INTERNAL MEDICINE DEPARTEMENT

DUSTIRA HOSPITAL / MEDICAL FACULTY OF GENERAL ACHMAD YANI

UNIVERSITY

CIMAHI

Name : Mr. Jumardin Room : XI No.Med.Rec : 267618

Gender : Male Age : 20 years old

Religion : Islam

Occupation : Army/Prada

Address : United dormitory of Pusdik Armed - Cimahi

Sent by : His Batallyon

Date of examination (Co. ass) : May 22th 2011

Date of treatment : May 19th 2011 : 17.30 p.m

Date of Exit : May 26th 2011

Diagnosis:

Doctor :

Co. ass : Malaria Tropikal

A. HISTORY TAKING (Auto)

CHIEF COMPLAINT : Fever

PATIENT’S ILLNESS :

Since 9 days before entering the hospital, the patient complained of sudden high

fever. fever preceded by chills about 30 minutes. after a fever for about 4 hours, the

fever will come down then arise sweat a lot so that the patient becomes wet clothes.

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after exiting the sweat, the patient felt his condition improved. complaint patient feels

every day.

Fever complaint was accompanied by weakness, headache, nausea without

vomiting and poor appetite.

Fever complaint was accompanied by that looks yellow eyes and a face that

looks pale.

Fever complaint was not accompanied by a decrease in consciousness or

convulsions.

Fever complaint was not accompanied by decreasement of urination, change of

urines color that get blackish. And complaint of defecation wasn’t found.

Fever complaint was not accompanied by severe pain in the calf or to make the

patient unable to walk, bleeding in the eye, and do not live in flood zones.

Fever complaint was not accompanied by a cough for more than three weeks,

sweat out in the evenings or drastic weight loss.

Fever complaints was not accompanied by rapid breathing and or shortness of

breath in time.

Patients had been visiting and living in malaria endemic area in Papua, from 1

January to 15 April 2011 to carry out tamtama education. patients did not drink malaria

prevention medication before going to the venue. While in Papua patients have never

experienced such complaints.

This is the first complaint that experienced by the patient, and family no one has

suffered from this disease.

Before the patient entered the hospital, the patient had previously been treated at

the unit physician, the patient was given paracetamol tablets and amoxicillin in the drink

3 times a day. but complaint of patients is not reduced and eventually the patient was

taken to the emergency room with dustira unity.

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a. General complaint

Fever : Present

Sleep : Present

Edema : Absent

Icteric : Present

Thirst : Absent

Appetite : Present

Weight : Absent

b. Head complaint

Sight : Absent

Nose : Absent

Tongue : Absent

Swallow dysfunction : Absent

Hearing : Absent

Mouth : Absent

Teeth : Absent

Voice : Absent

c. Neck Complaint

Suffocate in neck : Absent

Gland enlargement : Absent

Stiffness neck : Absent

d. Chest complaint

Shortness of breath : Absent

Chest pain : Absent

Wheezing : Absent

Cough : Absent

Palpitate : Absent

e. Stomach compliant

Local pain : Absent

Pain with pressure : Present

Pain in the entire stomach : Absent

Pain associated with :

- Food : Absent

- Defecation : Absent

- Menstruation : Absent

Sense of stomach tumor : Absent

Vomiting : Absent

Diarrhea : Absent

Obstipation : Absent

Tenesmi ad ani : Absent

Change in defecation : Absent

Change in Urine : Absent

Change in menstruation : Absent

f. Arm and Leg complaint

Stiffness : Absent

Fatigue : Absent

Joint/muscle pain : Absent

Numbness : Absent

Fractures : Absent

Pain behind the knee : Absent

Pain with pressure : Absent

Wound/scar : Absent

swollen : Absent

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g. Other Complaint

Skin : Absent

Armpit : Absent

Lymph node complaint : Absent

Endocrine gland complaint :

- Menstruation : -

- D.M : Absent

- Thyroid : Absent

- Others : Absent

Additional History Taking

a. Nutrition: Quality : Sufficient

Quantity : Sufficient

b. Contagious disease : Absent

c. Hereditary disease : Absent

d. Addiction : Absent

e. Venereal disease : Absent

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B. STATUS PRAESEN

I. GENERAL IMPRESSION

a. General

Awareness : Composmentis

Character : Cooperatif

Impression illness : Moderate

Movement : Unlimited

Sleep : Supine with one pillow

Height : 173 cm

Weight : 65 kg

Nutrition condition : BMI= 21,7

Skin nutrition : Sufficient

Muscle nutrition : Sufficient

Body shape : Athleticus

Estimated age : Appropriate

Skin: anemic (+), icteric (-)

b. Circulation

Blood Pressure : Right :100/60 mmHg Left : 100/60 mmHg

Pulse rate : Right :72x/second, regular,equal, adequate

Left :72x/second, regular,equal, adequate

Body temperature : 35,50C

Cold sweat : Present

Cyanosis : Absent

c. Respiratory condition

Type : Abdominothoracal

Frequency : 20x/ minute

Pattern : Normal

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Breath Smell : No abnormalities

Breath sound : No abnormalities

II. SPECIAL EXAMINATION

a. Head

1. Skull

Inspection : Symetric

Palpation : No abnormalities

2. Face

Inspection : Symetric, anemic (+), icteric (-)

