Incomplete Treatmenat of Malaria and Special Concerns in Pregnancy

LONG CASE

INCOMPLETE TREATMENT OF MALARIA AND

SPECIAL CONCERNS IN PREGNANCY

TUTOR

Dr. ADI WIJAYA, Sp. PD

ARRAGED BY

SITI AZLIZA BINTI YAACOB, S.Ked

NIM: 030.08.304

INTERNAL MEDICINE DEPARTMENT

H. MARZOEKI MAHDI HOSPITAL

MEDICINE OF UNIVERSITY TRISAKTI, JAKARTA

PERIODE 21 JANUARY – 29 MARCH

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CONTENTS

CHAPTER I

INTRODUCTION……………………………………………………………………………… 1

CHAPTER II: REPORT CASE

A. PATIENT IDENTITY………………………………………………………………. 2

B. HISTORY TAKING…………..…………………………………….……………… 2

C. PHYSICAL EXAMINATION………………………………………………………5

D. LABORATORY TEST……………………………………………………………… 9

E. RESUME…………………………………………………………………………….17

F. PROBLEMS…………………………………………………………………………18

G. ASSESSMENT …………………………………………………………………….. 19

H. THERAPY………………………………………………………………………….. 20

I. DISCUSSION AND ANALYSIS OF CASE……………………………………… 21

CHAPTER III : THE LITERATURE

1. LIFE CYCLE OF MALARIA PARASITES………………………………………. 39

2. DEFINITION AND EPIDEMIOLOGY…………………………………………….40

3. PATHOFISIOLOGY………………………………………………………………...41

4. CLINICAL DISEASE…………………………………………………………….. ..42

5. PATENT PARASITEMIA FOR MALARIA CAUSED BY P.VIVAX………….. 46

5.1 RELAPSE………………………………………………………………………. 47

5.2 REINFECTION …………………………...…………………………………….48

5.3 RECRUDESENCE……………………………………………………...……….48

5.4 RECURRENCE………………………………………………………………… 49

6. DIAGNOSIS OF MALARIA……………………………………………………… 49

a. Clinical Diagnosis………………..….………………………………………….. 50

b. Microscopic Diagnosis………………………………………………………….. 51

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c. Antigen Detection………………………………………………………………... 53

d. Molecular Diagnosis…………………………………..…………………………..54

e. Serology……………………………………………………………………..…….55

f. Drug Resistance Tests………………………………………….…………………56

7. TREATMENT OF MALARIA INFECTION ………………………….…………..56

7.1 TREATMENT OF MALARIA CAUSED BY P.VIVAX, P.OVALE OR

P.MALARIAE…………………………………………………………………...

…..587.2SUSCEPTIBILITY OF P.VIVAX AND P.MALARIAE TO

ANTIMALARIALS………………………………………...………………………..60

7.3 TREATMENT OF UNCOMPLICATED VIVAX MALARIA……………….. 61

7.3.1 Blood stage infection………………………………………………...…..61

7.3.2 Chloroquine-resistant vivax malaria…………………………………..…62

7.3.3 Liver stage infection……………………………………………………..62

i) Treatment : severe P. vivax malaria…………………………………………….64

ii) Monitoring therapeutic efficacy for vivax malaria………………………………65

iii) Areas prone to vivax malaria epidemics………………………………………..65

iv) Anti-relapse therapy in vivax malaria epidemics ……………………………….66

8. TREATMENT NOT RECOMMENDED…………………………….……………..66

9. TREATMENT DURING PREGNANCY…………………………………………..69

10. MALARIA ENDEMICITY AREA………………………………………………….74

10.1 HIGH TRASMISSION AREAS…………………………………….………….74

10.2 MALARIA TRANSMISSION LIMITS IN INDONESIA……………………..75

10.3 Risk for travelers……………………………………..…………………………77

CHALLENGES TO ELIMINATING MALARIA………………………………………….… 88

CONCLUSION………………………………………………………….…………………....... 89

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ABBREVIATIONS……………………………………………………………..……………… 90

REFERENCES

CHAPTER I

INTRODUCTION

A round the world, the malaria situation is serious and getting worse. Malaria threatens

the lives of 40% of the world’s population – over 2 200 million people. Each year, there are an

estimated 300-500 million clinical cases. Malaria is estimated to kill more than 1 million people

annually, the majority of whom are young children. Ninety per cent of malaria cases in the world

occur in Africa south of the Sahara. Children under 5 years of age and pregnant women are the

worst affected by malaria. It is one of the leading causes of death among young children.

Together with pneumonia, diarrhoea, measles and malnutrition, malaria is responsible for over

70% of deaths in young children especially in developing countries. Malaria during pregnancy

causes severe maternal illness and anaemia, and is also associated with low birth weight among

newborn infants, a leading risk factor for infant mortality.(1)

4

The objectives of these case report are to discuss all those involved in the management

of incompete treatment of malaria in pregnancy and most probably the parasite is come from the

high transmission area that is from Papua New Guinea.

The challenges that outcomes in this case are :

1. Incomplete of previous treatment.

2. Recurrency of malaria infection.

3. The infecting Plasmodium species

4. The clinical status of the patient

5. The drug susceptibility of the infecting parasites as determined by the geographic area.

CHAPTER II

CASE OF INTERNAL MEDICINE

H. MARZOEKI MAHDI HOSPITAL

LONG CASE

______________________________________________________________________________

Name : Siti Azliza Binti Yaacob NIM: 030.08.304

Tutor : dr. Adi Wijaya Sp. PD

Signature :

5

A. PATIENT IDENTITY

Name : Mrs.Hernawati

Family’s name : Ahmad Rifai

Place/born/age :Sukabumi / 5

September 1974 /

38 years old

Address :Kp. Sukamarah RT

02/01 Taman Sari

Bogor

Religion :Moeslim

Occupation :Housewife

Marital status :Married

Education :SMA

MR Number : 229575

Date of admission : 23 January 2013

Date of examination :1 February 2013

B. HISTORY TAKING

An autoanamnesis in ward on 1 February 2013 at 20.00 pm.

Chief complaint :

Mrs. H a 35 years old women with a week history of remitten fever along with shaking chills,

who presented with a chief complaint of increasing fatigue since 1 weeks ago.

Additional complaint:

The additional complaint was nausea, vomite that contain fluid, headache, loss of

appetite, arthralgia and abdominal discomfort.

History of present illness:

This is the 4rd admission for woman with a long history of remitten fever wit a shaking

chills.

6

At first, patient often frequently travel from Papua to Java since September 2011 as she

was employed in an oil palm plantations in Papua. She was first admitted to hospital in Papua on

Disember 2011 with the same complain. She was diagnosed with malaria oe specifically malaria

tertian (P.Vivax and P.Ovale). she was admitted in the hospital for only 7 days and she remained

controlled at Polyclinic for the next 14 days and the doctor declared that she was totally

recovered. However, unexpectedly she was confirmed with pregnancy on that time, G3 P2 A0. On

February 2012 she had an abortion.

On November 2012, she was admitted for the 2nd diagnosed with malaria in Papua. She

stated that she was admitted until she got cured. She could not recall the medication taken.

Next in the last months of Disember 2012, once again she was diagnosed with malaria for the 3rd

time. Then, she was admitted in the same hospital in Papua. At the same time she had her second

pregnancy which the first day of the last menstruation date was on 16 Disember 2012 (G 4 P2 A1).

While she was admitted she had a little bleeding through her vagina but the gestation was still in

a good condition.

Lastly on 16 January 2013 she decided to going back to Java with uneventfully condition.

She is still in fatigue condition, nausea and arthralgia. One week after she return to Java, she had

instable condition with increasing fatigue, with a sudden onset of flue-like symptoms and

sustained recurrent severe attacks with the highest temperature is 39.6°c with shaking chills and

sometimes with sweating and arthralgia almost every day. Then, with all those complained her

family took her to Marzoeki Mahdi Hospital, Bogor on 23 January 2013.

Past medical history

Varicella (+)

Measles (+)

Influenza (+)

Malaria (+)

Gastritis (+)

Appendicitis (+)

*malaria : 4 times already

Family history

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Relation Ages Gender Health

condition

Reason of

death

Dieases Y N Relation

Grandfather - ♂ - - 1.Allergic

2.Asthma

3.TB

4.Arthritis

5.Rheumatisme

6.Hypertension

7.Heart

8.Kidney

9.Stomach

10.Diabetes

11.Cancer

12.Epilepsy

13.Psychiatry

14.Suicide

15. Syphilis

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

Father

Mother

Mother

Grandmother - ♀ - -

Father 45 ♂ Plus Hypertension

Mother 73 ♀ Plus Heart disease

and diabetes

Siblings 41 ♂ - -

Children 12 ♂ - -

7 ♀ - -

G3P2A0

- - -

History of habitual:

She stated that she are rarely do the excersice. She does not smoke, or does not like to

drink coffee and tea. She also does not take any routine medication or herbs.

History of life:

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Birth : She was born at her with a spontaneous delivered by midwife. She could not recall her

body weight and heigh at birth.

History of diet:

Present diet : frequent of meal is 2x/day, with ½ portion and variation of food.

Apetite : loss of apetite.

C. PHYSICAL EXAMINATION

General condition : Mrs. H appears alert, oriented and cooperative.

Consciousness: conscious

Vital signs:

Blood pressure :100/70 mmHg

Pulse rate :90x/m

Respiration rate :20x/m

Temperature :39.3°c

NUTRITIONAL STATUS

WEIGHT : 53 kg HEIGHT: 155 cm

BMI: 53kg / (1.15)2 m = 22.06

EFFECT: Normal weight.

Psychological status:

Behavior : restless

Emotional : normal

Thinking : rasional

GENERAL PHYSICAL EXAMINATION

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Head : Normocephalic, atraumatic head, normal distribution of hair.

Lymph node : cervical and supraclavicula lymph nodes is not palpable enlarged.

Eyes :conjunctival pallor (+/+), sclera icterus (-/-),isochoric pupils, pupils equally

round, 3 mm of diameter, direct pupillary light reflex (+/+), indirect papillary

light reflex (+/+).

Ears : Normotia, secrete -/-, serumen -/-, intact timpany membrane+/+

Nose :septum deviation (-), secrete -/-, concha is normal, mucosa not hyperemic

Mouth : Dirty mouth (-), dry mouth (-), normal papil, mucosa hyperemic(-), sianosis (-)

Throat : Tonsils T1/T1 calm, pharynx hyperemic (-)

Neck : trachea is palpable in the midline and thyroid gland is normal without masses,

jugular vein’s pressure is normal 5-2mmHg.

Thorac :

Shape : Chest is of regular shape and size,symetrical with prominent ribs

and well-defined intercostal spaces.

Breast : atrophic and symmetric, nontender, no masses or discharges

Inspection :Chest expands symmetrically and bilaterally on inhalation,

breathing pattern is thoracoabdominal, there is no expansion of

intercostals.

Palpation : tactile vocal fremitus is symmetrical bilaterally, tenderness (+).

Percussion :resonant, No apparent dullness or hyper-resonance upon

percussion of the chest.

Auscultation : vesicular breath sounds, with no apparent crackles, wheezes (-/-),

ronchi (-/-).

Heart

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Inspection : puctum maximum of ictus cordis is not visible.

Palpation : Point of puctum maximum is located at the left fifth intercostal

space on the mid-clavicular line. No palpable heaves or thrills.

Percussion :

Left upper border : second left intercostal space on parasternal line.

Left lower border: fourth left intercostal space lateral to mid-cavicular line.

Right upper border: third right intercostals space on sternal line.

Right lower border : third-fourth right intercostal space on sternal line.

Auscultation : S1 and S2 is regular, murmur sound (-), gallop (-).

Blood vessel

Temporal artery : pulse is palpable

Carotid artery : pulse is palpable

Brachial artery : pulse is palpable

Radial artery : pulse is palpable.

Femoral artery : pulse is palpable

Popliteal artery : pulse is palpable

Posterior tibial artery : pulse is palpable

Dorsalis pedal artery : pulse is palpable

Abdominal

Inspection : bulging, symmetrical, smiling umbilical (-), caput medusa (-), spider nevi (-).

Palpation : There is no apparent tenderness to palpation, and no palpable masses. The

spleen and the lower edge of the liver are not palpable, and there is no evidence of hernia.

Percussion : tympanic

Auscultation : bowel sound (+) normal.

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Genital : there is no indication for examination.

Extremities

Upper limb

Right Left

Muscle : normotrophic normotrophic

Tone : normotonic normotonic

Joint : normal normal

Movement : active active

Power : scor : 5 scor : 5

Edema : - -

Warm acral : + +

Lower limb

Wound : - -

Varises : - -

Tone : normotonic normotonic

Joint : normal normal

Movement : active active

Power : scor : 5 scor : 5

Sensoric : normal normal

Edema : - -

Warm acral : + +

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D. LABORATORY TEST

23 January 2013 (In Emergency Room)

Hematology

Test performed Result Unit Recommended Interpretation

Hemoglobin 9.7 g/dl 13-18

Leukocyte 6.810 /mm3 4000-10000 N

Thrombocyte 73.000 mm3 150000-400000

Hematocrit 29 % 40-54

Serologic

Widal test

O Antigen

S. Typhosa Negative - - -

S.Paratyphi A Negative - - -

S.Paratyphi B Negative - - -

S.Paratyphi C Negative - - -

H Antigen

S. Typhosa Negative - - -

S.Paratyphi A Negative - - -

S.Paratyphi B Negative - - -

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S.Paratyphi C Negative - - -

Chemistry blood count

SGOT 36 U/l <42 N

SGPT 26 U/l <47 N

BUN 15.0 mg/dl 10-50 N

Creatinine 0.65 mg/dl 0.67-1.36 N

Blood glucose 142 mg/dl <140 N

Laboratory test : 24 January 2013

Test / 12 hours

Hematology 1st



Leukocyte 7.620 /mm3 4000-10000 N

Thrombocyte 59.000 mm3 150000-400000


Hematology 2nd


14


Leukocyte 6.870 /mm3 4000-10000 N

Thrombocyte 52.000 mm3 150000-400000


15


Hematology 1st



Leukocyte 6.620 /mm3 4000-10000 N

Thrombocyte 64.00 mm3 150000-400000


Hematology 2nd



Leukocyte 5.690 /mm3 4000-10000 N

Thrombocyte 47.000 mm3 150000-400000


Hematology


Malaria In a sample was found

the plasmodium Vivax

in a Early

trophozoite shape

(ring form)

- - -

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Laboratory test: 26 January 2013

Hematology



Leukocyte 5.740 /mm3 4000-10000 N

Thrombocyte 53.000 mm3 150000-400000


Laboratory test: 27 January 2013.

