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Malaria
Didi Candradikusuma
Tropical and Infectious DiseasesDepartment of Internal Medicine Dr. Saiful Anwar General Hospital
Brawijaya University School of Medicine
Malang
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IntroductionMalaria 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
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IntroductionThe relevance of malaria to modern nephrology
has emerged over the past few decades
because of:
It has been one of the leading causes of ARFin SEA, Vietnam, Indian Peninsula, Africa
Its responsible for a significant proportion of
chronic glomerular disease
Its becoming an increasingly recognizedcomplications of renal transplantations
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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
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Malarial is caused by Protozoon, Plasmodium, of whichfour 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, PapuaP. ovale NTT and Papua
Malarial Infection
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Malaria Distribution
Area of Malaria
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Life-Cycle of Malaria
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Life-Cycle of Malaria
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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
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Pathogenicity
Parasitized erythrocytes initiate the three
principal pathogenetic feature in
Plasmodium infection:
Hemodynamic Derangement
Immune Perturbation(gangguan)
Metabolic Disturbance
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Plasmodium species which
infect humans
Plasmodium vivax (tertian)
Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartian)
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Exo-erythrocytic(hepatic) cycle
Sporozoites
Mosquito SalivaryGland
Malaria LifeCycleLife Cycle
Gametocytes
Oocyst
ErythrocyticCycle
Zygote
Schizogony
Sporogony
Hypnozoites(for P. vivaxand P. ovale)
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Malaria Transmission Cycle
Parasite undergoes
sexual reproduction in
the mosquito
Some merozoites
differentiate into male or
female gametocyctes
Erythrocy t ic Cycle:
Merozoites infect red
blood cel ls to form
sch izonts
Dormant l iver s tages
(hypn ozoites) of P.
viv ax and P. ovale
Exo-erythroc yt ic (hepat ic) Cycle:
Sporozoites infect l iver cel ls and
develop into sch izonts, whic h release
merozoites into the blood
MOSQUITO HUMAN
Sporozoires in jected
in to human host dur ing
b lood m eal
Parasites
mature in
mosquito
midgut and
migrate to
salivary
glands
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Components of the Malaria Life
Cycle
Mosquito Vector
Human Host
Sporogonic cycle
Infective Period
Mosquito bites
gametocytemic
person
Mosquito bites
uninfectedperson
Prepatent Period
Incubation Period
Clinical Illness
Parasites visible
Recovery
Symptom onset
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Exo-erythrocytic (tissue)
phase
Blood is infected with sporozoites about30 minutes after the mosquito bite
The sporozoites are eaten by
macrophages or enter the liver cellswhere they multiply
pre-erythrocytic schizogeny
P. vivax and P. ovale sporozoites formparasites in the liver called hypnozoites
E h i ( i )
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Exo-erythrocytic (tissue)
phase
P. malariae orP. falciparum sporozoitesdo not form hypnozites, develop directly
into pre-erythrocytic schizonts in the
liver Pre-erythrocytic schizogeny takes 6-16
days post infection
Schizonts rupture, releasing merozoiteswhich invade red blood cells (RBC) in
liver
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Relapsing malaria
P. vivax and P. ovale hypnozoitesremain dormant for months
They develop and undergoe pre-
erythrocytic sporogeny
The schizonts rupture, releasing
merozoites and produce clinical relapse
E th ti (ti )
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Exo-erythrocytic (tissue)
phase
P. vivax and P. ovale hypnozoitesremain dormant for months
They develop and undergoe pre-
erythrocytic sporogeny
The schizonts rupture, releasing
merozoites and producing clinical
relapse
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Erythrocytic phase
Pre-patent period interval between date ofinfection and detection of parasites inperipheral 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 featuresdepending on species of malaria
E th ti h
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Erythrocytic phase
stages of parasite in RBC
Trophozoites are early stages with ring formthe 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 bloodstream, causing fever
These are asexual forms
E th ti h
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Erythrocytic phase
stages of parasite in RBC
Merozoites invade other RBCs and
schizongeny is repeated
Parasite density increases until hostsimmune response slows it down
Merozoites may develop into
gametocytes, the sexual forms of theparasite
S hi i i di i d
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Schizogenic periodicity and
fever patterns
Schizogenic periodicity is length of asexualerythrocytic 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
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Clinical presentation
Early symptoms Headache
Malaise
Fatigue Nausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent Could mistake for influenza or gastrointestinal
infection
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Clinical presentation
Acute febrile illness, may have periodic febrileparoxysms every 48 72 hours with
Afebrile asymptomatic intervals
Tendency to recrudesce or relapse overmonths to years
Anemia, thrombocytopenia, jaundice,hepatosplenomegaly, respiratory distress
syndrome, renal dysfunction, hypoglycemia,mental status changes, tropical splenomegalysyndrome
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Clinical presentation
Early symptoms Headache
Malaise
Fatigue Nausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent Could mistake for influenza or gastrointestinal
infection
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Clinical presentation
Signs Anemia
Thrombocytopenia
Jaundice Hepatosplenomegaly
respiratory distress syndrome
renal dysfunction
Hypoglycemia Mental status changes
Tropical splenomegaly syndrome
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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 inliver, separate from previous infection with samespecies (P.v. and P.o.)
