Malaria

JOY M. NICOLAS MD
PIDS – FELLOW IN TRAINING

 Time of Emperor Shih Huang Ti (2697–2590 BC)
 Earliest report for malaria - repeated paroxysmal fevers associated
with enlarged spleens and a tendency to epidemic occurrence
 name malaria, derived from ‘mal’aria’ (bad air in Medieval Italian) - first
used by Leonardo Bruni in a publication of 1476.

Charles Louis Alphonse Laveran
first to notice parasites in the blood of a
patient suffering from malaria

 Infected anopheline mosquito - Most typical
cause of transmission
 Approximately 45% are effective vectors
 A population of infected humans is necessary to
sustain transmission
▪ short life span of mosquitoes ( 5 to 20 days)
▪ the long incubation period required in
the mpsquito (8 to > 10 days)

 Endemic malaria – based on the parasite rate in children 2 to 9 years old
 HYPOENDEMIC – parasite rate 0 to 10%
 MESOENDEMIC – parasite rate 11 to 50%
 HYPERENDEMIC - parasite rate consistently >50% , with a high
proportion of adults having enlarged spleen
 HOLOENDEMIC – parasite rate consistently >75%, with a low
proportion of adults having enlarged spleen

 Autochthonous malaria – acquired locally
- Introduced malaria – migrant populations (asymptomatic)
provide blood meals for feeding anopheles under conditions
that can complete the life cycle enabling the mosquito to
infect others
- Imported malaria
- Induced malaria – acquired from exposure to infected blood
( blood transfusion, needle stick injury, laboratory accidents)
- Cryptic malaria – cases for which no explanation can be
found

 Blood born transmission – cannot result to relapses
 Congenital malaria – cannot occur if the mother is semi-
immune
 Transplacental transmission or breakdown of placental
barrier during delivery

 Incidence and severity of malaria –
 Intensity of exposure
 Presence of immunity
- children
- pregnant woman
- reservoirs of infection
 Genetic factors
▪ Duffy- negative blood type specific receptors – resistant to
infection with P. vivax
▪ Sickle hemoglobinopathies and protection against severe
malaria falciparum

 Anemia
 Lysis of RBCs
 Impaired erythropoiesis
 bone marrow suppression secondary to folic acid
deficiency
 Hemoglobinuria (blackwater fever) – intravascular
hemolysis - can result to renal failure
Cytokines (TNF, Interleukin 1) –
TNF stimulate nitric oxide – correlated with clearance
of parasites and recovery and severity of illness

 Sequestered infected RBC –
-facilitate adherence of these cells to vascular
endothelium
- can be responsible for cerebral
malaria, renal failure, watery diarrhea
 Hypoglycemia and lactic acidosis –
consumption of glucose by late parasites

 Recurrent infections
 RELAPSES - due to delaye maturation of dormant live stages
(hypnozoites) of P. vivax or P. ovale
 RECRUDESCENCE – parasitemia caused by the same parasite
responsible for the initial infection recurs after clearance or a
significant reduction in the initial parasitemia
▪ Occurs most commonly with P. falciparum
 RE-INFECTION - from different parasites and infection with more
than one type of Plasmodium occur especially in areas with high
intensity of transmission
▪ Noted in P. malaria

P. falciparum P. vivax P. ovale P. Malariae
Incubation 12 (8-25) 14 (8 – 27) 17 (15 - > 18) 28 (15- > 40)
period
Periodicity of none 48 48 72
febrile attacks
Earliest 10 days 3 days ? ?
apperance of
gametocytes
Relapse No Yes Yes No
Duration of 1-2 yr 1.5 – 4 yr 1.5 – 4 yr 3 – 50 yr
untreated
infection
RBC preference Younger cells Reticulocytes Reticulocytes Older cells
(but can invade
cells of all ages)

P. falciparum P. vivax P. ovale P. Malariae
Characteristic Ring forms Schuffner dots Schuffner dots Normal- sized
morphology Multiply infected Enlarged RBCs Enlarged RBCs cells
cells Band or
Banana shaped rectangular
gametocytes forms of
trophozoites

 Malaria paroxysm – results from lysis of parasitized RBCs and release of merozoites into
the circulation at the completion of asexual reproduction
- fever, chills
- headache - body ache
- fatigue - dizziness
- malaise
GI symptoms – nausea, vomiting, abdominal pain, diarrhea