Hematology



Leukocyte 4.580 mm3 4000-10000 N

Thrombocyte 64.000 mm3 150000-400000


Laboratory test : 28 January 2013.

Hematology 1st



Leukocyte 9.910 /mm3 4000-10000 N

17

Thrombocyte 95.000 mm3 150000-400000


Hematology 2nd



Leukocyte 8.890 /mm3 4000-10000 N

Thrombocyte 91.000 mm3 150000-400000


Laboratory test : 29 January 2013.

Hematology



Leukocyte 8.000 /mm3 4000-10000 N

Thrombocyte 123.000 mm3 150000-400000


Chemistry blood count

SGOT 25 U/l <42 N

SGPT 30 U/l <47 N

BUN 41.1 mg/dl 10-50 N

18

Creatinine 0.51 mg/dl 0.67-1.36

Blood glucose 143 mg/dl <140 N

Electrolyte


Natrium Na+ 139 136-146 N

Sodium K+ 4.5 3.5-5.0 N

Chloride Cl- 96 95-115 N

HEMOSTASIS


APTT 26.8 Dtk 25.9-39.5 N

Protrombin time 12.2 Dtk 11.8-14.4 N

Fibrinogen 214 mg/dl 200-400 N


Blood Gas Analysis


Ph 7.50 7.35-7.45

PCO2 30 30-50 N

PO2 74 70-700 N

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BE 0.0 -2-+3.0 N

TCO2 23.9 22-29 N

HCO3 23.0 18-23 N

BE act 0.7 -2.0- +3.0 N

SO2 97 95-98 N

O2 CT 16.6 15.0-23.0 N

Temp 35.6 N

FlO2 0.21

Hematology

Test performed Result Unit Interpretation

D-Dimer 6,809.36 ng/mL FEU


Hematology



Leukocyte 7.580 /mm3 4000-10000 N

Thrombocyte 217.000 mm3 150000-400000 N


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Laboratory test : 1 February 2013.

Hematology


Malaria Positive (+)

Malaria paracyte

was found

(Plasmodium

Vivax)

- - -

Another examination

1. ECG

Normal ECG

E. RESUME

A women, 35 years old was admitted to dr. H. Marzoeki Mahdi Hospital’s ER on 23

January that was complain increasing fatigue since a week before admitted to the hospital. She

was had a history of remittent fever a long with shaking chills. The additional complaint was

nausea, vomite that contain fluids, headache, loss of appetite, arthralgia and abdominal

discomfort. She had instable condition with increasing fatigue, with a sudden onset of flue-like

symptoms and sustained recurrent severe attacks with the highest temperature is 39.6°c with

shaking chills and sometimes with sweating and arthralgia almost every day. All of this

complains have be come progressively worst within a last week before admitted to the hospital.

In the past history patient often frequently travel from Papua to Java since September 2011 as

she was employed in an oil palm plantations in Papua. She was 3 times diagnosed of malaria in

Papua. When she was first diagnosed on Disember 2011, she was in pregnancy and then she was

21

admitted in hospital until totally recovered. She was had an abortion on February 2012. Upon the

recent diagnosed on Disember 2012, which was also in Papua, she was admitted and then

discharged instable condition. Than she was decided to going back to Java. Once again, she had

a 4 weeks gestation in pregnancy.

In physical examination, Mrs. H appears alert, oriented and cooperative. Consciousness is

conscious. The vital sign is blood pressure:100/70 mmHg, pulse rate:90x/m, respiration

rate:20x/m and temperature: 39.3°c. Eyes: conjunctival pallor (+/+), sclera icterus (-/-), Thorac

in inspection :Chest expands symmetrically and bilaterally on inhalation, Palpation : tactile vocal

fremitus is symmetrical bilaterally, tenderness (+), Percussion: resonant and auscultation:

vesicular breath sounds, wheezes (-/-), ronchi (-/-). Heart sound : S1 and S2 is regular, murmur

sound (-), gallop (-).

The result of heamatology test during her admission is hemoglobin : 9.7 g/dl, leukocyte :

6.810mm3, thrombocyte : 73.000mm3 , hematocrit : 29% and widal test is negative.

She was admitted to ward within observasion of febris, anemia and thrombocytopenia.

She was consult to Internal Medcine’s Specialist, dr. Adi Wijaya Sp. PD.

F. PROBLEMS

1. High fever

2. Dyspepsia (Nausea,vomit,abdominal

discomfort), Loss of apetite

3. Arthralgia

4. Anemia , Thrombositopenia

5. Recurrent malaria infection.

6. Pregnancy

7. Most probably she was infected from

the high transmission area that is

Papua New Guinea.

G. ASSESSMENT

Working Diagnose

Incomplete treatment of Malaria infection with pregnancy and anemia.

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Based on :

1. History taking :

She often frequently travel from Papua to Java since September 2011 as she was

employed in an oil palm plantations in Papua.

In the past history she was 3 times diagnosed of malaria in Papua.She decided going back

to Java after she had a 3rd diagnosed of malaria in Papua on Disember 2012.

She return to Java with uneventfully condition. She is still in fatigue condition, nausea

and arthralgia. One week after she return to Java, she had instable condition with

increasing fatigue, with a sudden onset of flue-like symptoms and sustained recurrent

severe attacks with the highest temperature is 39.6°c with shaking chills and sometimes

with sweating and arthralgia almost every day.

2. Physical examination

BP:100/70 mmHg, P : 90x/m, RR :20x/m and Temp : 39.3°c. Eyes: conjunctival pallor

(+/+),

3. Laboratory test

hemoglobin : 9.7 g/dl, leukocyte : 6.810mm3, thrombocyte : 73.000mm3 , hematocrit :

29% and widal test is negative.

Differential diagnosis :

1. Relapse of malaria.

2. Thyphoid fever

3. Dengue hemorrhagic fever.

H. THERAPY

1. Medicamentosa

IVFD RL /8hrs

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Oxygen canul 2L/m

Antipyretic : Paracetamol 3x1g

H2 Blocker : Ranitidine 2x1

Planning for transfusion of PRC 200cc.

Planning for giving of anti-malaria drugs.

2. Non-Medicamentosa

Bed rest total

And adequate of food and drink.

Prognosa:

Ad vitam: dubia ad bonam

Ad sanationam : dubia ad bonam

Ad fungsionam : dubia ad bonam

I. DISCUSSION AND ANALYSIS OF CASE

Working Diagnosis

Recrudencen Malaria fever with pregnancy

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Differential diagnosis

Typhoid fever

Dengue hemorrhagic fever

Analysis

This is the 4th diagnosed of malaria for a woman 35 years old . From the history taking ,

she was had a 3rd diagnosed since she was in Papua. She was in Papua since November 2011

until Disember 2012. She was admitted to the hospital in Papua for the 3 times and lastly on

Disember 2012. The first diagnosed she also was in pregnancy and then she had her abortion on

February 2012. On Disember 2012 she once again was diagnose with Malaria and also she was

had 4 weeks gestation of pregnancy. Then she decided to going back to Java on 16 Disember

2012. She return to Java with uneventfully condition. She is still in fatigue condition, nausea and

arthralgia. One week after she return to Java, she had instable condition with increasing fatigue,

with a sudden onset of flue-like symptoms and sustained recurrent severe attacks with the highest

temperature is 39.6°c with shaking chills and sometimes with sweating and arthralgia almost

every day. From the history taking we can suspect that is the treatment of malaria since in Papua

is incomplete and most probably, in this case the manifestations of malaria can be due to

recrudescence patern.

During she came to ER of Marzoeki Mahdi’s Hospital she was in fatigue condition, fever

with shaking chills, nausea, vomite that contain fluid, headache, loss of appetite, arthralgia and

abdominal discomfort. In physical examination she was appears alert, oriented and cooperative.

Consciousness is conscious. The vital sign is blood pressure:100/70 mmHg, pulse rate:90x/m,

respiration rate:20x/m and temperature: 39.3°c. Eyes: conjunctival pallor (+/+). In ER the blood

test was give result negative in widal test, anemia with Hb : 9.7g/dl, Ht: 29%, and

thrombocytopenia with thrombocyte : 73.000mm3. Through the history taking, physical

examination and blood test she was warded with working diagnose is observation of febris that

suspect of recurrent malaria infection with pregnancy and anemia.

Challenges to undergoing this case :

1. The infecting Plasmodium species

25

In this case, there is a P. vivax infections. As we know the P.vivax infection is require

treatment for the hypnozoite forms that remain dormant in the liver and can cause a relapsing

infection and also the P. vivax species have different drug resistance patterns in differing

geographic regions. Relapses originating from hypnozoites are characteristic of Plasmodium

vivax infections. Thus, reappearance of parasitemia after treatment can result from relapse,

recrudescence, or reinfection.

In this case, parasitemia are reappears after blood schizonticidal therapy during treatment

in Papua since one week before return to Java. It may be a recrudescence originating from

asexual blood-stage parasites that survived therapy.

Recrudescence with a long latency is the more likely explanation for this case, because

reinfection usually occurs after day 14 of treatment and in endemic areas. Recrudescence is a

recurrence of malaria within days or weeks of apparent cure, without new infection, and is

caused by inadequate clearing of parasites from the bloodstream so symptoms come back once

the treatment has stopped.. The patient could have recrudescence: when the patient takes

medication, the treatment kills most of the malaria parasites in the blood, and enough so the

patient feels better again, but some parasites still remain. Then, after the treatment finished, the

parasite is able to replicate again, they increase in number in the blood and the patient feels ill

again. In this case, we would say the infection came back from the blood, and the patient should

take another dose of anti-malarials, but of a different kind to that which they originally had, in

order to kill all of the parasites. Recrudescence that occur here can be due to incomplete or

inadequate treatment since in Papua.

2. The clinical status of the patient

Patient was in pregnancy since she was in Papua and now in 4 weeks of gestation. As we

know, pregnant women with symptomatic malaria infection are a high-risk group, and they must

promptly receive effective antimalarial treatment. Malaria in pregnancy is associated with low

birth weight, increased anaemia and, in low-transmission areas, an increased risk of severe

malaria and death. In this case, patient also was presenting an anemia that is common

complication of malaria in pregnancy. However, with the hemoglobin level at a first admission :

9.7g/dl is not indicate to be severe anemia which is based on literature the indication to be severe

26

anemia if patients who have one or more of the following clinical criteria (impaired

consciousness/coma, severe normocytic anemia [hemoglobin<7], renal failure, acute respiratory

distress syndrome, hypotension, disseminated intravascular coagulation, spontaneous bleeding,

acidosis, hemoglobinuria, jaundice, repeated generalized convulsions, and/or parasitemia of >

5%) are considered to have manifestations of more severe disease and should be treated

aggressively with parenteral antimalarial therapy.

In 4th day hospitalization on 27 January 2013 the hematology result was rapid

development of malaria which is hemoglobin : 7.4g/dl and hematocrite : 22% , so that we are are

decided to give. Based on literature, in low-transmission settings, a threshold of 20%

(haemoglobin 7 g/100 ml) is recommended to transfusion of blood. Lastly the 500cc of PRC

was transfused on that day. On the next day the hemoglobin level was slightly increased to 10.1

g/dl .

Beside that the prengnacy was be a challenges to initiate the therapy. Patient was in the

first trimester, so that the drug of choice for her may be considered both artemisin derivatives

and quinine. Based on literature, quinine is associated with recurrent hypoglycaemia. But in the

first trimester, the risk of hypoglycaemia is lower and the uncertainties over the safety of the

artemisinin derivatives are greater. However, weighing these risks against the evidence that

artesunate reduces the risk of death from severe malaria, both artesunate and quinine may be

considered.

The treatment must not be delayed in this case, with look at a patient’s condition. So that

we dicided to initiate the cloroquine peroral that is available, then changed to parenteral

artesunate when it available. It should be started immediately. Chloroquine was given in 3 days

with dose : I day : chloroquine 250mg 4 units, II day : chloroquine 250mg 4 unit and III day:

chloroquine 250mg 2 unit. The parenteral artesunate: Day I : Artesunat (D5% 100cc) 1x drip,

Dose = 2.4 mg/ kg body weight(Weight = 55kg x 2.4 mg= 132 mg). Day II : Artesunate (D5%

100cc) 1x1 ½ ampul drip. Day III: Artesunate (D5% 100cc) 1x1 ½ ampul drip.

3. The drug susceptibility of the infecting parasites as determined by the geographic area

Patient was acquiring P. vivax infections from regions in Indonesia and most probably

from Papua New Guinea. Reports have confirmed a high prevalence of chloroquine-resistant P.

27

vivax in Papua New Guinea. Where is persons acquiring P. vivax infections in Papua New

Guinea or Indonesia should initially be treated with a regimen recommended for chloroquine-

resistant P. vivax infections.

However, on 1 February 2013 patient was ask to discharge by her on dicision and there is

no provided any anti-malarial drugs that is the tablet of artesunate during she was discharged.

FOLLOW-UP

1st day of Hospitalization on 24 January 2013

Date Followup

24/1/13 S:

-Headache since yesterday before admitted to the hospital

-Fever (1 week ago), Shaking chills

-Nausea (+),vomit(-), Fatigue, Loss of apetite

-Difficult micturition , defecation (-)

-Prengnant in 4 weeks of gestation

O: Conscious, moderately illness.

BP: 100/60mmHg Pulse: 120x/m

RR: 30x/m Temp: 39.3°c

Eye : conjunctival pallor (+/+), sclera icterus (-/-)

Thorax:

-S1 and S2 is regular, murmur sound (-), gallop (-).

-vesicular breath sounds (+/+), wheezes (-/-), ronchi (-/-).

28

Abdomen:

-bulging, tenderness(-), tympanic, bowel sound (+)

Extremities : Warm acral (+), oedem (-)

1st 12hrs : - Hb: 8.7 g/dl Ht : 27%

Throm: 59.000 mm3

2nd 12hrs : - Hb: 8.4 g/dl Ht : 26%

Trom: 52.000 mm3

A: observation of febris with 4 months gestation pregnancy, anemia

and thrombocytopenia.

P:

IVFD RL /8hrs

Oxygen canul 2L/m

Paracetamol 3x1g

Ranitidine 2x1

-Haematology test /12hrs

-Microscopy examination.(blood smear)

2nd day of hospitalization on 25 January 2013.

25/1/13 S:

-Headache.

-Fever (+) , Shaking chills(at night)

29

-Fatigue, Nausea (+),vomit(-), Loss of apetite, abdominal

discomfort(+), Arthralgia(+).

-Micturition (+) normal , defecation (-)


O:Conscious, moderately illness.




