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Malaria

Didi Candradikusuma

Tropical and Infectious Diseases Department of Internal Medicine Dr. Saiful Anwar General Hospital Brawijaya University School of Medicine Malang

Introduction
Malaria is parasite disease of great epidemiologic importance in the tropics Each year: 300 500 million clinical case 40% population in tropic area are at risk 10.000 50.000 visiting people from tropical countries will contract malaria Malarial infection is caused by genus Plasmodium and Anopheles mosquitoes are definite hosts of malarial parasites Principal vector

Introduction
Clinical manifestation vary widely Usually characterized by fever, tachycardia, rigors(kekakuan), and sweating Clinically significant renal disease may complicate the infection of P. malariae and P. falciparum

Introduction
The relevance of malaria to modern nephrology has emerged over the past few decades because of: It has been one of the leading causes of ARF in SEA, Vietnam, Indian Peninsula, Africa Its responsible for a significant proportion of chronic glomerular disease Its becoming an increasingly recognized complications of renal transplantations

Malarial Infection
Malaria is an Italian word composed of mala and aria, means bad air for describe a fever which was wrongly attributed to exposure to poisonous air rising from marshes Described in the Hippocratic Collection (460 to 377 BC) Susruta (5th century AD) suggested its relation to mosquitoes Charles Laveran, discovered Plasmodium as the true causative agent (1880) Mapping the malaria genome

Malarial Infection
Malarial is caused by Protozoon, Plasmodium, of which four species are pathogenic to man : Plasmodium falciparum falciparum malaria Plasmodium malariae quartan malaria Plasmodium vivax vivax malaria Plasmodium ovale In Indonesia, the most species that infected human are P. falciparum and P. vivax P. malariae Lampung, NTT, Papua P. ovale NTT and Papua

Malaria Distribution
Area of Malaria

Life-Cycle of Malaria

Life-Cycle of Malaria

Pathogenicity

Several species affect humans different patterns of the disease because of genetic interspecies differences: - rate of multiplication - expression of different antigenic and ligand proteins - influences of host factors, etc divergence of the ability of different strains to invade human red cells of different ages

Pathogenicity

Parasitized erythrocytes initiate the three principal pathogenetic feature in Plasmodium infection:

Hemodynamic Derangement
Immune Perturbation(gangguan) Metabolic Disturbance

Plasmodium species which infect humans


Plasmodium vivax (tertian) Plasmodium ovale (tertian) Plasmodium falciparum (tertian) Plasmodium malariae (quartian)

Malaria Life Cycle Life Cycle

Sporogony
Oocyst
Sporozoites

Zygote

Mosquito Salivary Gland

Gametocytes

Exoerythrocytic (hepatic) cycle

Hypnozoites (for P. vivax and P. ovale)

Erythrocytic Cycle

Schizogony

Malaria Transmission Cycle


Sporozoires injected into human host during blood meal Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood

Parasites mature in mosquito midgut and migrate to salivary glands

MOSQUITO

HUMAN

Dormant liver stages (hypnozoites) of P. vivax and P. ovale

Parasite undergoes sexual reproduction in the mosquito

Some merozoites differentiate into male or female gametocyctes

Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts

Sporogonic cycle

Components of the Malaria Life Cycle


Infective Period
Mosquito bites uninfected person

Mosquito Vector
Parasites visible

Mosquito bites gametocytemic person

Human Host

Prepatent Period

Symptom onset Recovery

Incubation Period
Clinical Illness

Exo-erythrocytic (tissue) phase


Blood is infected with sporozoites about 30 minutes after the mosquito bite The sporozoites are eaten by macrophages or enter the liver cells where they multiply pre-erythrocytic schizogeny P. vivax and P. ovale sporozoites form parasites in the liver called hypnozoites

Exo-erythrocytic (tissue) phase


P. malariae or P. falciparum sporozoites do not form hypnozites, develop directly into pre-erythrocytic schizonts in the liver Pre-erythrocytic schizogeny takes 6-16 days post infection Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver

Relapsing malaria
P. vivax and P. ovale hypnozoites remain dormant for months They develop and undergoe preerythrocytic sporogeny The schizonts rupture, releasing merozoites and produce clinical relapse

Exo-erythrocytic (tissue) phase


P. vivax and P. ovale hypnozoites remain dormant for months They develop and undergoe preerythrocytic sporogeny The schizonts rupture, releasing merozoites and producing clinical relapse

Erythrocytic phase
Pre-patent period interval between date of infection and detection of parasites in peripheral blood Incubation period time between infection and first appearance of clinical symptoms Merozoites from liver invade peripheral (RBC) and develop causing changes in the RBC There is variability in all 3 of these features depending on species of malaria

Erythrocytic phase stages of parasite in RBC


Trophozoites are early stages with ring form the youngest Tropohozoite nucleus and cytoplasm divide forming a schizont Segmentation of schizonts nucleus and cytoplasm forms merozoites Schizogeny complete when schizont ruptures, releasing merozoites into blood stream, causing fever These are asexual forms

Erythrocytic phase stages of parasite in RBC


Merozoites invade other RBCs and schizongeny is repeated Parasite density increases until hosts immune response slows it down Merozoites may develop into gametocytes, the sexual forms of the parasite

Schizogenic periodicity and fever patterns


Schizogenic periodicity is length of asexual erythrocytic phase
48 hours in P.f., P.v., and P.o. (tertian) 72 hours in P.m. (quartian)

Initially may not see characteristic fever pattern if schizogeny not synchronous With synchrony, periods of fever or febrile paroxsyms assume a more definite 3 (tertian)- or 4 (quartian)- day pattern

Clinical presentation
Early symptoms
Headache Malaise Fatigue Nausea Muscular pains Slight diarrhea Slight fever, usually not intermittent

Could mistake for influenza or gastrointestinal infection

Clinical presentation
Acute febrile illness, may have periodic febrile paroxysms every 48 72 hours with Afebrile asymptomatic intervals Tendency to recrudesce or relapse over months to years Anemia, thrombocytopenia, jaundice, hepatosplenomegaly, respiratory distress syndrome, renal dysfunction, hypoglycemia, mental status changes, tropical splenomegaly syndrome

Clinical presentation
Early symptoms
Headache Malaise Fatigue Nausea Muscular pains Slight diarrhea Slight fever, usually not intermittent

Could mistake for influenza or gastrointestinal infection

Clinical presentation
Signs
Anemia Thrombocytopenia Jaundice Hepatosplenomegaly respiratory distress syndrome renal dysfunction Hypoglycemia Mental status changes Tropical splenomegaly syndrome

Types of Infections
Recrudescence
exacerbation of persistent undetectable parasitemia, due to survival of erythrocytic forms, no exo-erythrocytic cycle (P.f., P.m.)

Relapse
reactivation of hypnozoites forms of parasite in liver, separate from previous infection with same species (P.v. and P.o.)

Recurrence or reinfection
exo-erythrocytic forms infect erythrocytes, separate from previous infection (all species)

Can not always differentiate recrudescence from reinfection

Varies in severity and course Parasite factors


Species and strain of parasite Geographic origin of parasite Size of inoculum of parasite

Clinical presentation

Host factors
Age Immune status General health condition and nutritional status Chemoprophylaxis or chemotherapy use

Mode of transmission
Mosquito Bloodborne, no hepatic phase (transplacental, needlestick, transfusion, organ donation/transplant)

Malarial Paroxysm
Can get prodrome 2-3 days before
Malaise, fever,fatigue, muscle pains, nausea, anorexia Can mistake for influenza or gastrointestinal infection Slight fever may worsen just prior to paroxysm

Paroxysm
Cold stage - rigors Hot stage Max temp can reach 40-41o C, splenomegaly easily palpable Sweating stage Lasts 8-12 hours, start between midnight and midday