Recurrence or reinfection
exo-erythrocytic forms infect erythrocytes,separate from previous infection (all species)
Can not always differentiate recrudescencefrom reinfection
C
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Clinical presentation Varies in severity and course
Parasite factors
Species and strain of parasite
Geographic origin of parasite
Size of inoculum of parasite
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)
M l i l P
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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 andmidday
M l i l P
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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
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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
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Common features ofP.vivax
infections Incubation period in non-immunes 12-17 days
but can be 8-9 months or longer
Some strains from temperate zones showlonger incubation periods, 250-637 days
First presentation of imported cases 1 monthover 1 year post return from endemic area
Typical prodromal and acute symptoms
Can be severe However, acute mortality is very low
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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.
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Common features of
P.vivaxinfections Relapses
60% untreated or inadequately treated will
relapse
Time from primary infection to relapse variesby strain
Treat blood stages as well as give terminal
prophylaxis for hypnozoites
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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 bymore virulent species ofPlasmodia
Mixed infection with P.o. usually in thoseexposed in tropical Africa
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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 orpersisting hepatic cycle
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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 timeof blood donation or in cases of congenitaltransmission
Parasitemia rarely > 1%, all asexual stages canbe present
Can cause nephrotic syndrome, prognosis ispoor
Features of P falciparum
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Features ofP.falciparum
cases
Lack classical paroxysm followed by asymptomaticperiod
Headache,dizziness, muscle pain, malaise, anorexia,nausea, vague abdominal pain, vomiting
Fever constant or remittent
Postural hypotension, jaundice, tenderhepatosplenomegaly
Can progress to severe malaria rapidly in non-immunepatients
Cerebral malaria can occur with P.f.
Parasites can sequester in tissues, not detected on
peripheral smear
S h t i ti f i f ti ith
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Some characteristics of infection with
four species of human Plasmodia
P.v. P.o. P.m. P.f.
Pre-
erythroctic
stage (days)
6-8 9 14-16 5.5-7
Pre-patent
period (days)
11-13 10-14 15-16 9-10
Incubation
period (days)
15 (12-17)
or up to 6-12 months
17 (16-18)
or longer
28 (18-40)
or longer
12 (9-14)
Erythrocytic
cycle (hours)
48 (about) 50 72 48
S h t i ti f i f ti ith
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Some characteristics of infection with
four species of human Plasmodia
P.v. P.o. P.m. P.f.
Paraitemia
perl
Average
Maximum
20,000
50,000
9,000
30,000
6,000
20,000
20,000-50,000
2,000,000
Primary
attack*
Mild-
severe
Mild Mild Severe in
non-
immunes
Febrile
paroxysms
(hours)
8-12 8-12 8-10 16-36 or
longer
S h t i ti f i f ti ith
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Some characteristics of infection with
four species of human Plasmodia
P.v. P.o. P.m. P.f.
Invasion
requirements
Duffy ve
blood
group
? ? ?
Relapses ++ ++ - -
Recrude-
scences
+ + - -
S h t i ti f i f ti ith
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Some characteristics of infection with
four species of human Plasmodia
P.v. P.o. P.m. P.f.
Period of
recurrence **
Variable Variable Very long short
Duration ofuntreated
infection
(years)
1.5-5 Probablysame as
P.v.
3-50 1-2
*The severity of infection and the degree of parasitemia are greatly influenced by the immune response. Chemo
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
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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 longpersistence of species
Neonate can be diagnosed with parasitemiawithin 7 days of birth or longer if no other riskfactors for malaria (mosquito exposure, bloodtransfusion)
Fever, irritability, feeding problems, anemia,hepatosplenomegaly, and jaundice
Be mindful of this problem even if mother hasnot been in malarious area for years before
delivery
Immunity
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Immunity
Influenced by
GeneticsAge
Health condition
Pregnancy status
Intensity of transmission in region
Length of exposure
Maintenance of exposure
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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 improvesresistance to P.v.