Thorax:

-S1 and S2 is regular, murmur sound (-), gallop (-).

-vesicular breath sounds (+/+), wheezes (-/-), ronchi (-/-).

Abdomen:

-bulging, distention (-), tenderness(+), tympanic, bowel sound (+)

-Extremities : Warm acral (+), oedem (-)

1st 12hrs : - Hb: 7.9 g/dl Ht : 24%

Throm: 64.000 mm3

2nd 12hrs : - Hb: 7.5 g/dl Ht : 22%

Trom: 47.000 mm3

Malaria : In a sample was found the plasmodium Vivax in a Early

trophozoite shape (ring form)

A: observation of febris et causa Malaria with 4 months gestation

pregnancy, anemia and thrombocytopenia.

30

P:

-IVFD RL /8hrs

-Paracetamol 3x1g

-Ranitidine 2x1

-Ceftriaxone (NaCl 100cc) 1x2 drip

-Chloroquine 250mg 4unit


3rd day of hospitalization on 26 January 2013-03-07

26/1/13 S:

-Headache.


-Fatigue

-Nausea (+),vomit(-)

-Loss of apetite, abdominal discomfort(+),

-Arthralgia(+).






31


Thorax:

S1 and S2 is regular, murmur sound (-), gallop (-).

vesicular breath sounds (+/+), wheezes (-/-), ronchi (-/-).

Abdomen:

-bulging, distention (-), tenderness(+), tympanic, bowel sound (+)


1st 12hrs : - Hb: 7.9 g/dl Ht : 22%

Throm: 53.000 mm3

A: observation of febris et causa Malaria with 4 months gestation

pregnancy, anemia and thrombocytopenia.

P:

-IVFD RL /8hrs

-Paracetamol 3x1g

-Ranitidine 2x1


-Dexamethasone 2x1

-Chloroquine 250mg 4unit


4th day of hospitalization on 27 January 2013

27/1/13 S:

32

-Severe headache .


-Fatigue ,Nausea (+),vomit(-),Loss of apetite,

-Arthralgia(+).







Thorax:



Abdomen:

-bulging, distention (-), tenderness(-), tympanic, bowel sound (+)


1st 12hrs : - Hb: 7.4 g/dl Ht : 22%

Throm: 64.000 mm3

A: Malaria with 4 months gestation pregnancy, anemia and

thrombocytopenia.

P:

33

-IVFD RL /8hrs

-Ranitidine 2x1

-Ceftriaxon 2x2gr drip

-Dexamethason 2x1gr

-Farmadol 1x1

-Chloroquin 250mg 2 unit

-Transfusion of PRC 500cc

-Kina 3.7 amp + 500cc D5% /4hrs 1x/daily (still on planning)

Haematology test /12hrs

5th day hospitalization on 28 January 2013

28/1/13 S:

-Severe headache .


-Fatigue ,Nausea (+),vomit(-), Loss of apetite,

-Arthralgia(+).







34

Thorax:



Abdomen:



1st 12hrs : - Hb: 10.1 g/dl Ht : 30%

Throm: 95.000 mm3

2nd 12hrs : -Hb : 10.2g/dl Ht : 31%

Throm : 91.000mm3


thrombocytopenia.

P:

-IVFD RL /8hrs

-Duplastan 2x1

-Ranitidine 2x1

-Ceftriaxon 2x2gr drip

-Dexamethason 2x1gr

-Farmadol 1x1 drip

-Planning to give kina

-Day I : 3,7 ampul kina+500cc D5% / 6 hours, 1x/day

35

-Dose : 20mg /kgweight / 4-6 hours in D5% 500cc.

-Day 2 : 2 ampul + 200cc D5% / 2 hours , 3x/day.

-Dose : 10 mg/kgweight / 2 hours in 200cc D5% , 3x/day

*Weight : 55kg



29/1/13 S:

-Severe headache .


-Fatigue, Nausea (+),vomit(-), Loss of apetite,

-Arthralgia(+).





RR: 18x/m Temp: 36 °c


Thorax:



Abdomen:

36



Haematology: Hb : 10.1 g/dl Ht : 30%

Throm : 123.00 mm3

General glucose : 143 mg/dl

Electrolyte and hemostasis in normal level.


thrombocytopenia.

P:

-IVFD RL /8hrs

-Darplex tab 1x4tablet


-Dexamethasone 2x1g

-Farmadol 1x1 drip

-Pospond to give kina, there is no drug provided.

-Day I : Artesunat (D5% 100cc) 1x drip

-Dose = 2.4 mg/ kgweight

*Weight = 55kg x 2.4 mg= 132 mg



37

30/1/13 S:

-Severe headache cant sleep

-Fatigue, Nausea (+),vomit(-), Loss of apetite,

-Arthralgia(+).



O: Conscious, moderately illness.




Thorax:



Abdomen:



Blood gas analysis was in normal result just there is little increase in

pH : 7.50.

D-Dimer test : 6,809.36 ng/mL FEU


thrombocytopenia.

38

P:

-IVFD RL /8hrs

-Ranitidine 2x1

-Ceftriaxone (NaCl 100cc) 2x2g drip

-Dexamethasone 2x1g

-Farmadol 1x1 drip

-Day II : Artesunate (D5% 100cc) 1x1 ½ ampul drip

-Gived in 3 days from 30/ Jan/ 13-1 /Feb/ 13 NEXT ORAL


8th hospitalization on 31 January 2013

31/1/13 S:

-Mild headache

-Fatigue, Nausea (+),vomit(-), Apetite is quite good

-Arthralgia(+).





RR: 20x/m Temp: 36.2 °c


39

Thorax:



Abdomen:



Haematology test: Hb : 10.1 g/dl Ht : 31%

Throm : 217,000 mm3 (N)

A: Malaria with 4 months gestation pregnancy and anemia

P:

-IVFD RL /8hrs

-Ranitidine 2x1

-Ceftriaxone (NaCl 100cc) 2x2g drip

-Dexamethasone 2x1

-Farmadol 1x1 drip

-Artesunate (D5% 100cc) 1x1 ½ ampul drip


9th hospitalization on 1 February 2013

1/2/13 S :

-Mild headache

40

-Nausea (+),vomit(-), Apetite is good

-Arthralgia(+).



O:Conscious, mild illness.




Thorax:



Abdomen:



Haematology test:

Malaria : Positive (+), Malaria paracyte was found (Plasmodium

Vivax)

A: Malaria with 4 months gestation pregnancy and anemia

P:

-IVFD RL /8hrs

-Ranitidine 2x1

41

-Farmadol 1x1 drip

-Artesunate (D5% 100cc) 1x1 ½ ampul drip

*patient was unrecommended discharged by doctor which is

personal dicision.

CHAPTER III

THE LITERATURE

1. DEFINITION AND EPIDEMIOLOGY

Malaria is caused by infection of red blood cells with protozoan parasites of the

genus Plasmodium . The parasites are inoculated into the human host by a feeding female

42

anopheline mosquito. The four Plasmodium species that infect humans are P. falciparum,

P. vivax, P. ovale and P. malariae. Increasingly, human infections with the monkey malaria

parasite, P. knowlesi, have also been reported from the forested regions of South-East Asia.(1)

The World Health Organization estimates that malaria caused approximately 655,000

deaths in 2010. Most are in young children in sub-Saharan Africa. Malaria can also cause

dangerously low birth weights and permanent disability.(8)

Pregnant women and their unborn children are highly susceptible to malaria infection.

Yet, authoritative documents barely mention malaria as a threat for pregnancy and normal foetal

development in countries of the South-East Asia (SEA) Region. Almost all the published

literature on the subject refers to Africa by presenting data principally related to Plasmodium

falciparum which is supposed to cause a variety of adverse consequences, such as anaemia,

cerebral malaria and deaths, etc. of both the mother and the baby. However, in some countries of

the SEA Region, such as India and Sri Lanka, the dominant species is P.vivax, while in

Myanmar and Thailand P.falciparum is the prevalent infection. P.malariae is also recorded in

dense forests of countries of the Region. This article reviews 16 studies from India, 13 from

Thailand, three from Sri Lanka, three from Myanmar and one from Indonesia, to estimate the

burden of malaria-related adverse outcomes in the vulnerable group of pregnant women and their

unborn children, in areas of stable and unstable (epidemic prone) transmission.(3)

2. LIFE CYCLE OF MALARIA PARASITES

Malaria is transmitted through the bite of an infected, female Anopheles mosquito and

occasionally through blood transfusion. When a mosquito bites a person it sucks up blood. If the

person has malaria, some of the parasites in the blood will be sucked into the mosquito. The

malaria parasites multiply and develop in the mosquito. After 10-14 days they are mature and

ready to be passed on to someone else. If the mosquito now bites a healthy person, the malaria

parasites enter the body of the healthy person.(4)

43

Figure 1: Life cycle of malaria parasites

The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-

infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites

infect liver cells and mature into schizonts , which rupture and release merozoites . (Of

note, inP. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause

relapses by invading the bloodstream weeks, or even years later.) After this initial replication in

the liver (exo-erythrocytic schizogony ), the parasites undergo asexual multiplication in the

erythrocytes (erythrocytic schizogony ). Merozoites infect red blood cells . The ring stage

trophozoites mature into schizonts, which rupture releasing merozoites . Some parasites

differentiate into sexual erythrocytic stages (gametocytes) . Blood stage parasites are

responsible for the clinical manifestations of the disease.

The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested

by an Anopheles mosquito during a blood meal . The parasites’ multiplication in the mosquito

44

is known as the sporogonic cycle . While in the mosquito's stomach, the microgametes

penetrate the macrogametes generating zygotes . The zygotes in turn become motile and

elongated (ookinetes) which invade the midgut wall of the mosquito where they develop into

oocysts . The oocysts grow, rupture, and release sporozoites , which make their way to the

mosquito's salivary glands. Inoculation of the sporozoites into a new human host perpetuates

the malaria life cycle.(5)

3. PATOFISIOLOGY

The incubation period, from the time of mosquito bite until clinical symptoms appear, is

typically 7 to 30 days. Symptoms include fever, headache, nausea, vomiting, and myalgias. Due

to the cycling parasitemia in the bloodstream, patients will often experience symptoms every 2 to

3 days, depending on the type ofPlasmodium with which they are infected.

In the human, plasmodial infection is a complicated reproductive life cycle involving

hepatic and erythrocytic infection. Once the sporozoite enters the liver, it multiplies and exits

into the bloodstream in the merozoite form. The merozoite then invades erythrocytes, leading to

phagocytosis of infected blood cells by the spleen. Malarial symptoms are caused mainly by the

red blood cell invasion and the body’s inflammatory response.7 Malarial infection causes

marked immunoglobulin synthesis and, in the case ofP falciparum, creates immunoglobulin

complexes and increased production of tumor necrosis factor. The ability of P falciparum to

cause cytoadherence of erythrocytes to vascular walls leads to sequestration of infected cells in

small blood vessels, causing end organ damage via hemorrhage or infarct.6,7Phagocytosis of

infected blood cells in the spleen helps clear infection, but also contributes to profound anemia

and folic acid deficiency.

It has been established that repeated malarial infections lead to some immunity. In fact, in

areas where malaria incidence is episodic rather than endemic, patients will present with more

severe forms of the disease, as their previously “learned immunity” appears to fade over time. It

is not surprising, therefore, that malaria-naive and immunocompromised patients are prone to

more severe infection. This puts pregnant women, children, travelers to endemic regions, and

45

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760896/#B7



persons with coexisting HIV infection at highest risk for morbidity and mortality secondary to

malarial infection.(9)

4. CLINICAL DISEASE

Infection with malaria parasites may result in a wide variety of symptoms, ranging from

absent or very mild symptoms to severe disease and even death. Malaria disease can be

categorized as uncomplicated or severe (complicated). In general, malaria is a curable disease if

diagnosed and treated promptly and correctly.

All the clinical symptoms associated with malaria are caused by the asexual erythrocytic

or blood stage parasites. When the parasite develops in the erythrocyte, numerous known and

unknown waste substances such as hemozoin pigment and other toxic factors accumulate in the

infected red blood cell. These are dumped into the bloodstream when the infected cells lyse and

release invasive merozoites. The hemozoin and other toxic factors such as glucose phosphate

isomerase (GPI) stimulate macrophages and other cells to produce cytokines and other soluble

factors which act to produce fever and rigors and probably influence other severe

pathophysiology associated with malaria.

Plasmodium falciparum-infected erythrocytes, particularly those with mature

trophozoites, adhere to the vascular endothelium of venular blood vessel walls and do not freely

circulate in the blood. When this sequestration of infected erythrocytes occurs in the vessels of

the brain it is believed to be a factor in causing the severe disease syndrome known as cerebral

malaria, which is associated with high mortality.(10)

Pregnancy-malaria and intensity of transmission: Clinical presentation and severity of malaria

in pregnancy differ in areas of high transmission and low transmission due to differences in the

level of immunity. In high endemic areas, acquired immunity is high, mortality is less common,

asymptomatic and incidental parasitemia are not uncommon. Sequestration of MP in the placenta

and long standing placental malaria occur and peripheral blood may be negative for MP. Higher

parasitemia, particularly in II and III trimester; anemia and altered placental integrity result in

less nutritional support leading to LBW, abortion, stillbirth, premature birth and low birth

weight, and excess infant mortality/morbidity. These problems are more common in first and

46

http://www.cdc.gov/malaria/about/disease.html#severe

http://www.cdc.gov/malaria/about/disease.html#uncomplicated

second pregnancies as the parasitemia level decreases with increasing number of pregnancy. HIV

infection extends this to all pregnancies and makes it worse. The strategy for management of

malaria in pregnant population in areas of high transmission include intermittent treatment and

use of insecticide treated bednets.(14)

In areas of low transmission, the problems are dramatically different. The risk of malaria

infection during pregnancy is greater and can result in maternal death and spontaneous abortion

in up to 60% of cases. Low birth weight can occur even in cases of treated malaria; however,

silent malaria rather rare. The strategy involves measures to avoid malaria by

ITMs/chemoprophylaxis and early diagnosis and prompt treatment of cases.(14)

Table 1 : Comparison of occurrence of complications in areas of high and low transmission

Complication High Transmission Low transmission

Hypoglycemia - ++

Severe Anemia +++ +++

Pulmonary oedema - ++

ARF - ++

Hyperpyrexia + +++

Placental malaria +++ +++

LBW babies +++ +++

Abortions - +++

Congenital malaria - +++

Clinical features:

Atypical manifestations of malaria are more common in pregnancy, particularly in the 2nd half of

pregnancy.