CHILDREN –
fever, headache or GI symptoms
- anemia
- Jaundice
- hepatospleenomegaly

 Anemia
 Thrombocytopenia
 Leukopenia
 Abnormal liver function test
 Hypoglycemia
 Hyponatremia
 Elevated creatinine or BUN

 Cerebral malaria – most common complication of falciparum
malaria
- Occurs mostly in 3 – 6 years old
- Alteration of consciousness w/o any explanation during infection of
malaria
- Comatose
- Generalized convulsions
- Increase of intracranial pressure
- histopathology – occasional hemorrhages and perivascular infiltrates

 SEVERE ANEMIA -
 Seen most commonly in less than 1 years old
 Occur most often in areas with year round transmission
 Clinical consequences of anemia
▪ Rate of development of anemia, severith of anemia
▪ Higher risk of complications as hemoglobin decreases less than 5
g/dL
 HYPOGLYCEMIA
 Associated with poor prognosis
 Due to combination of parasite consumption of glucose
and inadequate gluconeogenesis in the liver

 ACID-BASE CHANGES
 Metabolic acidosis – marker of severity  HYPERPNEA

 RENAL COMPLICATION
 Acute renal failure – life-threatening
▪ Oliguric and reversible if immediately dialized
• occur more frequently in those patients treated with quinine or
quinidine
• Histologic changes resembles those of acute tubular necrosis
• Nephrotic syndrome and chronic renal failure – endemic
and associated with P. malariae

• PULMONARY EDEMA
- Consistent with pulmonary leak syndrome
- Develops late in the course of severe malaria
• HYPERACTIVE MALARIAL SYNDROME
- Massive spleenomegaly, high concentrations of total
serum IgM and malarial antibodies of multiple
immunoglobulin classes and clinical and immunologic
response to antimalarial agents
- Seems to involve chronic exposure to malaria resulting in
chronicstimulationof the immune system and genetic
factors

• HYPERACTIVE MALARIAL SYNDROME
- Huge spleen and enlarged liver
- Anemia and increased reticulocyte count; thrombocytopenia or
neutropenia
- Increases the risk of acquiring bacterial infection

• History of travel in endemic areas
• Microscopy
• Thin smear - speciation of the organism
- Giemsa stain – preserves the Schuffner dots
- has low sensitivity – low parasite load (<100 to 300 uL) – too small
to detect
• Thick smear – speciation cannot be identified
- Estimating the parasites density – assessing the likelihood of
development of complications associated with high parasite density and
for evaluating response to therapy

• FLUORESCENT MICROSCOPY
• Identification of parasitized RBCs stained with acridine orange in the RBC layer of
centrifuged blood
• DETECTION OF PARASITE ANTIGEN

 First Line Treatment
Artemether-Lumefantrine tablet twice a day on days 1 to 3
(1 tablet contains 20 mg Artemether and 120 mg Lumefantrine)
AND
Primaquine tablet on day 4 (single dose)
(1 tablet contains 15 mg base of Primaquine)

Day of Artemether-Lumefantrine
treatment Use body weight in kgs as basis
5-<15 kg 15 - < 25 kg 25-<35 kg > 35 kg
If weight cannot betaken, use age as basis
6 mon- 3 yo 4-8 yo 9-13-yo If > 35 kg
Day 1 1 tab 2 tabs 3 tabs 4 tabs
8 hrs after 1 tab 2 tabs 3 tabs 4 tabs
Day 2 1 tab BID 2 tabs BID 3 tabs BID 4 tabs BID
Primaquine tablet (PQ)
Use body weight in kgs as basis: use 0.75 mg base/kg BW single dose
If weight cannot be taken use age as basis
Day4
< 1 yo 1-3yo 4-6 yo 7 -11 yo > 12 yo
Contraindicated ½ PQ single 1 PQ tablet 2 PQ tablets 3 PQ tablets
dose single dose single dose single dose

 Second Line Treatment

Quinine sulphate + Doxycycline or
Tetracycline or Clindamycin

Age Group/ Quinine Plus any of the three antibiotics below
Condition Sulfate Doxycycline Tetracycline Clindamycin
(300 or 600
mg/tablet)