Malarial Paroxysm
Periodicity
Days 1 and 3 for P.v., P.o., (and P.f.) tertian Usually persistent fever or daily paroxyms for P.f. Days 1 and 4 for P.m. - quartian

Presentation of P.v.
Lack classical paroxysm followed by asymptomatic period Headache,dizziness, muscle pain, malaise, anorexia, nausea, vague abdominal pain, vomiting Fever constant or remittent Postural hypotension, jaundice, tender hepatosplenomegaly

Common features of P.vivax infections


Incubation period in non-immunes 12-17 days but can be 8-9 months or longer Some strains from temperate zones show longer incubation periods, 250-637 days First presentation of imported cases 1 month over 1 year post return from endemic area Typical prodromal and acute symptoms
Can be severe However, acute mortality is very low

Common features of P.vivax infections


Most people of West African descent are resistant to P.v.
Lack Duffy blood group antigens needed for RBC invasion

Mild severe anemia, thrombocytopenia, mild jaundice, tender hepatosplenomegaly Splenic rupture carries high mortality
More common with P.v. than with P.f.

Common features of P.vivax infections


Relapses
60% untreated or inadequately treated will relapse Time from primary infection to relapse varies by strain Treat blood stages as well as give terminal prophylaxis for hypnozoites

Common features of P. ovale infections


Clinical picture similar to P.v. but Spontaneous recovery more common Fewer relapses Anemia and splenic enlargement less severe Lower risk of splenic rupture Parasite often latent and easily suppressed by more virulent species of Plasmodia Mixed infection with P.o. usually in those exposed in tropical Africa

Common features of P. malariae infections


Clinical picture similar to P.v. but prodrome may be more severe Incubation period long 18- 40 days Anemia less pronounced than P.v. Gross splenomegaly but risk of rupture less common than in P.v. No relapse no hepatic phase or persisting hepatic cycle

Common features of P. malariae infections


Undetectable parasitemia may persist with symptomatic recrudescences
Frequent during first year Then longer intervals up to 52 years

Asymptomatic carriers may be detected at time of blood donation or in cases of congenital transmission Parasitemia rarely > 1%, all asexual stages can be present Can cause nephrotic syndrome, prognosis is poor

Features of P.falciparum cases


Lack classical paroxysm followed by asymptomatic period Headache,dizziness, muscle pain, malaise, anorexia, nausea, vague abdominal pain, vomiting Fever constant or remittent Postural hypotension, jaundice, tender hepatosplenomegaly Can progress to severe malaria rapidly in non-immune patients Cerebral malaria can occur with P.f. Parasites can sequester in tissues, not detected on peripheral smear

Some characteristics of infection with four species of human Plasmodia


P.v. Preerythroctic stage (days) 6-8 P.o. 9 P.m. 14-16 P.f. 5.5-7

Pre-patent period (days) Incubation period (days)


Erythrocytic cycle (hours)

11-13

10-14

15-16

9-10

15 (12-17) 17 (16-18) 28 (18-40) 12 (9-14) or up to 6- or longer or longer 12 months 48 (about) 50 72 48

Some characteristics of infection with four species of human Plasmodia


P.v. Paraitemia per l Average Maximum Primary attack* Febrile paroxysms (hours) P.o. P.m. P.f.

20,000 50,000 Mildsevere 8-12

9,000 30,000 Mild

6,000 20,000 Mild

20,00050,000 2,000,000 Severe in nonimmunes 16-36 or longer

8-12

8-10

Some characteristics of infection with four species of human Plasmodia


P.v. P.o. P.m. P.f.