47

Fever: Patient may have different patterns of fever - from afebrile to continuous fever, low grade

to hyper pyrexia. In 2ndhalf of pregnancy, there may be more frequent paroxysms due to

immunosuppression.

Anemia: In developing countries, where malaria is most common, anemia is a common feature

of pregnancy. Malnutrition and helminthiasis are the commonest causes of anemia. In such a

situation, malaria will compound the problem. Anemia may even be the presenting feature of

malaria and therefore all cases of anemia should be tested for MP. Anemia as a presenting

feature is more common in partially immune multigravidae living in hyperendemic areas.

Splenomegaly: Enlargement of the spleen may be variable. It may be absent or small in 2nd half

of pregnancy. A preexisting enlarged spleen may regress in size in pregnancy.

Complications: Complications tend to be more common and more severe in pregnancy. A

patient may present with complications of malaria or they may develop suddenly. Acute

pulmonary edema, hypoglycemia and anemia are more common in pregnancy. Jaundice,

convulsions, altered sensorium, coma, vomiting / diarrhoea and other complications may be seen. (14)

48

Figure 2: The pathofisiology of anemia

Malaria especially falciparum malaria: (1) Destroys red cells and so causes anaemia, which may

be megaloblastic if she also has a secondary folate deficiency. (2) Causes abortions, perinatal

deaths, premature labour, and low birthweight (IUGR, 19.13). If she is non-immune, her placenta

may be so heavily parasitized that it is black with malarial pigment. Malaria may be more serious

in areas where it is unstable, than in those in which it is stable. In an area of stable malaria, she

may only get attacks when she is pregnant, especially during the second trimester, and while she

is a primip.(14)

Antimalarials have their risks. In a village mother in an endemic area the risks lie

strongly with the parasite—she needs prophylaxis, either from the antenatal clinic, or through

PHC workers—if you can get them the drugs. For a minimally exposed visitor to an endemic

area, you will have to balance the risk of malaria against those of the drugs to prevent it.(14)

Chloroquine gives the best and safest protection against sensitive strains of P.

falciparum, and all the other malaria parasites. Proguanil is safe in pregnancy. Although the

antifolate pyrimethamine is theoretically embryopathic, it seems to be safe in practice. One

49

contributor considers it should be supplemented with folic acid, especially during the first

trimester. Avoid ’Fansidar’ (pyrimethamine/sulphadoxine) except for the treatment of

chloroquine-resistant strains (see below). ’Maloprim’ (dapsone/pyrimethamine) is controversial;

one tablet a week gives fairly good protection if there is little resistance locally to

pyrimethamine, and is said not to be embryopathic. One contributor considers it should be

supplemented with with folic acid.(14)

Figure 3: Phatofisiology

5. PATENT PARASITEMIA FOR MALARIA CAUSED BY P.VIVAX

Relapses originating from hypnozoites are characteristic of Plasmodium vivax infections.

Thus, reappearance of parasitemia after treatment can result from relapse, recrudescence, or

reinfection. It has been assumed that parasites causing relapse would be a subset of the parasites

that caused the primary infection.(15) When a parasitemia reappears after blood schizonticidal

therapy, it may be a relapse from the liver, a reinfection by a mosquito, or a recrudescence

originating from asexual blood-stage parasites that survived therapy. The emergence of CQ-

resistant P. vivax favors the last possibility.(16)

50

Renewed manifestations of malaria can be due to relapse, reinfection, recrudescence, and

recurrence.(16)

5.1 RELAPSE

Relapse is defined as renewed manifestation arising from survival of exoerythrocytic

forms (hypnozoites) either at relatively short intervals or after long period (8-24 weeks). It takes

a minimum of 8 weeks to have a relapse. It is also characterized by an asymptomatic latency

period measured in months or years,This is confined to P. Vivax and P. Ovale infections.

Relapse refers to clinical malaria caused by parasites in the bloodstream originating from

dormant liver stages called hypnozoites seeded by sporozoites from infectious anopheline

mosquitoes. Relapse may occur weeks to years following the primary episode of parasitemia and

clinical disease. Many weeks, months or even years later, these dormant liver stages can re-

activate and enter the blood again, causing new malaria symptoms. In this case, the liver was the

source of the parasites. Again, the active blood infection should be treated with anti-malarials.

Tissue schizonticides, like primaquine, prevent relapse by killing the stages of the organism in

the liver. However it is usually due to primaquine resistance or incomplete response or

inadequate primaquine treatment.(16)

Biological basis for relapses

Two species of human malaria determine a relapsing infection: P.vivax and P.ovale. In

these two species some of the liver trophozoites immediately start the exo-erythrocytic

schizogonic cycle which has been described above, while others remain into the liver in a latent

(dormant) stage for varying periods of time and are termed hypnozoites (Krotoski, 1985). The

lenght of the period of dormancy varies with the subpopulations of P.vivax and P.ovale: the

relapse, in other words, is not triggered by host factors (waning of immunity) but rather seems to

be a genetically determined intrinsic property of th e parasite. A single inoculation of sporozoites

of a relapsing species contains a mixture of genetically distinct parasites that give rise to discrete

subpopulations of exoerythrocitic trophozoites. The number of relapses, as their periodicity,

seems to be a characteristic of the parasite strain. At one side of the spectrum of possibilities is

the P.vivax hibernans strain who has a homogeneus population of sporozoites characterized by a

latency of 250 days or more. At the other side is P.vivax chesson strain with an heterogeneus

population of spor ozoites, some programmed for immediate development, others to determine

51

relapses at intervals of 2 to 3 months for a period of up to 2 years (Coatney, 1950). Actually, the

two group of st rains are considered to differ to the extent to justify their separation into two

subspecies (Garnham, 1966).(6)

5.2 REINFECTION

Reinfection is a fresh infection occurring in a patient who has suffered from Malaria and

can occur at any time after 2 weeks of the 1st attack. This may be due to persistent source of

infection such as an asymptomatic carrier or persistent malaria in the neighbourhood or

household because of high endemicity and persistent breeding centres for mosquitoes.(16) The

person could have been successfully treated, but then re-infected again by being bitten by an

infected mosquito. In these cases, the person should focus on improved malaria prevention, such

as sleeping under a long-lasting insecticide treated bednet.

5.3 RECRUDESENCE

Recrudesence is a renewed manifestation of infection due to survival of erythrocytic

forms. This occurs with Falciparum infections usually, but there are recent reports of Vivax

recrudescences too. It was originally defined as return of fever within 8 weeks of primary attack.

Recrudescence is a recurrence of malaria within days or weeks of apparent cure, without new

infection, and is caused by inadequate clearing of parasites from the bloodstream. The patient

could have recrudescence: when the patient takes medication, the treatment kills most of the

malaria parasites in the blood, and enough so the patient feels better again, but some parasites

still remain. Then, after the treatment finished, the parasite is able to replicate again, they

increase in number in the blood and the patient feels ill again. In this case, you would say the

infection came back from the blood, and the patient should take another dose of anti-malarials,

but of a different kind to that which they originally had, in order to kill all of the parasites.

Recrudescence can be due to in-complete or inadequate treatment as a result of drug resistance

or improper choice of medicate an antigenic variation, and multiple infec-tion by different

strains.

5.4 RECURRENCE

52

Recurrence is a renewed manifestation arising from an exerythrocytic source (usually

>24 weeks). This term is synonymous with long term relapse and has become obsolete. We have

used the term recurrent malaria with respect to all the causes of renewed manifestation of

malaria.

Clinical features of recurrent malaria

These patients are usually anemic and they invariably have moderate splenomegaly. They

gene rally follow all antimosquito personal prophylaxis. Ravichandran at el have reported

significant impairment of liver function tests in these patients. Sumitha et al have reported

significant fall in plasma cholesterol, phospholipids with increase in triglycerides and non--

esterified free fatty acids. Certain peculiar parasite forms and phagocytosis by neutrophils are

reported in the peripheral smear of these patients. High gametocytes, rare crisis forms,

pseudopartheno, genesis form, equatorial trophozoilas, malaria pigment containing leuocytes and

phagocytosed parasites were found inrelapsing vivax malaria. For the future, PCR, genotyping

may be able to identify the genotype of the primary attack and recurrences and help resolve the

problem of distinguishing recrudescences from reinfection. (1) Family History : If all members

of the family are suffering from res current attacks reinfection is likely. (II) History of living in a

locality which is a breeding centre for mosquitoes may suggest reinfection. (III) History of

treatment details: If chloroquine therapy was associated with vomiting inadequate chloroquine

dosage could be responsible. (IV)Peripheral smear details Mixed infections are more likely to

recur. Repeat smear examination en day 7, 14, 21, 28 after the treatment for early diagnosis of

recurrence is mandatory.

6. DIAGNOSIS OF MALARIA

Prompt and accurate diagnosis of malaria is part of effective disease management. The

diagnosis of malaria is based on clinical suspicion and on the detection of parasites in the blood

( parasitological or confirmatory diagnosis). High sensitivity of diagnosis in malaria-endemic

areas is particularly important for the most vulnerable population groups, such as young children

and the non-immune population, in whom the disease can be rapidly fatal, while high specificity

will reduce unnecessary treatment with antimalarials and improve diagnosis of other febrile

illnesses in all settings. Thus, high quality malaria diagnosis is important in all settings.(1)

53

Malaria can be suspected based on the patient's travel history, symptoms, and the

physical findings at examination. However, for a definitive diagnosis to be made, laboratory tests

must demonstrate the malaria parasites or their components.(1)

Diagnosis of malaria can be difficult:

Where malaria is not endemic any more (such as in the United States), health-care

providers may not be familiar with the disease. Clinicians seeing a malaria patient may forget to

consider malaria among the potential diagnoses and not order the needed diagnostic tests.

Laboratorians may lack experience with malaria and fail to detect parasites when examining

blood smears under the microscope.

In some malaria-endemic areas, malaria transmission is so intense that a large proportion

of the population is infected but not made ill by the parasites. Such carriers have developed just

enough immunity to protect them from malarial illness but not from malarial infection. In that

situation, finding malaria parasites in an ill person does not necessarily mean that the illness is

caused by the parasites.

6.1 Clinical Diagnosis

Clinical diagnosis is based on the patient's symptoms and on physical findings at examination.

The first symptoms of malaria (most often fever, chills, sweats, headaches, muscle pains,

nausea and vomiting) are often not specific and are also found in other diseases (such as the "flu"

and common viral infections). Likewise, the physical findings are often not specific (elevated

temperature, perspiration, tiredness). In severe malaria (caused by Plasmodium falciparum),

clinical findings (confusion, coma, neurologic focal signs, severe anemia, respiratory difficulties)

are more striking and may increase the index of suspicion for malaria.

If possible, clinical findings should always be confirmed by a laboratory test for malaria.

In addition to ordering the malaria specific diagnostic tests described below, the health-care

provider should conduct an initial workup and request a complete blood count and a routine

chemistry panel. In the event that the person does have a positive malaria test, these additional

tests will be useful in determining whether the patient has uncomplicated or severe

54

http://www.cdc.gov/malaria/about/disease.html

manifestations of the malaria infection. Specifically, these tests can detect severe anemia,

hypoglycemia, renal failure, hyperbilirubinemia, and acid-base disturbances. (8)

6.2 Microscopic Diagnosis

Microscopic examination remains the "gold standard" for laboratory confirmation of

malaria. These tests should be performed immediately when ordered by a health-care provider.

They should not be saved for the most qualified staff to perform or batched for convenience. In

addition, these tests should not be sent out to reference laboratories with results available only

days to weeks later. It is vital that health-care providers receive results from these tests within

hours in order to appropriately treat their patients infected with malaria.(8)

Technique

A blood specimen collected from the patient is spread as a thick or thin blood smear,

stained with a Romanovsky stain (most often Giemsa), and examined with a 100X oil immersion

objective. Visual criteria are used to detect malaria parasites and to differentiate (when possible)

the various species. Wright’s stain, which is commonly used in hospital laboratories for

examining blood (called a CBC with manual differential), can be used if Giemsa stain is not

available. However, species determination might be more difficult.(8)

Figure 4: Trophozoite of P. vivax in a thick blood smear.

Developing trophozoites of P. vivax become increasingly amoeboid, with tenuous

pseudopodial processes and large vacuoles. Schüffner's dots are visible with proper staining.

55

Pigment tends to be fine and brown. Infected RBCs are usually noticeably larger than uninfected

RBCs.

Figure 5: Ring-form trophozoites of P. vivax in thin blood smears

Ring-form trophozoites of P. vivax usually have a thick cytoplasm with a single, large

chromatin dot. Rings may be difficult to distinguish from those of P. ovale. The cytoplasm

becomes amoeboid and Schüffner's dots may appear as the trophozoites mature. Infected RBCs

are often larger than uninfected RBCs. Multiply-infected RBCs are not uncommon.

Advantages

Microscopy is an established, relatively simple technique that is familiar to most

laboratorians. Any laboratory that can perform routine hematology tests is equipped to perform a

thin and thick malaria smear. Within a few hours of collecting the blood, the microscopy test can

provide valuable information. First and foremost it can determine that malaria parasites are

present in the patient’s blood. Once the diagnosis is established – usually by detecting parasites

in the thick smear – the laboratorian can examine the thin smear to determine the malaria species

and the parasitemia, or the percentage of the patient’s red blood cells that are infected with

malaria parasites. The thin and thick smears are able to provide all 3 of these vital pieces of

information to the doctor to guide the initial treatment decisions that need to be made acutely.(8)

Disadvantages

Microscopy results are only as reliable as the laboratories performing the tests. In the

United States, there are, on average, 1500 cases of malaria diagnosed and reported each year.

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Thus, the average laboratorian does not perform this test regularly, and may not be maintaining

optimal proficiency.

6.3 Antigen Detection

Various test kits are available to detect antigens derived from malaria parasites. Such

immunologic ("immunochromatographic") tests most often use a dipstick or cassette format, and

provide results in 2-15 minutes. These "Rapid Diagnostic Tests" (RDTs) offer a useful

alternative to microscopy in situations where reliable microscopic diagnosis is not available.

Malaria RDTs are currently used in some clinical settings and programs. However, before

malaria RDTs can be widely adopted, several issues remain to be addressed, including improving

their accuracy; lowering their cost; and ensuring their adequate performance under adverse field

conditions. The World Health Organization is conducting comparative performance evaluations

of many of the RDTs which are commercially available worldwide based on a panel of parasites

derived from a global network of collection sites.

A Rapid Diagnostic Test (RDT) is an alternate way of quickly establishing the diagnosis

of malaria infection by detecting specific malaria antigens in a person's blood. RDTs have

recently become available in the United States.