Adults, non- 10 mg 3 mg/kg bw 250 mg 4 times 10 mg/kg bw
pregnant salt/kg bw once a day (QD) a day (QID) for 7 twice a day
women and dose every 8 for 7 days days (BID) for 7 days
children 8 hours for 7
years and days
above

Children < 8 As above Contra- Contra- 10 mg/kg bw
years old indicated indicated twice a day
(BID) for 7 days

Parenteral Quinine Dihydrocloride Infusion
PLUS
Tetracycline/Doxycycline/Cljndamycin

Age Group Quinine Dihydrochloride
Loading Dose Maintenance Dose
Adult 20 mg salt/kg in 500 ml 10 mg salt/kg in
D5W or 0.9NaCl for 4 0.9NaCl or D5W IV drip
hours IV drip for 4 hours every 8
(The total dose must not hours
exceed 2,000 mg)
Children 8 years to 16 15 mg salt/kg IV drip for 4 10 mg salt/kg IV drip
years hours in 10 ml/kg D5W or for 4 hours every 8
0.9 NaCl hours in D5W or 0.9
(infusion rate must not NaCl
exceed 5mg/kg per hour)
Children 7 years and 10 mg salt/kg in IV drip for 10 mg salt/kg IV drip
younger 4 hours every 12 hours

 Dosing Schedule for Pre-referral Treatment with
Artesunate Suppository (AS) in Adults
Weight (kg) Artesunate Regimen (single dose)
Dose (Preparation of AS is available in 50, 200 and 400
mg)

< 40 10 mg/kg Use appropriate number of 50 or 200 mg preparation

40 – 59 400 mg One 400 mg preparation
60 – 80 800 mg Two 400 mg preparation
> 80 1200 mg Three 400 mg preparation

Chloroquine tablet on Days 1 to 3
(1 tablet contains 150 mg base of Chloroquine)
AND
Primaquine tablet on Days 4 to 17
(1 tablet contains 15 mg. base of Primaquine
base)

Day of Treatment CQ
(1) Use weight in kgs (2) If weight cannot be taken, use age as basis
as basis 0-11 mos 1-3 4-6 7- 12-15 y.o. > 16 y.o.
y.o. y.o. 11
y.o.

Day 1 10 mg/kg 1/2 1 1½ 2 3 4
Day 2 10 mg/kg ½ 1 1½ 2 3 4
Day 3 5 mg/kg 1/2 1/2 1 1 1½ 2

Day 4-17 PQ
(1) Use weight in (2) If weight cannot be taken, use age as basis
kgs as basis 0-11 mos 1-3 4-6 7-11 y.o. > 12 y.o.
y.o. y.o.

0. 5 mg-base per contra- ½ ½ 1 daily 1 daily
kilogram per day indicated dail dail
y y

Chloroquine tablet on Days 1 to 3
( 1 tablet contains 150 mg base of Chloroquine)
AND
Primaquine tablet on Day 4 (single dose)
(1 tablet contains 15 mg base of Primaquine)

Day of Treatment CQ
(1) Use body weight (2) If weight cannot be taken, use age as basis
in kgs as basis 0-11 mos. 1-3 4-6 7- 12-15 y.o. > 16 y.o.
y.o. y.o. 11
y.o.

Day 1 10 mg/kg 1/2 1 1½ 2 3 4
Day 2 10 mg/kg ½ 1 1½ 2 3 4
Day 3 5 mg/kg 1/2 1/2 1 1 1½ 2

Day 4 PQ
(1) Use body weight (2) If weight cannot be taken, use age as basis
in kgs as basis 0-11 mos. 1-3 4-6 7-11 > 12
y.o. y.o. y.o.
y.o.

0.75 mg-base per contra- ½ 1 2 tabs singe 3 tabs single
kilogram per day indicated tab tab dose dose
sin sin
gle gle
dos dos
e e

 P. falciparum and P. vivax
Artemether Lumefantrine+ Primaquine.
Day of Treatment AL
(1) Use body weight in kgs as basis
5 - <15 15 - 25 - <35 kg ≥35 kg
kg <25
kg
(2) If weight cannot be taken, use age as basis
(6 mos.– (4- 8 (9-13 y.o.) If (> 13
3 y.o.) y.o.) y.o.)
Day 2 1 tab 2 tabs 3 tabs BID 4 tabs
BID BID BID
Day 3 1 tab 2 tabs 3 tabs BID 4 tabs
BID BID BID

P. falciparum and P. vivax
Day 4-17 PQ
(1) Use weight in (2) If weight cannot be taken, use age as basis
kgs as basis 0-11 mos 1-3 4-6 7-11 y.o. > 12 y.o.
y.o y.o
. .

