesunate or qunine plus any of the ff: 1. Tetracylinr 4 mg/kg qid x 7d 2. Doxycycline 3 mg/kg x 7d 3. Clindamycin 10 mg/kg bid x 7d or Atovaquoneproguanil 10 mg/kg bid x 7d

Quinine or quinidine first line

Age group Children 8 y.o. and below Children above 8 y.o. to 16 y.o. Adults Loading Dose 10 mg salt/kg in 0.9 NaCl or D5W drip x 4H 15 mg salt/kg in 0.9 NaCl or D5W drip x 4H Maintenance Dose 10 mg salt/kg in 0.9 NaCl or D5W drip x 4H every 12 H 10 mg salt/kg in 0.9 NaCl or D5W drip x 4H every 8H

20 mg salt/kg in 0.9 NaCl or D5W drip 10 mg salt/kg in 0.9 NaCl or x 4H D5W drip x 4H (total dose must not exceed 2.000mg) every 8 H 20 mg salt/kg in 0.9 NaCl or D5W drip 10 mg salt/kg in 0.9 NaCl or x 4H D5W drip x 4H (total dose must not exceed 2.000mg) every 8 H

Pregnant women

Recommended for persons who are at high risk for severe and complicated malaria (nonimmune travellers to endemic areas, primigravids during entire pregnancy and who resides in endemic areas)
Chloroquine generally safe and has little teratogenic effect
First trimester 2 tablets weekly 2 weeks before travel, during stay and until four weeks after leaving the areas Second and third trimester Pyrimethamine-sulfadoxine 3 tablets single dose for every 3 months of stay

Nonpregnants, nonlactating adults: Chloroquine 150 mg, 2 tablets weekly Children: Chloroquine 150 mg, at 5 mg/kg weekly