Technique

A blood specimen collected from the patient is applied to the sample pad on the test card

along with certain reagents. After 15 minutes, the presence of specific bands in the test card

window indicate whether the patient is infected with Plasmodium falciparum or one of the other

3 species of human malaria. It is recommended that the laboratory maintain a supply of blood

containing P. falciparum for use as a positive control.

Advantages

High-quality malaria microscopy is not always immediately available in every clinical

setting where patients might seek medical attention. Although this practice is discouraged, many

healthcare settings either save blood samples for malaria microscopy until a qualified person is

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available to perform the test, or send the blood samples to commercial or reference laboratories.

These practices have resulted in long delays in diagnosis. The laboratories associated with these

health-care settings may now use an RDT to more rapidly determine if their patients are infected

with malaria.

Disadvantages

The use of the RDT does not eliminate the need for malaria microscopy. The RDT may

not be able to detect some infections with lower numbers of malaria parasites circulating in the

patient’s bloodstream. Also, there is insufficient data available to determine the ability of this test

to detect the 2 less common species of malaria, P. ovale and P. malariae. Therefore all negative

RDTs must be followed by microscopy to confirm the result.

In addition, all positive RDTs should also followed by microscopy. The currently

approved RDT detects 2 different malaria antigens; one is specific for P. falciparum and the

other is found in all 4 human species of malaria. Thus, microscopy is needed to determine the

species of malaria that was detected by the RDT. In addition, microscopy is needed to quantify

the proportion of red blood cells that are infected, which is an important prognostic indicator.(12)

6.4 Molecular Diagnosis

Parasite nucleic acids are detected using polymerase chain reaction (PCR). Although this

technique may be slightly more sensitive than smear microscopy, it is of limited utility for the

diagnosis of acutely ill patients in the standard healthcare setting. PCR results are often not

available quickly enough to be of value in establishing the diagnosis of malaria infection.

PCR is most useful for confirming the species of malarial parasite after the diagnosis has

been established by either smear microscopy or RDT.

6.5 Serology

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Serology detects antibodies against malaria parasites, using either indirect

immunofluorescence (IFA) or enzyme-linked immunosorbent assay (ELISA). Serology does not

detect current infection but rather measures past exposure.

Indirect Fluorescent Antibody Test

Malaria antibody detection is performed using the indirect fluorescent antibody (IFA)

test. The IFA procedure can be used to determine if a patient has been infected with Plasmodium.

Because of the time required for development of antibody and also the persistence of antibodies,

serologic testing is not practical for routine diagnosis of acute malaria. However, antibody

detection may be useful for:

Screening blood donors involved in cases of transfusion-induced malaria when the

donor's parasitemia may be below the detectable level of blood film examination

Testing a patient, usually from an endemic area, who has had repeated or chronic malaria

infections for a condition known as tropical splenomegaly syndrome

Testing a patient who has been recently treated for malaria but in whom the diagnosis is

questioned.

Species-specific testing is available for three of the four human species: P. falciparum, P.

vivax, and P. malariae. P. ovale antigens are not always readily available and so antibody testing

is not performed routinely. Cross reactions often occur between Plasmodium species

and Babesiaspecies. Blood stage Plasmodium species schizonts (meronts) are used as antigen.

The patient's serum is exposed to the organisms; homologous antibody, if present, attaches to the

antigen, forming an antigen-antibody (Ag-Ab) complex. Fluorescein-labeled anti-human

antibody is then added, which attaches to the patient's malaria-specific antibodies. When the

slide is examined with a fluorescence microscope, if parasites fluoresce an apple green color, a

positive reaction has occurred.

Enzyme immunoassays have also been employed as a tool to screen blood donors, but

have limited sensitivity due to use of only Plasmodium falciparum antigen instead of antigens of

all four human species.

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Indirect fluorescent antibody (IFA) test. The fluorescence indicates that the patient serum

being tested contains antibodies that are reacting with the antigen preparation (here, Plasmodium

falciparum parasites).

6.6 Drug Resistance Tests

Drug resistance tests must be performed in specialized laboratories to assess the

susceptibility to antimalarial compounds of parasites collected from a specific patient. Two main

laboratory methods are available:

In vitro tests: The parasites are grown in culture in the presence of increasing

concentrations of drugs; the drug concentration that inhibits parasite growth is used as endpoint.

Molecular characterization: Molecular markers assessed by PCR or gene sequencing also

allow the prediction, to some degree, of resistance to some drugs. CDC recommends that all

cases of malaria diagnosed in the United States should be evaluated for evidence of drug

resistance.

7. TREATMENT OF MALARIA INFECTION

Treatment of malaria depends on many factors including disease severity, the species of

malaria parasite causing the infection and the part of the world in which the infection was

acquired. The latter 2 characteristics help determine the probability that the organism is resistant

to certain antimalarial drugs. Additional factors such as age, weight, and pregnancy status may

limit the available options for malaria treatment.(1)

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It is preferable that treatment for malaria should not be initiated until the diagnosis has

been established by laboratory invest igations. "Presumptive treatment" without the benefit of

laboratory confirmation should be reserved for extreme circumstances (strong clinical suspicion,

severe disease, impossibility of obtaining prompt laboratory diagnosis). Once the diagnosis of

malaria has been made, appropriate antimalarial treatment must be initiated immediately.

Treatment should be guided by three main factors: (10)

The infecting Plasmodium species

The clinical status of the patient

The drug susceptibility of the infecting parasites as determined by the geographic area

where the infection was acquired and th e previous use of antimalarial medicines.

The infecting Plasmodium species: Determination of the infecting Plasmodium species for

treatment purposes is important for three main reasons. Firstly, P. falciparum and P. knowlesi

infections can cause rapidly progressive severe illness or death while the other species, P. vivax,

P. ovale, or P. malariae, are less likely to cause severe manifestations. Secondly, P. vivax and P.

ovale infections also require treatment for the hypnozoite forms that remain dormant in the liver

and can cause a relapsing infection. Finally, P. falciparum and P. vivax species have different

drug resistance patterns in differing geographic regions. For P. falciparum and P. knowlesi

infections, the urgent initiation of appropriate therapy is especially critical. (10)

The clinical status of the patient: Patients diagnosed with malaria are generally categorized as

having either uncomplicated or severe malaria. Patients diagnosed with uncomplicated malaria

can be effectively treated with oral antimalarials. However, patients who have one or more of the

following clinical criteria (impaired consciousness/coma, severe normocytic anemia

[hemoglobin<7], renal failure, acute respiratory distress syndrome, hypotension, disseminated

intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated

generalized convulsions, and/or parasitemia of > 5%) are considered to have manifestations of

more severe disease and should be treated aggressively with parenteral antimalarial therapy.

The drug susceptibility of the infecting parasites: Finally, knowledge of the geographic area

where the infection was acquired provides information on the likelihood of drug resistance of

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the infecting parasite and enables the treating clinician to choose an appropriate drug or drug

combination and treatment course. In addition, if a malaria infection occurred despite use of a

medicine for chemoprophylaxis, that medicine should not be a part of the treatment regimen. If

the diagnosis of malaria is suspected and cannot be confirmed, or if the diagnosis of malaria is

confirmed but species determination is not possible, antimalarial treatment effective against ch

loroquine-resistant P. falciparum must be initiated immediately. Malaria is a nationally

notifiable disease and all cases should be reported to your state health department, which are

forwarded onto the CDC. After initiation of treatment, the patient's clinical and parasitologic

status should be monitored. In infections with P. falciparum or suspected chloroquine-resistant

P. vivax , blood smears should be made to conf irm adequate parasitologic response to treatment

(decrease in parasite density).(5)

7.1 TREATMENT OF MALARIA CAUSED BY P.VIVAX, P.OVALE OR P.MALARIAE

Resistance to Therapies for Infection by Plasmodium vivaxTABLE 1.

Classes and representative antimalarial drugsa

Type of drug TargetClinical

application Prophylaxis Licensed drug(s)Experimental

drug(s)

Blood schizontocide

Trophozoite in blood

Treatment of acute malaria

Suppressive Chloroquine, quinine, mefloquine, doxycycline, AV-PG, DH-PP

Tafenoquine, ACTs

Primary tissue schizontocide

Active schizont in liver

None Causal Primaquine Tafenoquine

Hypnozoitocide Dormant hypnozoite in liver

Prevention of relapse

None Primaquine Tafenoquine, elubaquine

Gametocytocide Gametocyte in blood

Prevention of transmission

None Primaquine Tafenoquine, artesunate, artemether

Sporontocide Forms in mosquito including

Prevention of transmission

Causal prophylaxis

Primaquine Tafenoquine

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Type of drug TargetClinical

application Prophylaxis Licensed drug(s)Experimental

drug(s)

sporozoite

↵a AV-PG, atovaquone-proguanil (Malarone); DH-PP, dihydroartemisinin-piperaquine (Artekin); ACTs, artemisinin combined therapies (many in evaluation).

Resistance to Therapies for Infection by Plasmodium vivaxTABLE 2.

Malaria chemotherapeutic terminology

Term Definition

Blood schizontocides Drugs aimed at asexual blood-stage parasites to effect a cure of clinical malaria

Primary tissue schizontocide

Drug aimed at primary asexual liver-stage parasites to prevent primary blood infection

Hypnozoitocide Drugs aimed at latent asexual liver-stage parasites (hypnozoites) to prevent recurrent infection of blood, called a relapse

Gametocytocide Drugs aimed at sexual blood-stage parasites to prevent infection of mosquitoes

Sporontocide Drug aimed at stages of sporogonic development in the mosquito, including sporozoites

Radical cure Elimination of clinically relevant forms of the parasite from the body using one or more drugs

Suppressive prophylaxis Chemical suppression of patent parasitemia by a drug or drugs that are active against asexual blood stages

Causal prophylaxis Prevention of infection of blood with a drug or drugs that are active against asexual liver stages

Presumptive antirelapse therapy

Presumptive treatment with a hypnozoitocide following exposure to infection, also called terminal prophylaxis

Relapse New parasitemia originating from hypnozoites

Reinfection New parasitemia originating from new infectious mosquito bite

Recrudescence New parasitemia originating from the original parasitemia

Recurrence New parasitemia of unknown origin

P. vivax ,the second most important species causing human malaria, accounts for about

40% of malaria cases worldwide; it is the dominant malaria species outside Africa. It is prevalent

in endemic areas in the Asia, Central and South America, Middle East and Oceania. In

Africa, it is rare, except in the Horn, and it is almost absent in West Africa. In most areas where

P. vivax is prevalent, malaria transmission rates are low, and the affected populations, therefore,

achieve little immunity to this parasite. Consequently, people of all ages are at risk. The other

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two human malaria parasite species P. malariae and P. ovale are generally less prevalent, but

they are distributed worldwide, especially in the tropical areas of Africa.(1)

Among the four species of Plasmodium that affect humans, only P. vivax and P. ovale

form hypnozoites, parasite stages in the liver, which can result in multiple relapses of

infection weeks to months after the primary infection. Thus, a single infection causes repeated

bouts of illness. The objective of treating malaria caused by P. vivax and P. ovale is to cure

(radical cure) both the blood stage and the liver stage infections, and, thereby, prevent both

recrudescence and relapse, respectively. Infection with P. vivax during pregnancy, as with

P. falciparum , reduces birth weight. In primigravidae, the reduction is approximately two thirds

of that associated with P. falciparum (110 g compared with 170 g), but this adverse effect does

not decline with successive pregnancies, unlike with P. falciparum infections.(1)

The clinical features of uncomplicated malaria are too non-specific for a clinical

diagnosis of the species of malaria infection to be made. Diagnosis of P. vivax malaria is based

on microscopy. Although rapid diagnostic tests based on immunochromatographic methods are

available for the detection of non-falciparum malaria, their sensitivities below parasite densities

of 500/µl are low. Their relatively high cost is a further impediment to their wide use in

endemic areas. Molecular markers for genotyping P. vivax parasites have been developed

to assist epidemiological and treatment studies, but these are still under evaluation.(1)

Treatment : P. vivax and P. ovale

Chloroquine (or hydroxychloroquine) remains an effective choice for all P. vivax and P.

ovale infections except for P. vivax infections acquired in Papua New Guinea or Indonesia. The

regimens listed for the treatment of P. falciparum are also effective and may be used. Reports

have confirmed a high prevalence of chloroquine-resistant P. vivax in these two specific areas.

Rare cases of chloroquine-resistant P. vivax have also been documented in Burma (Myanmar),

India, and Central and South America. Persons acquiring P. vivax infections from regions other

than Papua New Guinea or Indonesia should initially be treated with chloroquine. If the patient

does not respond to chloroquine, treatment should be changed to one of the two regimens

recommended for chloroquine-resistant P. vivax infections. Persons acquiring P. vivax

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infections in Papua New Guinea or Indonesia should initially be treated with a regimen

recommended for chloroquine-resistant P. vivax infections. The three treatment regimens for

chloroquine-resistant P. vivax infections are quinine sulfate plus doxycycline or tetracycline, or,

Atovaquone-proguanil, or mefloquine. These three treatment options are equally recommended.

In addition to requiring blood stage treatment, infections with P. vivax and P. ovale can relapse

due to hypnozoites that remain dormant in the liver. To eradicate the hypnozoites, patients

should be treated with a 14-day course of primaquine phosphate. CDC recommends a

primaquine phosphate dose of 30 mg (base) by mouth daily for 14 days. Because primaquine

can cause hemolytic anemia in persons with glucose-6-phosphate-dehydrogenase (G6PD)

deficiency, persons must be screened for G6PD deficiency prior to starting primaquine treatment.

For persons with borderline G6PD deficiency or as an alternate to the above regimen,

primaquine may be given at the dose of 45 mg (base) orally one time per week for 8 weeks;

consultation with an expert in infectious disease and/or tropical medicine is advised if this

alternative regimen is considered in G6PD-deficient persons. Primaquine must not be used

during pregnancy. For pediatric patients, the treatment options are the same as for adults except

the drug dose is adjusted by patient weight. The pediatric dose should never exceed the adult

recommended adult dose. For children less than 8 years old, doxycycline and tetracycline are

generally not indicated; therefore, for chloroquine-resistant P. vivax, mefloquine is the

recommended treatment. If it is not available or is not being tolerated and if the treatment

benefits outweigh the risks, atovaquone-proguanil or artemether-lumefantrine should be used

instead.Primaquine should be given to pediatric patients only af ter they have been screened for

G6PD deficiency.(5)

7.2 SUSCEPTIBILITY OF P.VIVAX AND P.MALARIAE TO ANTIMALARIALS

There are very few recent data on the in vivo susceptibility of P. ovale and P. malariae to

antimalarials. Both species are regarded as very sensitive to chloroquine, although there is

a single recent report of chloroquine resistance in P. malariae . Experience indicates that P.

ovale and P. malariae are also susceptible to amodiaquine, mefloquine and the artemisinin

derivatives. Their susceptibility to antifolate antimalarials, such as sulfadoxine-pyrimethamine, is

less certain. P. vivax susceptibility has been studied extensively and, now that short-term

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culture methodologies have been standardized, clinical studies have been supported by in vitro

observations. P. vivax is generally still sensitive to chloroquine, although resistance is

prevalent and increasing in some areas (notably Indonesia, Peru and Oceania). Resistance to

pyrimethamine has increased rapidly in some areas, and sulfadoxine-pyrimethamine is,

consequently, ineffective. There are insufficient data on current susceptibility to proguanil

and chlorproguanil, although resistance to proguanil was selected rapidly when it was first

used in P. vivax endemic areas.