0. 5 mg-base per contra- ½ ½ 1 daily 1 daily
kilogram per day indicated dai dai
ly ly

Artemether-Lumefantrine for 3 days (Refer to Table 4.4)
b. Primaquine (0.75 mg/kg) single dose on Day 4 (Refer to Table 4.4

 P. falciparum and P. Malariae
Artemether-Lumefantrine for 3 days

Primaquine (0.75 mg/kg) single dose
on Day 4

Artemether-Lumefantrine for 3 days (Refer to Table 4.4)
b. Primaquine (0.75 mg/kg) single dose on Day 4 (Refer to Table 4.4

 P. Falciparum, P. vivax and P. Malariae
Artemether-Lumefantrine for 3 days

Primaquine (0.5 mg/kg/day) single dose
on Day 4 for 14 days

5-<15 kg 15 - < 25 kg 25-<35 kg > 35 kg
6 mon- 3 yo 4-8 yo 9-13-yo If > 35 kg
Day4
< 1 yo 1-3yo 4-6 yo 7 -11 yo > 12 yo
Contraindicated ½ PQ single ½ PQ single 1 PQ tablets 1 PQ tablets
dose dose single dose single dose

 P. vivax and P. Malariae
Chloroquine (25 mg/kg) for 3 days
Primaquine (0.5 mg/kg/day) single dose
on Day 4 for 14 days

Stage of Treatment by Species
Pregnancy Pf Pv/Po/P Relapse P. Mixed
Uncomplicated Severe m vivax Infection
1st QN Parenteral QN infusion CQ CQ QN
trimester + + +
Clindamycin (oral) Clindamycin IV Clindamyci
(1) If Quinine infusion not available, n (oral)
give QN tab orally or by NGT
(2) Shift to oral Clindamycin if
patient can already tolerate oral
meds
(3) If QN not available (either tab or
infusion), is last resort requiring
consent of patient/relatives
2nd QN Parenteral QN infusion CQ CQ QN
trimester + + +
Clindamycin (oral) Clindamycin IV Clindamyci
(1) If above not available, give QN n (oral)
tab orally or by NGT If above
(2) Shift to oral Clindamycin if not
patient can already tolerate oral available,
meds AL can be
(3) If QN + is not available, can be given
given

Stage of Treatment by Species
Pregnancy Pf Pv/Po/P Relapse Mixed
Uncomplicated Severe m P. vivax Infection
3rd QN Parenteral QN infusion CQ CQ QN
trimester + + +
Clindamycin (oral) Clindamycin IV Clindamyc
(1) If above not available, give QN in (oral)
tab orally or by NGT If above
(2) Shift to oral Clindamycin if not
patient can already tolerate oral available,
meds AL can be
(3) If QN + is not available, can be given
given
Post-partum PQ SD PQ SD PQ 14 PQ 14 PQ 14
(2 weeks after
delivery)
Lactating QN Parenteral QN infusion CQ CQ QN
+ + + + +
Clindamycin (oral) Clindamycin IV PQ PQ 14 Clindamyc
+ (1) If above not available, give QN in
PQ tab orally or by NGT (oral)
(2) Shift to oral Clindamycin if +
patient can already tolerate oral PQ14
meds or
(3) If QN + is not available, can be AL
given +
PQ 14

 Uncomplicated Pf Malaria
Population Group Medicine Dosing Schedule
Pregnant Quinine Sulphate 10 mg/kg every 8 hours
for 7 days