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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 forsymptomatic disease as adults
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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 endemicarea
Can change with movement to area with differentendemicity
Decreases during pregnancy, risk improves withincreasing gravidity
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Clinical Features
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Clinical Features
Based on severity of the complications,
malaria
- Uncomplicated Malaria
- Severe Malaria
Anemia and neutrophil leucocytosisprominent laboratory finding
Dx is confirmed by direct visualization of the
parasite in Giemsa-stain peripheral blood
smearAcridine-orange staining enhanced the Dx
accuracy
Cli i l F
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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 extra-
erythrocytic reservoir cycle in the liver
M
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Management
Antimalarial agents
Supportive and symptomatictreatment
Treatment for complications
Treatment Modalities
M
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Management
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 thefollowing 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 chloroquine-
resistant
Antimalarial
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Management
Day Antimalarial Dose
1Artesunat
Amodiaquine
Primaquine
200 mg800 mg
30 45 mg
2
Artesunat
Amodiaquine
200 mg
800 mg
3
Artesunat
Amodiaquine
200 mg
800 mg
Uncomplicated malaria
First Line
(Depkes RI, 2005)
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Management
Day Antimalarial Dose
1Quinine
Tetracycline/Doxycyclin
Primaquine
3 x 2 tab4 x 1 cap
30 45 mg
2 - 7
Quinine
Tetracycline/Doxycyclin
3 x 2 tab
4 x 1 cap
Uncomplicated malaria
Second Line
(Depkes RI, 2005)
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Management
Artesunat
Initial dose 2.4 mg/kgBW i.v. for 2 minutes
followed 1.2 mg/kgBW i.v. / 12 hand 1.2 mg/kgBW i.v. / d, d2 d7
Arthemeter
Initial dose 160 mg i.m. d1
followed 80 mg i.m. d2 d5
Severe malariaFirst Line
(Depkes RI, 2005)
Management
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Management
Quinine is the most widely used in the tx of chloroquine-resistant falciparum malaria
In severe malaria, should be administered as a loadingdose by rate-controlled infusion instead by bolus i.v
The normal loading dose: 20mg/kg over 4 hor 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 hReduction dose is not necessary when serum creatininare 3 mg/dL or lower
Severe malariaSecond Line
(Depkes RI, 2005)
Management
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Management
In more severe renal failure, the quinine
dose should be reduced by 1/3 on the 3rddIn areas of multidrug resistance, addictionof 7-day Doxycycline 3mg/kg/d orTetracyclin 4mg/kg 4 x/d to Quinine
decrease of recrudescenceAnother chemotherapeutic: Mefloquine,Benflumetol, and Proguanil
Primaquine for P. vivax and P. ovale toeradicate hypnozoites and subsequentrelapses
Management
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Management
A-B-C
Anti Pyretics
Anti ConvulsantsNutrition
etc
Supportive and Symptomatic Treatment
Management
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Management
For ARF detection, serum creatinin should be
measured daily in severe malaria patients
ClinicallyOliguric manifestation (urine output
< 400 mL/d) would receive a fluid challengeof up to 20 mL/kg of 0.9% saline infused over 60
mnts
Examination for fluid overload after every 200
mL of fluid replacementIf fluid replacement is not successful
Furosemide should be i.v. administered
Treatment for Complications
Management
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Management
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 5g/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
Treatment for Complications..
Management
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Management
If Fluid replacement with or without the aboveprocedure 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 institutedearly in the course
Indications for dialysis include:
Clinical indications uraemic symptoms,
symptomatic volume overload, pericardial rubLaboratory 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
Treatment for Complications..
Management
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Management
Peritoneal Dialysis less effective than hemodialysisbecause hypercatabolic states, impaired peritonealmicrocirculation, vasoconstriction reduce thecapability of solute transport
Efficacy P.D return to normal when parasitemiadeclines
If hemodialysis is selected, the procedure should beperformed frequently and initiated early in the courseof illness
Haemofiltrations also effectiveThere were no significant changes in plasmaantimalarial during hemodialysis
Treatment for Complications..
Management
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Management
Exchange Blood Transfusion helpful in patientswith heavy parasitemia and those with severe
jaundice
Apheresis successfully support anuric patients
with cerebral and pulmonary complicationsProstacyclin useful in patients with severe
intravascular hemolysis
Patients with ARDS empiric antibiotic coverage
There is no place for corticosteroid
Treatment for Complications..
Prognosis
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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 dieDialysis patients mortality rate 25 %
Nephropathy in Quartan Malaria
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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
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Acute Transient Nephritis
During 2nd or 3rd week after infectionResolves completely over a duration of a few
weeks
Mild proteinuria, but may occasionally be
severe, maybe precipitated by muscularexertion this disorder does not impair renal
function
Pathologic studies: predominant depositions of
IgM, complement, and malarial antigen
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