In general, P. vivax is sensitive to all the other antimalarial drugs and slightly less

sensitive to mefloquine (although mefloquine is still effective). In contrast to P. falciparum ,

asexual stages of P. vivax are susceptible to primaquine. Thus, chloroquine plus primaquine

can be considered as a combination treatment. The only drugs with significant activity against

the hypnozoites are the 8-aminoquinolines (buloquine, primaquine, tafenoquine).

There is no standardized in vitro method of drug assessment for hypnozoiticidal activity.

In vivo assessment suggests that tolerance of P. vivax to primaquine in eastern Asia and

Oceania is greater than elsewhere.

7.3 TREATMENT OF UNCOMPLICATED VIVAX MALARIA

7.3.1 Blood stage infection

For chloroquine-sensitive vivax malaria (i.e. in most places where P. vivax is

prevalent), oral chloroquine at a total dose of 25 mg base/kg body weight is effective and well

tolerated. Lower total doses are not recommended, as these might encourage the

emergence of resistance. Chloroquine is given in an initial dose of 10 mg base/kg body weight

followed by either 5 mg/kg body weight at 6 h, 24 h and 48 h or, more commonly, by 10 mg/kg

body weight on the second day and 5 mg/kg body weight on the third day. Recent studies have

also demonstrated the efficacy of the recommended artemisinin-based combination therapy

(ACTs) in the treatment of vivax malaria. The exception to this is artesunate plus sulfadoxine-

pyrimethamine. Though there has been one study from Afghanistan reporting good efficacy to

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AS+SP, it appears that P. vivax has developed resistance to sulfadoxine-pyrimethamine more

rapidly than P. falciparum has; hence, artesunate plus sulfadoxine- pyrimethamine may not be

effective overall against P. vivax in many areas.

7.3.2 Chloroquine-resistant vivax malaria

There is evidence that amodiaquine, mefloquine and quinine are effective in the

treatment of chloroquine-resistant P. vivax malaria. ACTs based on either amodiaquine,

mefloquine or piperaquine, rather than monotherapy, are the recommended treatment of choice.

Two trials have compared DHA+PPQ to alternative ACTs (AL6 and AS+AQ) in Indonesia.

There are no trials comparing DHA+PPQ and AS+MQ in P. vivax mono-infection.

7.3.3 Liver stage infection

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To achieve a radical cure, relapses must be prevented by giving primaquine. The

frequency and pattern of relapses varies geographically. Whereas 50–60% of P. vivax

infections in South-East Asia relapse, the frequency is lower in Indonesia (30%) and the

Indian subcontinent (15–20%). Some P. vivax infections in the Korean peninsula (now the most

northerly of human malarias) have an incubation period of nearly one year. Moreover, the P.

vivax populations emerging from hypnozoites commonly differ from the populations that caused

the acute episode. Activation of heterologous hypnozoites populations is the most common

cause of the first relapse in patients with vivax malaria. Thus, the preventive efficacy of

primaquine must be set against the prevalent relapse frequency. It appears that the total dose of

8-aminoquinoline given is the main determinant of curative efficacy against liver-stage

infection. In comparison with no primaquine treatment, the risk of relapse decreased by the

additional milligram per kilogram body weight of primaquine given. Primaquine should be given

for 14 days.

A Cochrane Review14 reports both direct and indirect comparison of a 14-day versus 5-

day regimen of primaquine. The review reports indirect evidence of the superiority of the 14-day

regimen. No difference has been shown between the 5-day regimen and chloroquine alone (3

trials, 2104 participants; odds ratio [OR] 1.04, 95% CI 0.64–1.69), while the 14-day

regimen is significantly better at reducing relapses (6 trials, 1072 participants; OR 0.24, 95% CI

0.12–0.45). The usual adult oral dose is 15 mg base (0.25 mg/kg body weight per day), but in

South-East Asia, particularly Indonesia, and in Oceania, higher doses (0.5 mg base/kg body

weight per day) are required. Primaquine causes abdominal discomfort when taken on an

empty stomach; it should always be taken with food. There has been debate as to whether

primaquine should be given in endemic areas. Repeated vivax malaria relapses are

debilitating at any age, and so they must be prevented. However, in situations where

transmission is intense with a high rate of re-infection, simply preventing relapses is

unlikely to lower the incidence of infection or disease. Therefore, in areas of sustained

high transmission, the benefits of the widespread deployment of primaquine are not

considered to outweigh the risks associated with this medication. In low-transmission areas, on

the other hand, the benefits of primaquine in preventing relapses will exceed its risks and its

routine use to prevent relapses is recommended in patients who are not G6PD-deficient.

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i) Treatment : severe P. vivax malaria

Although P. vivax malaria is considered to be benign malaria, with a very low case-

fatality ratio, it may still cause a severe and debilitating febrile illness. It can also occasionally

result in severe disease, as in P. falciparum malaria. Severe P. vivax malaria manifestations

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that have been reported are cerebral malaria, severe anaemia, severe thrombocytopenia and

pancytopenia, jaundice, splenic rupture, acute renal failure and acute respiratory distress

syndrome. Severe anaemia and acute pulmonary oedema are not uncommon. The underlying

mechanisms of severe manifestations are not fully understood. Prompt and effective treatment

and case management should be the same as for severe and complicated falciparum

malaria.

ii) Monitoring therapeutic efficacy for vivax malaria

The antimalarial sensitivity of vivax malaria needs monitoring to track and respond

to emerging resistance to chloroquine. The 28-day in vivo test for P. vivax is similar to that for

P.falciparum, although the interpretation is slightly different. Genotyping can distinguish a

relapse or recrudescence from acquisition of a new infection, but it is not possible to distinguish

reliably between a relapse and a recrudescence as they derive from the same infection. Relapse

is unlikely if parasitaemia recurs within 16 days of administering treatment but, after that time,

relapse cannot be distinguished from a recrudescence. Any P.vivax infection that recurs within

28 days, whatever its origin, must be resistant to chloroquine (or any other slowly eliminated

antimalarial) provided adequate treatment has been given. In the case of chloroquine, adequate

absorption can be confirmed by measurement of the whole blood concentration at the time of

recurrence. Any P.vivax infection that has grown in vivo through a chloroquine blood

concentration of > 100 ng/ml must be chloroquine resistant. Short-term in vitro culture allows

assessment of in vitro susceptibility. There are no molecular markers yet identified for

chloroquine resistance. Antifolate resistance can be monitored by molecular genotyping of the

gene that encodes dihydrofolate reductase (Pvdhf r). Since ACTs are increasingly being used for

the treatment of vivax infections in situations where it is resistance to chloroquine, the

sensitivity of P. vivax to ACTs must also be routinely monitored.

iii) Areas prone to vivax malaria epidemics

In areas with pure P. vivax epidemics, and where drug resistance has not been reported,

chloroquine is the most appropriate medicine once the cause of the epidemic has been

established. Resistance of P. vivax to chloroquine has been reported from Oceania and South-

East Asia, but it is probably limited in distribution. Though there is insufficient knowledge at

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present to allow specific recommendations to be made for treatment of P. vivax

epidemics in areas of suspected resistance.(1)

iv) Anti-relapse therapy in vivax malaria epidemics

The 14-day anti-relapse therapy for vivax malaria is impractical in most epidemic

situations because of the duration of treatment and poor compliance. Moreover, it is not an

effective strategy as long as the risk of re-infection is high. If adequate records are kept, anti-

relapse therapy can be given in the post-epidemic period to patients who have previously been

treated with blood schizonticides. Primaquine 0.25–0.5 mg base/kg body weight in two divided

daily doses should be given for 14 days, as there is no evidence that shorter courses are effective.

Appropriate health education should be provided to encourage adherence in situations where

primaquine is given without supervision.(1)

8. TREATMENT NOT RECOMMENDED

Several other supportive strategies and interventions have been used in severe malaria

patients in an effort to further reduce the mortality, but very few are supported by

evidence of benefit and many have proved harmful. Heparin, prostacyclin, desferoxamine,

pentoxifylline, low molecular weight dextran, urea, high-dose corticosteroids, acetylsalicylic

acid, deferoxamine, anti-tumour necrosis factor antibody, cyclosporin, dichloroacetate,

adrenaline and hyperimmune serum are not recommended. In addition, the use of corticosteroids

increases the risk of gastrointestinal bleeding and seizures, and has been associated with

prolonged coma resolution times when compared with placebos.

8.1 Fluid therapy

The degree of fluid depletion varies considerably in patients with severe malaria. As a

result, it is not possible to give general recommendations on fluid replacement. Each patient must

be individually assessed and fluid resuscitation based on estimated deficit. In high-transmission

settings, children commonly present with severe anaemia and hyperventilation (sometimes

termed “respiratory distress”) resulting from severe metabolic acidosis and anaemia; they

should be treated by blood transfusion. In general, children tolerate rapid fluid resuscitation

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better than adults; they are less likely to develop pulmonary oedema. In adults, there is a very

thin dividing line between over-hydration, which may produce pulmonary oedema, and

under-hydration contributing to shock, worsening acidosis and renal impairment. Careful and

frequent evaluations of the jugular venous pressure, peripheral perfusion, venous filling, skin

turgor and urine output should be made. Where the nursing facilities permit, a central venous

catheter should be inserted and the central venous pressure measured directly (target 0–5 cm

H2O).

8.2 Blood transfusion

Severe malaria is associated with rapid development of anaemia as infected and

uninfected erythrocytes are haemolysed and/or removed from the circulation by the spleen.

Ideally fresh cross-matched blood should be transfused. However, in most settings cross-

matched virus-free blood is in short supply. As with fluid resuscitation, there have not

been enough studies to provide strong evidence-based recommendations on the indications for

transfusion, so the recommendations given here are based on expert opinion. In high-

transmission settings, blood transfusion is generally recommended for children with a

haemoglobin level of < 5 g/100ml (haematocrit < 15%). In low-transmission settings, a

threshold of 20% (haemoglobin 7 g/100 ml) is recommended. However, these general

recommendations still need to be tailored to the individual, as the pathological consequences of

rapid development of anaemia are worse than those of chronic or acute anaemia where there has

been adaptation and a compensatory right shift in the oxygen dissociation curve.

8.3 Exchange blood transfusion

There have been many anecdotal reports and several series claiming benefit for exchange

blood transfusion (EBT) in severe malaria but no comparative trials, and there is no

consensus on whether it reduces mortality or how it might work. The rationale for EBT has been

variously proposed as:

Removing infected red blood cells from the circulation and,therefore, lowering the

parasite burden (although only the circulating relatively non-pathogenic stages are removed;

this is also achieved rapidly with artemisinin derivatives), reducing rapidly both the antigen load

and the burden of parasite-derived toxins, metabolites and toxic mediators produced by the host;

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and replacing the rigid unparasitized red cells by more deformable cells and, therefore,

alleviating microcirculatory obstruction.

Exchange blood transfusion requires intensive nursing care and a relatively large volume

of blood, and it carries significant risks. There is no consensus on the indications, benefits and

dangers involved, or on practical details such as the volume of blood that should be exchanged. It

is, therefore, not possible to make any recommendation regarding the use of EBT.

8.4 Use of anticonvulsants

The treatment of convulsions in cerebral malaria with intravenous (or, if this is

not possible, rectal) benzodiazepines or intramuscular paraldehyde is similar to that for

repeated seizures from any cause. In a large double-blind placebo-controlled evaluation of a

single prophylactic intramuscular injection of 20 mg/kg body weight of phenobarbital

(phenobarbitone) in children with cerebral malaria there was a reduction in seizures, but a

significant increase in mortality in phenobarbital recipients. This resulted from respiratory

arrest, and it was associated with additional benzodiazepine use. A 20 mg/kg dose of

phenobarbital should not be given without respiratory support, but whether a lower dose

would be effective and safer, or whether if ventilation is given, mortality would not be increased

is not known. In the absence of further information, prophylactic anticonvulsants are not

recommended.

8.5 Concomitant use of antibiotics

The threshold for administering antibiotic treatment should be low in severe malaria.

Septicaemia and severe malaria are associated and there is a diagnostic overlap, particularly in

children. Unexplained deterioration may result from a supervening bacterial infection. Although

enteric bacteria (notably Salmonella) have predominated in most trial series, a variety of bacteria

have been cultured from the blood of patients diagnosed as having severe malaria; so broad-

spectrum antibiotic treatment should be given initially until a bacterial infection is excluded..