Clindamycin 10 mg/kg twice a day
for 7 days

Lactating Above Plus PQ on Day 0.75 mg per kg, single
4 dose

• Severe Pf Malaria
Quinine Dihydrochloride Infusion + Clindamycin IV
Population Group Medicine Dosing Schedule
Pregnant Women Quinine 20 mg/kg infused over 10 mg/kg every 8 hours
Dihydrochloride 4 hours (in 500 ml 5% infused over 2-4 hours
dextrose water or 0.9% If patient can already
saline) tolerate oral meds, shift
to oral QN Sulphate (10
mg/kg every 8 hours) to
complete 7 days at
same dose
Clindamycin 10 mg/kg IV twice a day; shift to oral clindamycin;
as soon as patient tolerates oral clindamycin at
same dose to complete 7 days
Lactating Women Above Plus PQ 0.75 mg per kg, single dose
after 7 days of
Clindamycin

Plasmodium vivax, ovale, malaria and Mixed
Infection
 acute P. vivax or P. Ovale -
No. of Chloroquine Tablet Primaquine
(150 mg base/tablet) (15 mg base/tablet)
Day of Treatment Day 1 Day 2 Day 3 Pregnant Women:
By weight 10 mg/kg 10 mg/kg 5 mg/kg Withheld until delivery
If weight cannot be 4 tabs 4 tabs 2 tabs .
taken Lactating Women: Take
Primaquine beginning
Day 4 to Day 17at 0.5
mg/kg b.w. per day
Post-partum Women
(2 weeks after delivery)
for 14 days at 0.5 mg/kg
b.w. per day

 Dosing Schedule for Pregnant and Lactating Mothers with
Relapse P. vivax Malaria Infection
Chloroquine Tablet Primaquine Tablet
Wk1 Wk2 Wk3 Wk4 Wk5 Wk6 Wk7 Wk8 Pregnant Women: Withheld
2 2 2 2 2 2 2 2 until delivery
tabs tabs tabs tabs tabs tabs tabs tabs Lactating Women: Take
Primaquine beginning Day 4
up to Day 17 at 0.5 – 0.75
mg/kg b.w. per day to a
maximum of 30 – 45 mg per
day
Post-partum Women
(2 weeks after delivery) for
14 days at 0.5 – 0.75
mg/kg/b.w. per day to a
maximum of 30 – 45 mg per
day

• Dosing Schedule for Pregnant and Lactating Mothers with
P. malariae Malaria Infection
No. of Chloroquine Tablet Primaquine
Day of Treatment Day 1 Day 2 Day 3 Pregnant Women:
By weight 10 mg/kg 10 mg/kg 5 mg/kg Withheld until delivery
Lactating Women:
If weight cannot be 4 tabs 4 tabs 2 tabs Take Primaquine on
taken Day 4 at 0.75
mg/kg/b.w.
Post-partum Women
(2 weeks after delivery)
single dose at 0.75
mg/kg/b.w.

Dosing Schedule for 2nd and 3rd Trimester Pregnant and
Lactating Mothers With Mixed Infection
Day of Treatment AL
Use weight in kgs as basis If weight cannot be taken, use
age as basis
< 35 kgs (≥35 kg 9 - 13 y.o. > 13 y.o.
Day 1 3 tabs 4 tabs 3 tabs 4 tabs
8 hrs after 3 tabs 4 tabs 3 tabs 4 tabs
Day 2 3 tabs twice a day 4 tabs twice a 3 tabs twice a 4 tabs
(BID) day (BID) day (BID)
Day 3 3 tabs twice a day 4 tabs twice a 3 tabs twice a 4 tabs twice a
(BID) day (BID) day (BID) day (BID)
Day 4-17 PQ
(1) For Pregnant Women: withheld until delivery
(2) For Post Partum/Lactating Women:
Use 0.5 mg base per kg 1 tab daily
per day

< 6 months of age
Age Group/ Condition Quinine Sulfate Plus
(300 or 600 Clindamycin
mg/tablet)

Children < 8 years old 10 mg salt/kg bw 10 mg/kg bw twice a day
dose every 8 hours (BID) for 7 days
for 7 days

6 – 11 months
Day of treatment Artemether-Lumefantrine
Use body weight in kgs as basis (
5-<15 kg
6 mon- 3 yo
Day 1 1 tab
8 hrs after 1 tab
Day 2 1 tab BID
Day 3 1 tab BID