Invasion requirements
Relapses Recrudescences

Duffy ve blood group ++


+

++ +

Some characteristics of infection with four species of human Plasmodia


P.v. Period of Variable recurrence ** Duration of 1.5-5 untreated infection (years) P.o. Variable Probably same as P.v. P.m. Very long 3-50 P.f. short 1-2

*The severity of infection and the degree of parasitemia are greatly influenced by the immune response. Chemop May suppress an initial attack for weeks or months. ** Patterns of infection and of relapses vary greatly in different strains. Bruce-Chwatt Essential Malariology, 3rd rev ed. 1993

Congenital malaria
Transplacental infection
Can be all 4 species Commonly P.v. and P.f. in endemic areas P.m. infections in nonendemic areas due to long persistence of species

Neonate can be diagnosed with parasitemia within 7 days of birth or longer if no other risk factors for malaria (mosquito exposure, blood transfusion) Fever, irritability, feeding problems, anemia, hepatosplenomegaly, and jaundice Be mindful of this problem even if mother has not been in malarious area for years before delivery

Immunity
Influenced by
Genetics Age Health condition Pregnancy status Intensity of transmission in region Length of exposure Maintenance of exposure

Immunity
Innate
Red cell polymorphisms associated with some protection
Hemoglobin S sickle cell trait or disease Hemoglobin C and hemoglobin E Thalessemia and Glucose 6 phosphate dehydrogenase deficiency (G6PD)

Red cell membrane changes


Absence of certain Duffy coat antigens improves resistance to P.v.

Immunity
Acquired
Transferred from mother to child
3-6 months protection Then children have increased susceptibility

Increased susceptibility during early childhood


Hyper- and holoendemic areas
By age 5 attacks usually < frequent and severe Can have > parasite densities with fewer symptoms

Meso- or hypoendemic areas


Less transmission and repeated attacks May acquire partial immunity and be at higher risk for symptomatic disease as adults

Immunity
Acquired
No complete immunity
Can be parasitemic without clinical disease

Need long period of exposure for induction May need continued exposure for maintenance Immunity can be unstable
Can wane as one spends time outside endemic area Can change with movement to area with different endemicity Decreases during pregnancy, risk improves with increasing gravidity

Clinical Features

Clinical Features

Based on severity of the complications, malaria - Uncomplicated Malaria - Severe Malaria Anemia and neutrophil leucocytosis prominent laboratory finding Dx is confirmed by direct visualization of the parasite in Giemsa-stain peripheral blood smear Acridine-orange staining enhanced the Dx accuracy

Clinical Features

DNA probe not yet widely applicable Serology limited Dx value, especially in endemic areas Disease may become chronic if sporozoon manages to establish a persistent extraerythrocytic reservoir cycle in the liver

Management
Treatment Modalities

Antimalarial agents Supportive and symptomatic treatment Treatment for complications

Management
Antimalarial

Chloroquine is the gold standard treatment of malaria Initially doses 10mg base/kgBW per os, followed by 5mg/kgBW after 6 8 h and on the following days 2 and 3 For i.v: 10mg/kgBW as an infusion drip over 4 h, followed by 5mg/kgBW over 2 h at 12-h interval for a total dose of 25 mg/kgBW But, many P. falciparum strains are chloroquineresistant

Management
Uncomplicated malaria First Line

Day
1

Antimalarial
Artesunat Amodiaquine Primaquine Artesunat Amodiaquine Artesunat Amodiaquine

Dose
200 mg 800 mg 30 45 mg 200 mg 800 mg 200 mg 800 mg

(Depkes RI, 2005)

Management
Uncomplicated malaria Second Line

Day
1

Antimalarial
Quinine Tetracycline/Doxycyclin Primaquine Quinine Tetracycline/Doxycyclin

Dose
3 x 2 tab 4 x 1 cap 30 45 mg 3 x 2 tab 4 x 1 cap

2-7

(Depkes RI, 2005)

Management
Severe malaria
First Line

Artesunat Initial dose 2.4 mg/kgBW i.v. for 2 minutes followed 1.2 mg/kgBW i.v. / 12 h and 1.2 mg/kgBW i.v. / d, d2 d7 Arthemeter Initial dose 160 mg i.m. d1 followed 80 mg i.m. d2 d5

(Depkes RI, 2005)