73

9. TREATMENT DURING PREGNANCY

Pregnant women with symptomatic acute malaria are a high-risk group, and they must

promptly receive effective antimalarial treatment. Malaria in pregnancy is associated with low

birth weight, increased anaemia and, in low-transmission areas, an increased risk of severe

malaria and death. In high-transmission settings, despite the adverse effects on fetal growth,

malaria is usually asymptomatic in pregnancy or associated with only mild, non-specific

symptoms.(1)

Women in the second and third trimesters of pregnancy are more likely to develop severe

malaria than other adults, and, in low-transmission settings, this is often complicated by

pulmonary oedema and hypoglycaemia. Maternal mortality is approximately 50%, which is

higher than in non-pregnant adults. Fetal death and premature labour are common. Parenteral

antimalarials should be given to pregnant women with severe malaria in full doses without

delay. Parenteral artesunate is preferred over quinine in the second and third trimesters, because

quinine is associated with recurrent hypoglycaemia. In the first trimester, the risk of

hypoglycaemia is lower and the uncertainties over the safety of the artemisinin derivatives are

greater. However, weighing these risks against the evidence that artesunate reduces the risk of

death from severe malaria, both artesunate and quinine may be considered as options until

more evidence becomes available. Treatment must not be delayed; so if only one of the drugs

artesunate, artemether or quinine is available, then it should be started immediately.(1)

There is insufficient information on the safety and efficacy of most antimalarials in

pregnancy, particularly for exposure in the first trimester.(1)

First trimester

Organogenesis occurs mainly in the first trimester; this is, therefore, the time of greatest

concern for potential teratogenicity, although development of the nervous system continues

throughout pregnancy. Although data from prospective studies are limited, antimalarial

medicines considered safe in the first trimester of pregnancy are quinine, chloroquine,

clindamycin and proguanil. Pregnant women in the first trimester with uncomplicated

falciparum malaria should be treated with quinine plus clindamycin for seven days (and quinine

74

monotherapy if clindamycin is not available). Artesunate plus clindamycin for seven days is

indicated if this treatment fails.(1)

In reality, women often do not declare their pregnancies in the first trimester or are not

yet aware that they are pregnant; so all women of child bearing age should be asked about the

possibility of their being pregnant before being given antimalarials, a standard practice for the

administration of any medicine in potentially pregnant women. Nevertheless, early pregnancies

will often be exposed inadvertently to the available first-line treatment in the population, mostly

ACTs. Published prospective data on a limited number of exposed pregnancies in the first

trimester (n = 123) indicate no adverse effects of artemisinins (and the partner drugs) on

pregnancy or on the health of the fetus and neonates. The available data are sufficient to exclude

a 5.3-fold or greater increase in risk of overall major birth defects and provide assurance in

counselling women following early first trimester exposure, indicating that there is no need

for them to seek to have their pregnancy interrupted because of this exposure. However,

more data on the safety of artemisinins in early pregnancy are urgently needed. The recently

introduced Pregnancy Exposure.Registry will shed more light on the risks to patients in the first

trimester of pregnancy who are inadvertently exposed to antimalarials, including ACTs.

Second and third trimesters

There is increasing experience with artemisinin derivatives in the second and third

trimesters (over 1500 documented pregnancies). There have been no adverse effects on the

mother or fetus. The current assessment of benefits compared with potential risks suggests that

the artemisinin derivatives should be used to treat uncomplicated falciparum malaria in the

second and third trimesters of pregnancy. The choice of combination partner is difficult because

of limited information. Mefloquine monotherapy has been associated with an increased risk of

stillbirth in large studies in Thailand, but not in Malawi. The current standard six-dose

artemether plus lumefantrine regimen has been evaluated in 125 women in the second and third

trimesters in a controlled trial for the treatment of uncomplicated falciparum malaria on the

Burmese-Thai border. It was well tolerated and safe, but efficacy was inferior to seven

days of artesunate monotherapy. Reduced efficacy probably resulted from low drug

concentrations in later pregnancy. Although many pregnant women in Africa have been exposed

to artemether plus lumefantrine in the second and third trimesters of pregnancy, formal studies

75

to evaluate its efficacy and safety in pregnant women in Africa are still ongoing. Similarly, many

pregnant women in Africa have been treated with amodiaquine alone or combined with SP or

artesunate; however the use of amodiaquine in pregnancy has only been documented in just

over 500 pregnancies (with safety assessments in 450 of them). Amodiaquine use in Ghanaian

pregnant women in the second and third trimesters was associated with frequent minor side

effects, but it was not associated with liver toxicity or bone marrow depression or adverse

neonatal outcome. There is no published information about the combination of amodiaquine and

artesunate.

On the Burmese-Thai border, DHA+PPQ has been used successfully in the second and

third trimesters of pregnancy in 50 women for rescue therapy and for treatment in 104 pregnant

women in West Papua province (Indonesia). Sulfadoxine-pyrimethamine, though considered

safe, is compromised for treatment in many areas because of increasing resistance. If AS+SP is

used for treatment, the co-administration of high dose (5 mg) daily folate supplementation

should be avoided as this compromises the efficacy of SP in pregnancy. Lower folate dosing

(0.4–0.5 mg/day) should be used in women receiving AS+SP for the treatment of malaria, or

treatments other than SP should be used. Clindamycin is also considered safe, but it must be

given for seven days in combination with quinine. Quinine is associated with an increased

risk of hypoglycaemia in late pregnancy, and it should be used only if effective alternatives are

not available. Primaquine and tetracyclines should not be used in pregnancy.

76

Lactating women

The amounts of antimalarials that enter breast milk and are consumed by the

breastfeeding infant are relatively small. Tetracycline is contraindicated in breastfeeding

mothers because of its potential effect on the infant’s bones and teeth. Primaquine should

not be used in nursing women, unless the breastfed infant has been determined not to be G6PD-

deficient.

i) Alternatives For Pregnant Women with uncomplicated malaria.

Malaria infection in pregnant women is associated with high risks of both maternal and

perinatal morbidity and mortality. While the mechanism is poorly understood, pregnant women

have a reduced immune response and therefore less effectively clear malaria infections. In

addition, malaria parasites sequester and replicate in the placenta. Pregnant women are three

times more likely to develop severe disease than non-pregnant women acquiring infections from

the same area. Malaria infection during pregnancy can lead to miscarriage, premature delivery,

low birth weight, congenital infection, and/or perinatal death.

For pregnant women diagnosed with uncomplicated malaria caused by P. malariae, P.

vivax, P. ovale, or chloroquine-sensitive P. falciparum infection, prompt treatment with

77

chloroquine (treatment schedule as with non-pregnant adult patients) is recommended.

Alternatively, hydroxychloroquine may be given instead. For pregnant women diagnosed with

uncomplicated malaria caused by chloroquine-resistant P. falciparum infection, prompt

treatment with either mefloquine or a combination of quinine sulfate and clindamycin is

recommended. Quinine treatment should continue for 7 days for infections acquired in Southeast

Asia and for 3 days for infections acquired elsewhere; clindamycin treatment should continue for

7 days regardless of where the infection was acquired. For pregnant women diagnosed with

uncomplicated malaria caused by chloroquine-resistant P. vivax infection, prompt treatment with

mefloquine is recommended. Doxycycline and tetracycline are generally not indicated for use in

pregnant women. However, in rare instances, doxycycline or tetracycline can be used in

combination with quinine if other treatment options are not available or are not being tolerated,

and the benefit of adding doxycycline or tetracycline is judged to ou tweigh the risks. According

to its U.S. labels, atovaquone/proguanil and artemether-lumefantrine are classified as a

pregnancy category C medications and are generally not indicated for use in pregnant women

because there are no adequate, well-controlled studies in pregnant women. However, for

pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P.

falciparum infection, atovaquone -proguanil or artemether lumefantrine may be used if other

treatment options are not available or are not being tolerated, and if the potential benefit is

judged to outweigh the potential risks. For P. vivax or P. ovale infections, primaquine

phosphate for radical treatment of hypnozoites should not be given during pregnancy. Pregnant

patients with P. vivax or P. ovale infections should be maintained on chloroquine prophylaxis

for the duration of their pregnancy. The chemoprophylactic dose of chloroquine phosphate is

300mg base (=500 mg salt) orally once per week. After delivery, pregnant patients with P. vivax

or P. ovale infections who do not have G6PD deficiency should be treated with primaquine.

Pregnant women di agnosed with severe malaria should be treated aggressively with parenteral

anti malarial therapy .(10)

Obstetric advice should be sought at an early stage, the paediatricians alerted, and blood

glucose checked frequently. Hypoglycaemia should be expected, and it is often recurrent if the

patient is receiving quinine. Severe malaria may also present immediately following delivery.

Postpartum bacterial infection is a common complication in these cases.

78

10. MALARIA ENDEMICITY AREA

General considerations

Malaria is a common and life-threatening disease in many tropical and subtropical areas.

It is currently endemic in over 100 countries, which are visited by more than 125 million

international travellers every year. Each year many international travellers fall ill with malaria

while visiting countries where the disease is endemic, and well over 10 000 are reported to fall ill

after re-turning home; however, underreporting means that the real figure may be as high as 30

000. International travellers from non-endemic areas are at high risk of malaria and its

consequences because they lack immunity. Immigrants from endemic areas who now live in non-

endemic areas and return to their home countries to visit friends and relatives are similarly at risk

because of waning or absent immunity. Fever occurring in a traveller within 3 months of leaving

a malaria-endemic area is a medical emergency and should be investigated urgently. Travellers

who fall ill during travel may find it difficult to access reliable medical care. Travellers who

develop malaria upon return to a non-endemic country pres -ent particular problems: doctors

may be unfamiliar with malaria, the diagnosis may be delayed, and effective antimalarial

medicines may not be registered and/or available, resulting in progression to severe and

complicated malaria and, con -sequently, high case-fatality rates.(12)

10.1 HIGH TRASMISSION AREAS

Malaria transmission occurs in many tropical and subtropical countries. Where malaria is

found depends mainly on climatic factors such as temperature, humidity, and rainfall. Malaria is

transmitted in tropical and subtropical areas, where

Anopheles mosquitoes can survive and multiply

Malaria parasites can complete their growth cycle in the mosquitoes (“extrinsic

incubation period”)

79

Temperature is particularly critical. For example, at temperatures below 20°C

(68°F),Plasmodium falciparum (which causes severe malaria) cannot complete its growth cycle

in theAnopheles mosquito, and thus cannot be transmitted.

10.2 MALARIA TRANSMISSION LIMITS IN INDONESIA

The spatial limits of Plasmodium vivax defined by Annual Parasite Incidence and the

temperature mask.(11)

Areas were defined as stable (dark grey areas, where PvAPI≥0.1 per 1,000 pa), unstable

(medium grey areas, where PvAPI<0.1 per 1,000 pa), or no risk (light grey, where PvAPI = 0 per

1,000 pa).

80

Plasmodium vivax

Plasmodium falciparum

P. falciparum/P. vivax malaria risk is classified into no risk, unstable risk of <0.1 case per 1,000

population (API), low stable risk of ≥0.1 to <1.0 case per 1,000 population (API), and stable risk

of ≥1.0 case per 1,000 population (API). Risk was defined using health management information

system data and the transmission limits were further refined using temperature and aridity data.

Data from the international travel and health guidelines (ITHG) were used to identify zero risk in

certain cities, islands and other administrative areas.(10)

10.3 Risk for travellers

81

During the transmission season in malaria-endemic areas, all non-immune travellers

exposed to mosquito bites, especially between dusk and dawn, are at risk of malaria. This

includes previously semi-immune travellers who have lost or partially lost their immunity during

stays of 6 months or more in non-endemic areas. Children of such migrants to non-endemic areas

are particularly at risk when they return to malarious areas to visit friends and relatives.

Most cases of falciparum malaria in travellers occur because of poor adherence to, or

complete failure to use, prophylactic drug regimens, or use of inappropriate medicines, combined

with failure to take adequate precautions against mosquito bites. Studies on travellers’

behaviour have shown that adherence to treatment can be improved if travellers are informed

of the risk of infection and believe in the benefit of prevention strategies. Late-onset vivax and

ovale malaria may occur despite effective prophylaxis, as they cannot be prevented with

currently recom -mended prophylactic regimens which act only against blood-stage parasites.

Malaria risk is not evenly distributed where the disease is prevalent. Travellers to

countries where the degree of malaria transmission varies in different areas should seek advice

on the risk in the particular zones that they will be visiting. If specific information is not

available before travelling, it is recommended that precautions appropriate for the highest

reported risk for the area or country should be taken; these precautions can be adjusted when

more information becomes available on arrival. This applies particularly to individuals

backpacking to remote places and visiting areas where diagnostic facilities and medical care are

not readily available. Travellers staying overnight in rural areas may be at highest risk. Culturally

sensi -tive approaches are needed to advise different groups of travellers.

Travellers to forested areas of South-East Asia where human P. knowlesi infections have

been reported should protect themselves against mosquito bites between dusk and dawn to

prevent infection and take the usual chemoprophylaxis where indicated (Country list).

Precautions

Travellers and their advisers should note the four principles – the ABCD – of

malaria protection:

82

Be Aware of the risk, the incubation period, the possibility of delayed onset, and the main

symptoms.

Avoid being Bitten by mosquitoes, especially between dusk and dawn.

Take antimalarial drugs ( Chemoprophylaxis) when appropriate, to prevent infection

from developing into clinical disease.

Immediately seek Diagnosis and treatment if a fever develops 1 week or more after

entering an area where there is a malaria risk and up to 3 months (or, rarely, later) after

departure from a risk area.

Protection against mosquito bites

All travellers should be advised that individual protection from mosquito bites between

dusk and dawn is their first line of defence against malaria. Practical measures for

protection are described in Chapter 3, in the section “Protection against vectors”.

Chemoprophylaxis

The most appropriate chemoprophylactic antimalarial drug(s) (if any) for the

destination(s) should be prescribed in the correct dosages.

Travellers and their doctors should be aware that NO ANTIMALARIAL

PROPHYLACTIC REGIMEN GIVES COMPLETE PROTECTION, but good

chemoprophylaxis (adherence to the recommended drug regimen) does reduce the risk of fatal

disease. The following should also be taken into account:

Dosing schedules for children should be based on body weight.

Antimalarials that have to be taken daily should be started the day before arrival

in the risk area (or earlier if drug tolerance needs to be tested before departure).

Weekly chloroquine should be started 1 week before arrival.

83

Weekly mefloquine should preferably be started 2–3 weeks before departure, to achieve

higher pre-travel blood levels and to allow side-effects to be detected before travel so that

possible alternatives can be considered.

All prophylactic drugs should be taken with unfailing regularity for the duration of the

stay in the malaria risk area, and should be continued for 4 weeks after the last possible exposure

to infection, since parasites may still emerge from the liver during this period. The single

exception is atovaquone–proguanil, which can be stopped 1 week after return because of its

effect on early liver-stage parasites (“liver schizonts”); premature interruption of its daily

prophylaxis regimen may lead to loss of the causal prophylactic effect, in which case

atovaquone–proguanil prophylaxis should also be continued for 4 weeks upon return.

Depending on the type of malaria at the destination, travellers should be advised about

possible late-onset P. ovale and P. vivax. Depending on the malaria risk in the area visited

(Country list), the recom-mended prevention method may be mosquito bite prevention only, or

mosquito bite prevention in combination with chemoprophylaxis or stand-by emergency

treatment, as follows.

84

All antimalarial drugs have specific contraindications and possible side-effects.

Adverse reactions attributed to malaria chemoprophylaxis are common, but most are minor and

do not affect the activities of the traveller. Serious adverse events – defined as constituting an

apparent threat to life, requiring or prolonging hos -pitalization, or resulting in persistent or

significant disability or incapacity – are rare and normally identified in post-marketing

surveillance once a drug has been in use for some time. Severe neuropsychiatric disturbances

(seizures, psychosis, encephalopathy) occur in approximately 1 in 10 000 travellers receiving

mefloquine prophylaxis, and have also been reported for chloroquine at a similar rate. For

malaria prophylaxis with atovaquone–proguanil or doxycycline, the risks of rare serious adverse

events have not yet been established. The risk of drug-associated adverse events should be

weighed against the risk of malaria, especially P. falciparum malaria, and local drug-resistance

patterns.