Age Group Quinine Dihydrochloride
Children 8 years to 16 15 mg salt/kg IV drip for 4 10 mg salt/kg IV drip
years hours in 10 ml/kg D5W or for 4 hours every 8
0.9 NaCl hours in D5W or 0.9
(infusion rate must not NaCl
exceed 5mg/kg per hour)
Children 7 years and 10 mg salt/kg in IV drip for 10 mg salt/kg IV drip
younger 4 hours every 12 hours

Weight Age Artesunate Regimen (single dose)
(kg) dose (mg) (available in 50 mg, 200 mg and
400 mg suppositories)

5 – 8.9 0 - 12 months 50 One 50 mg

9 – 19 13- 42 months 100 Two 50 mg

20 – 29 43- 60 months 200 One 200 mg

30 – 39 6 - 13 years 300 Two 50 mg and one 200 mg

> 40 > 14 years 400 One 400 mg

 In endemic areas, this condition is diagnosed only when
parasites are identified within 14 days after birth
 If parasites are seen in blood films after the first week of life,
neonatal malaria is a possibility

Day 1: 10 mg/kg
Day 2: 10 mg/kg
Day 3: 5 mg/kg (half dose of Days 1 and 2)

 suspected when blood has been transfused
within the past six months

Classification of Treatment Outcomes (WHO, 2005)
Response Criteria
Adequate Clinical Absence of parasitemia on Day 28 irrespective of temperature, without meeting
and Parasitological any of the criteria of Early Treatment Failure or Late Clinical Failure or Late
Response (ACPR) Parasitological Failure.

Early Treatment Development of danger signs or severe malaria on Day 1, Day 2 or Day 3 in the
Failure (ETF) presence of parasitemia; OR
Parasitemia on Day 2 higher than Day 0 count irrespective of axillary temperature;
OR
Parasitemia on Day 3 with axillary temperature ≥ 37.5 °C; OR
Parasitemia on Day 3 ≥ 25% of count on Day 0.
Late Clinical Failure Development of danger signs or severe malaria on any day from Day 4 to Day 28
(LCF) in the presence of parasitemia, without previously meeting any of the criteria of
Early Treatment Failure; OR
Presence of parasitemia and axillary temperature ≥ 37.5oC (or history of fever) on
any day from Day 4 to Day 28, without previously meeting any of the criteria of
ETF.
Late Parasitological Presence of parasitemia on any of the scheduled return on Day 7, Day 14, Day 21
Failure (LPF) or Day 28, and axillary temperature < 37.5oC without previously meeting any of the
criteria of ETF.

Dosing Schedule of Artemether-Lumefantrine (AL)
and Primaquine (PQ) in the Treatment of Uncomplicated Plasmodium falciparum Malaria
Infection

5-<15 kg 15 - < 25 kg 25-<35 kg > 35 kg
6 mon- 3 yo 4-8 yo 9-13-yo If > 35 kg

Day4
< 1 yo 1-3yo 4-6 yo 7 -11 yo > 12 yo
Contraindicated ½ PQ single 1 PQ tablet 2 PQ tablets 3 PQ tablets
dose single dose single dose single dose

Drugs Schedule Dose
Pregnant Adult Pediatric
A. For People Travelling To Endemic Areas
Doxycycline Tablet Start two to contraindicate 1 tablet < 8 years:
(100 mg) three days d contraindicated
prior to travel, > 8 years old:
daily while in 2 mg/kg up to 100
the area and mg daily
continue up to
four weeks
upon leaving
the area
Mefloquine Start 1-2 contraindicate 1 tablet weekly < 45 kg: 5 mg/kg bw
Tablet weeks before d 5-10 kg ⅛ tab
(250 mg base) travel; take 10-19 kg ¼ tab
weekly while 20-30 kg ½ tab
in the area, 31-45 kg ¾ tab
and continue
up to four
weeks upon
leaving the
area

Drugs Schedule Dose
Pregnant Adult Pediatric
A. For People Travelling To Endemic Areas
Choloroquine Start 2 weeks 2 tablets NA < 8 years: 5 mg/kg
before travel, b.w.
take weekly < 8 years: 2 tablets
while in the
area and
continue 4
weeks after
leaving the
area
B. For Pregnant Women Residing in Endemic Areas
Sulphadoxine If resident in 3 tablets each
Pyrimethamiine stable on 2nd and 3rd
transmission trimesters
area only

Malaria

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