Management
Severe malaria
Second Line

Quinine is the most widely used in the tx of chloroquineresistant falciparum malaria In severe malaria, should be administered as a loading dose by rate-controlled infusion instead by bolus i.v The normal loading dose: 20mg/kg over 4 h or initial dose 7mg/kg over 30 minutes (inf. Pump) followed immediately by 10mg/kg over 4 h The maintenance dose: 10mg/kg for 7 d should be infused at a rate-not > 6mg/kg/h every 8 / 12 h Reduction dose is not necessary when serum creatinin are 3 mg/dL or lower
(Depkes RI, 2005)

Management In more severe renal failure, the quinine dose should be reduced by 1/3 on the 3rd d In areas of multidrug resistance, addiction of 7-day Doxycycline 3mg/kg/d or Tetracyclin 4mg/kg 4 x/d to Quinine decrease of recrudescence Another chemotherapeutic: Mefloquine, Benflumetol, and Proguanil Primaquine for P. vivax and P. ovale to eradicate hypnozoites and subsequent relapses

Management
Supportive and Symptomatic Treatment

A-B-C Anti Pyretics Anti Convulsants Nutrition etc

Management
Treatment for Complications

For ARF detection, serum creatinin should be measured daily in severe malaria patients Clinically Oliguric manifestation (urine output < 400 mL/d) would receive a fluid challenge of up to 20 mL/kg of 0.9% saline infused over 60 mnts Examination for fluid overload after every 200 mL of fluid replacement If fluid replacement is not successful Furosemide should be i.v. administered

Management
Treatment for Complications.. Dose of Furosemide: initially 40 mg increasing to 100, 200, and 400mg at half-hour intervals Several studies could not elicit clearly that dopamine, administered i.v. at the low dose 2.5 to 5 g/kg/min, improves renal function or outcome in ARF patients Combination of dopamine and furosemide attenuate further deterioration of renal function and shorten the clinical course of ARF when serum creatinine < 5 mg/dL Anuric condition or s.c. > 5 mg/dL ineffective

Management
Treatment for Complications.. If Fluid replacement with or without the above procedure is ineffective further fluid should be restricted and kept CVP between 8 12 cm H2O Monitored for need of dialysis Dialysis has improved the survival when instituted early in the course Indications for dialysis include: Clinical indications uraemic symptoms, symptomatic volume overload, pericardial rub Laboratory indications severe metabolic acidosis (HCO3 < 15 mEq/l), hyperkalemia (> 6.5 mEq/l), rapid increase s.c. greater than 2.5 3.0 mg/dL/d

Management
Treatment for Complications.. Peritoneal Dialysis less effective than hemodialysis because hypercatabolic states, impaired peritoneal microcirculation, vasoconstriction reduce the capability of solute transport Efficacy P.D return to normal when parasitemia declines If hemodialysis is selected, the procedure should be performed frequently and initiated early in the course of illness Haemofiltrations also effective There were no significant changes in plasma antimalarial during hemodialysis

Management
Treatment for Complications.. Exchange Blood Transfusion helpful in patients with heavy parasitemia and those with severe jaundice Apheresis successfully support anuric patients with cerebral and pulmonary complications Prostacyclin useful in patients with severe intravascular hemolysis Patients with ARDS empiric antibiotic coverage There is no place for corticosteroid

Prognosis
Overall mortality among this with ARF 45 %, without ARF 10 % Anuric patients and delayed rate of renal function recovery worse mortality 50 75 % without dialysis rapid die Dialysis patients mortality rate 25 %

Nephropathy in Quartan Malaria

P. malariae infection is common in tropical Africa, parts of Indian subcontinent, Myanmar, Sri lanka, Malaysia, Indonesia P. malariae tends to invade older erythrocytes infection rate < 1 % There are 2-distinct forms of P. malariae associated glomerulonephritis: - Acute Transient Nephritis - Chronic Malarial Nephropathy

Acute Transient Nephritis

During 2nd or 3rd week after infection Resolves completely over a duration of a few weeks Mild proteinuria, but may occasionally be severe, maybe precipitated by muscular exertion this disorder does not impair renal function Pathologic studies: predominant depositions of IgM, complement, and malarial antigen

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