Each of the antimalarial drugs is contraindicated in certain groups and indi-

viduals, and the contraindications should be carefully observed to reduce the risk of serious

adverse reactions. Pregnant women, people travelling with young children, and people with

85

chronic illnesses should seek individual medical advice. Any traveller who develops severe

side-effects to an antima-larial should stop taking the drug and seek immediate medical

attention. This applies particularly to neurological or psychological disturbances experienced

with mefloquine prophylaxis. Mild nausea, occasional vomiting or loose stools should not

prompt discontinuation of prophylaxis, but medical advice should be sought if symptoms persist.

Considerations when choosing a drug for malaria prophylaxis:

Recommendations for drugs to prevent malaria differ by country of travel and can be found

in the country-specific tables of the Yellow Book. Recommended drugs for each country are

listed in alphabetical order and have comparable efficacy in that country.

No antimalarial drug is 100% protective and must be combined with the use of personal

protective measures, (i.e., insect repellent, long sleeves, long pants, sleeping in a mosquito-

free setting or using an insecticide-treated bednet).

For all medicines, also consider the possibility of drug-drug interactions with other medicines

that the person might be taking as well as other medical contraindications, such as drug

allergies.

When several different drugs are recommended for an area, the following table might help in

the decision process.

DrugReasons that might make you

consider using this drug

Reasons that might make you

avoid using this drug

Atovaquone/Proguanil

(Malarone)-Good for last-minute travelers

because the drug is started 1-2 days

before traveling to an area where

malaria transmission occurs

-Some people prefer to take a daily

medicine

-Good choice for shorter trips

-Cannot be used by women who

are pregnant or breastfeeding a

child less than 5 kg

-Cannot be taken by people with

severe renal impairment

-Tends to be more expensive than

some of the other options

86

http://www.cdc.gov/malaria/travelers/country_table/index.html





because you only have to take the

medicine for 7 days after traveling

rather than 4 weeks

-Very well tolerated medicine – side

effects uncommon

-Pediatric tablets are available and

may be more convenient

(especially for trips of long

duration)

-Some people (including children)

would rather not take a medicine

every day

Chloroquine

-Some people would rather take

medicine weekly

-Good choice for long trips because

it is taken only weekly

-Some people are already taking

hydroxychloroquine chronically for

rheumatologic conditions. In those

instances, they may not have to take

an additional medicine

-Can be used in all trimesters of

pregnancy

-Cannot be used in areas with

chloroquine or mefloquine

resistance

-May exacerbate psoriasis

-Some people would rather not

take a weekly medication

-For trips of short duration, some

people would rather not take

medication for 4 weeks after travel

-Not a good choice for last-minute

travelers because drug needs to be

started 1-2 weeks prior to travel

Doxycycline-Some people prefer to take a daily

medicine

-Good for last-minute travelers



-Cannot be used by pregnant

women and children <8 years old


take a medicine every day


87






-Tends to be the least expensive

antimalarial

-Some people are already taking

doxycycline chronically for

prevention of acne. In those

instances, they do not have to take

an additional medicine

-Doxycycline also can prevent some

additional infections (e.g.,

Rickettsiae and leptospirosis) and so

it may be preferred by people

planning to do lots of hiking,

camping, and wading and swimming

in fresh water



-Women prone to getting vaginal

yeast infections when taking

antibiotics may prefer taking a

different medicine

-Persons planning on considerable

sun exposure may want to avoid

the increased risk of sun

sensitivity

-Some people are concerned about

the potential of getting an upset

stomach from doxycycline

Mefloquine

(Lariam)-Some people would rather take

medicine weekly

-Good choice for long trips because

it is taken only weekly

-Can be used during pregnancy

-Cannot be used in areas with

mefloquine resistance

-Cannot be used in patients with

certain psychiatric conditions

-Cannot be used in patients with a

seizure disorder

-Not recommended for persons

with cardiac conduction

abnormalities

-Not a good choice for last-minute

88





travelers because drug needs to be

started at least 2 weeks prior to

travel


take a weekly medication




Primaquine -It is the most effective medicine for

preventing P. vivax and so it is a

good choice for travel to places with

> 90% P. vivax

-Good choice for shorter trips

because you only have to take the

medicine for 7 days after traveling

rather than 4 weeks

-Good for last-minute travelers




-Some people prefer to take a daily

medicine

-Cannot be used in patients with

glucose-6-phosphatase

dehydrogenase (G6PD) deficiency

-Cannot be used in patients who

have not been tested for G6PD

deficiency

-There are costs and delays

associated with getting a G6PD

test done; however, it only has to

be done once. Once a normal

G6PD level is verified and

documented, the test does not

have to be repeated the next time

primaquine is considered

-Cannot be used by pregnant

women

-Cannot be used by women who

89





are breastfeeding unless the infant

has also been tested for G6PD

deficiency

-Some people (including children)

would rather not take a medicine

every day

-Some people are concerned about

the potential of getting an upset

stomach from primaquine

Long-term use of chemoprophylaxis

Adherence and tolerability are important aspects of chemoprophylaxis use in long-

term travellers. There are few studies on chemoprophylaxis use in travel lasting more than

6 months.

The risk of serious side-effects associated with long-term prophylactic use of chloroquine

and proguanil is low, but retinal toxicity is of concern when a cumulative dose of 100 g of

chloroquine is reached. Anyone who has taken 300 mg of chloroquine weekly for more than 5

years and requires further prophylaxis should be screened twice-yearly for early retinal changes.

If daily doses of 100 mg chloroquine have been taken, screening should start after 3 years.

Data indicate no increased risk of serious side-effects with long-term use of mefloquine

if the drug is tolerated in the short-term. Pharmacokinetic data indicate that mefloquine

does not accumulate during long-term intake.

Available data on long-term chemoprophylaxis with doxycycline (i.e. more than 12

months) is limited but reassuring. There are few data on long-term use of doxycycline in women,

but use of this drug is associated with an increased frequency of Candida vaginitis.

90

Atovaquone–proguanil is registered in European countries with a restriction on duration

of use (varying from 5 weeks to 1 year); such restrictions do not apply in the United States.

Special grop

Some groups of travellers, especially young children, pregnant women, the elderly and

immunosuppressed travellers, are at particular risk of serious consequences if they become

infected with malaria. Recommendations for these groups are difficult to formulate because

safety data are limited. The special concerns for immigrants from endemic areas who live in

non-endemic areas and return to their home countries to visit friends and relatives

Pregnant women

Malaria in a pregnant woman increases the risk of maternal death, miscarriage, stillbirth

and low birth weight with associated risk of neonatal death. Pregnant women should be

advised to avoid travelling to areas where malaria transmission occurs. When travel cannot

be avoided, it is very important to take effective preventive measures against malaria, even when

travelling to areas with transmission only of vivax malaria. Pregnant women should seek

medical help immediately if malaria is suspected; if this is not possible, they should take SBET.

Medical help must be sought as soon as possible after starting SBET. There is very limited

information on the safety and efficacy of most antimalarials in pregnancy, particularly during the

first trimester. However, inadvertent exposure to antima -larials is not an indication for

termination of the pregnancy.

Mosquito bite prevention

Pregnant women are particularly susceptible to mosquito bites and should therefore be

vigilant in using protective measures, including insect repellents and insecticide-treated

mosquito nets. They should take care not to exceed the recommended dosage of insect

repellents.

Chemoprophylaxis

91

In Type II areas, with exclusively P. vivax transmission or where P. falciparum can be

expected to be fully sensitive to chloroquine, prophylaxis with chloroquine alone may be

used. In the few remaining Type III areas, prophylaxis with chloroquine plus proguanil can be

safely prescribed, including during the first 3 months of pregnancy. In Type IV areas,

mefloquine prophylaxis may be given during the second and third trimesters, but there is limited

information on the safety of mefloquine during the first trimester. In light of the danger of

malaria to mother and fetus, experts increasingly agree that travel to a chloroquine-resistant P.

falciparum area during the first trimester of pregnancy should be avoided or delayed at all costs;

if this is truly impossible, good preventive measures should be taken, including prophylaxis with

mefloquine where this is indicated. Doxycycline is contraindicated during pregnancy. The

atovaquone–proguanil combination has not been sufficiently investigated to be prescribed in

pregnancy.

Treatment

Clindamycin and quinine are considered safe, including during the first trimester of

pregnancy; artemisinin derivatives can be used to treat uncomplicated malaria in the second

and third trimesters, and in the first trimester only if no other adequate medicines are

available. Chloroquine can be safely used for treatment of vivax malaria in pregnancy, but

primaquine anti-relapse treatment should be postponed until after delivery. Artemether–

lumefantrine, atovaquone–proguanil and dihydroartemisinin–piperaquine have not been

sufficiently investigated to be prescribed in pregnancy.

The recommended treatment for uncomplicated falciparum malaria in the first trimester is

quinine +/– clindamycin. For the second and third trimesters, the options are: ACT in

accordance with national policy; artesunate + clindamycin; or quinine + clindamycin.

Pregnant women with falciparum malaria, particularly in the second and third

trimesters of pregnancy, are more likely than other adults to develop severe malaria, often

complicated by hypoglycaemia and pulmonary oedema. Maternal mortal -ity in severe malaria is

approximately 50%, which is higher than in non-pregnant adults. Fetal death and premature

labour are common. Pregnant women with severe malaria must be treated without delay with

full doses of parenteral anti-malarial treatment. In the first trimester, either quinine or artesunate

92

can be used. In the second and third trimesters, artesunate is the first option and artemether the

second option. Treatment must not be delayed, so if only one of the drugs artesunate, artemether

or quinine is available it should be started immediately.

Women who may become pregnant during or after travel

Malaria prophylaxis may be taken, but pregnancy should preferably be avoided during

the period of drug intake and for 1 week after doxycycline, 3 weeks after atovaquone–proguanil,

and 3 months after mefloquine prophylaxis is stopped. If pregnancy occurs during antimalarial

prophylaxis, this is not considered to be an indication for pregnancy termination.

CHALLENGES TO ELIMINATING MALARIA

Multi-island country

The Indonesian archipelago consists of over 17,000 islands spread out over 1.9 million

square kilometers. Although only 6,000 of these islands are inhabited, the challenges associ-ated

with malaria control in the world’s fourth most populous nation are significant. Ethnic and

linguistic diversity, an ex-tremely mobile population, a tropical climate, a lack of infra-structure,

logistical challenges to delivering health services, and frequent natural disasters contribute to the

challenge of eliminating malaria in Indonesia.(10)

Accurate surveillance and treatment

The majority of malaria cases are still diagnosed clinically in most Indonesian provinces

outside of the highly populated urban centers. Lack of equipment and trained laboratory

personnel have made it difficult to scale up laboratory diag-nostics in remote areas. Drug

resistance is also a formidable problem, and many first- and second-line drugs are becom -ing

ineffective in endemic areas.(10)

Information, education, and communication

Numerous gaps in communication and education exist among the various provinces of

Indonesia. Although cam-paigns for education, mass insecticide-treated net distribu -tion, and

IRS have been conducted with some success, many Indonesians living in endemic areas still do

93

not see malaria as a serious disease and have little knowledge of its diagno-sis, treatment, and

prevention.(10)

CONCLUSION

Malaria infection during pregnancy is an enormous public health problem, with

substantial risks for the mother, her fetus and the neonate. There are fewer data about the role of

P. vivax , there is evidence that it can also cause anaemia and low birth weight (Nosten et al.,

1999). Low birth weight is an important contributor to infant mortality (McCormick, 1985;

McDermott et al., 1996). It has been estimated that malaria during pregnancy is responsible for

5–12% of all low birth weight and 35% of preventable low birth weight (Steketee, Wirima &

Campbell, 1996) and contributes to 75 000 to 200 000 infant deaths each year (Steketee et al.,

2001).(2)

However, the problem of malaria in pregnancy was not described until the early 20th

century. This was followed by almost four decades of descriptive studies in sub-Saharan Africa

that focused on the frequency of Plasmodium falciparum placental infection and its adverse eff

ects. In the past two decades, many comprehensive reviews have highlighted various aspects of

malaria in pregnancy and its effect on maternal, newborn, and infant health. In this review, we

compile these estimates across the spectrum of disease manifestations, including what is known

in low and unstable transmission areas within and outside of sub-Saharan Africa and of species

other than P falciparum. We used data from review articles, and included new data that were

recently published if it provided important new information or insights.(7)

The effect of infection in the first trimester, and the longer term effects of malaria in

pregnancy beyond infancy are largely unknown and may be substantial. Better estimates are also

needed of the effects of malaria in pregnancy outside Africa, and on maternal morbidity and

mortality globally. Global risk maps would allow better estimation of potential impact of

successful control of malaria in pregnancy.

Despite numerous economic, political, and environmental setbacks, Indonesia has made

progress in malaria control over the last few decades. Increased scale-up of diagnostics,

treatment, and education of citizens and health care provid-ers should provide the catalyst

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Indonesia needs to move from control to pre-elimination and ultimately achieve its national goal

of elimination by 2030.(10)

ABBREVIATIONS

ACT artemisinin-based combination therapy

AL artemether plus lumefantrine combination

AQ amodiaquine

AS artesunate

AS+AQ artesunate plus amodiaquine combination

AS+MQ artesunate plus mefloquine combination

AS+SP artesunate plus sulfadoxine-pyrimethamine combination

BW body weight

CI confidence interval

CQ chloroquine

DHA+PPQ dihydroartemisinin plus piperaquine combination

EIR entomological inoculation rate

GRADE Grading of Recommendations Assessment, Development and Evaluation

G6PD glucose-6-phosphate dehydrogenase

HIV/AIDS human immunodeficiency virus/ acquired immunodeficiency syndrome

HRP2 histidine-rich protein 2

IC50 concentration providing 50% inhibition

IV intravenous

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IM intramuscular

MIC minimum inhibitory concentration

MQ mefloquine

OR odds ratio

PCR polymerase chain reaction

Pf HRP2 Plasmodium falciparum histidine-rich protein-2

p LDH parasite-lactate dehydrogenase

PQ primaquine

Pvdhfr Plasmodium vivax dihydrofolate reductase

RCT randomized controlled trial

RDT rapid diagnostic test

RR relative risk

SP sulfadoxine-pyrimethamine

WHO World Health Organization

WMD weighted mean difference

REFERENCES

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Incomplete Treatmenat of Malaria and Special Concerns in Pregnancy

Documents