Palpation : No abnormalities

3. Eyes

Location : Symetric

Eyelids : No abnormalities

Cornea : No abnormalities

Cornea reflex : +/+

Pupils : Circle , Ishokor

Convergence Reaction : +/+

Sclera : Sub icteric

Conjunctiva : Anemic

Iris : No abnormalities

Movement : Normal to every direction

Light Reaction : Direct+/+, Indirect +/+

Visus : Examination is not conducted

Funduskopi : Examination is not conducted

4. Ears

Inspection : Symetric

Palpation : No abnormalities

Hearing : No abnormalities

5. Nose

Inspection : No abnormalities

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Obstruction : Absent

Snot : Absent

6. Lips

Cyanosis : Absent

Kheilitis : Absent

Stomatitis angularis : Absent

Rhagaden : Absent

Perleche : Absent

7. Teeth and Gums : Gums : No abnormalities

8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8

8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8

X: Toothless O = Caries

8. Tongue

Size : Normal

Shape : No abnormalities

Movement : No abnormalities

Surface : anemic (-)

Frenulum lingue : ikterik (-)

9. Mouth Cavity

Hyperemic : Absent

Lichen : Absent

Aphtea : Absent

Spots : Absent

10. Neck Cavity

Mucous Membrane : No abnormalities

Pharyng posterior wall : No hyperemic

Tonsils : T1 – T1 quite

b. Neck

1. Inspection

Trachea : Deviation not seen

Glandula thyroid : Enlargement not seen

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Venous expantion : Absent

Neck venous pulsation : Absent

Jugular venous pressure : 5 + 1 cmH2O, not increase

2. Palpation

Lymph nodes : No enlargement

Glandula Thyroid : No enlargement

Tumor : Absent

Neck muscle : No abnormalities

Neck stiffness : Absent

c. Axilla

1. Inspection

Armpit hair : No abnormalities

Tumor : Absent

2. Palpation

Lymph nodes : No enlargement

Tumor : Absent

d. Thorax Examination

Anterior thorax

1. Inspection

General shape : Symetric

ØAnteroposterior &Sagital : ØAnteroposterior < Ø transversal

Epigastric Angle : < 900

Intercostals Space : Not widening nor narrowing

Movement : Symetric

Skin : anemic (+), icteric (-)

Musculatur : No abnormalities

Tumor : Absent

Ictus cordis : Not seen

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Other pulsation : Absent

Venectation : Absent

2. Palpation

Skin : No abnormalities

Musculatur : No abnormalities

Mammae : No abnormalities

Intercostals Space : Not widening nor narrowing

Lung Right Left

- Movement : Symetric Symetric

- Vocal fremitus : Normal Normal

Ictus cordis :

- Location : ICS V Linea midclavicularis sinistra

- Intensity : not bounding

- Widening : not present

- Thriil : not present

3. Percussion

Lung Right Left

- Percussion sound : Sonor Sonor

- Liver lung border : ICS V Linea midclavicula dextra

- Diafragmatic displacement : 1 intercostal space (2 cm)

Heart

- Up border : ICS II Linea sternalis sinistra

- Right Border : Linea sternalis dextra

- Left Border : ICS V linea midclavicularis sinistra

4. Auscultation

Lung Right Left

- Main breath sound : Vesicular Vesicular

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- Additional breath sound : Ronkhi(-) Ronkhi(-)

Wheezing(-) Wheezing(-)

- Vocal resonance : Normal Normal

Heart

- Rhythm : regular

- Main heart Sound : M1 > M2, P1 < P2

T1 > T2, A1 < A2, A2 > P2

- Additional heart sound : Absent

- Obsteperous of heart : Absent

- Pericardial friction rub : Absent

Posterior Thorax

1. Inspection

Shape : Symetric

Movement : Symetric

Skin : ikterik (-) anemic (-)

Musculatur : No abnormalities

2. Palpation Right Left

Intercostal space : Not widening nor narrowing

Musculatur : No abnormalities No abnormalities

Vocal fremitus : Normal Normal

3. Percussion

Lower border : Vertebra Th-X Vertebra Th-XI

Diafragmatic displacement : 1 intercostal space (2 cm)

4. Auscultation

Main breath sound : Vesicular Vesicular

Additional breath sound : Rhonchi (-) Rhonchi (-)

Wheezing (-) Wheezing (-)

Vocal resonance : Normal Normal

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e. Abdomen

1. Inspection

Shape : Flat

Abdomen muscle : No abnormalities

Skin : icteric (-)

Movement in breathing : No abnormalities

Intestines movement : Unseen

Pulsation : Absent

Venectation : Absent

2. Palpation

Abdomen : Soft

Local palpation pressure : present a/r hipokondrium dextra

Diffuse palpation pressure : Absent

Detached pain : Absent

Defance musculair : Absent

Liver : Palpable

- Enlargement : 3 cm BAC, 5 cm BPX

- Consitence : expansible

- Surface : witness

- Edge : sharp

- Pain With Presure : present

Spleen : Palpable

- Enlargement : Schuffner I-II

- Consistence : soft

- Surface : witness

- Incisura : difficult in value

- Pain with pressure : absent

Tumour/mass : Not palpable

Ren : Not palpable

Pain with pressure : -/-

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3. Percussion

Percussion sound : Tympany, dull ; Traube`s space (+)

Ascites :

- Side dullness : (-)

- Shifting dullness : (-)

- Fluid wave : (-)

4. Auscultation

Bowel sound : (+) Normal

Bruit : Absent

Others : No abnormalities

f. CVA(Costo vertebral angel) : Knocking pain -/-

g. Groin

1. Inspection

Tumor : Absent

Lymph nodes : Unseen enlargement

Hernia : Absent

2. Palpassion

Tumor : Absent

Lymph node : No enlargement

Hernia : Absent

Pulsasi A. Femoralis : Palpable

3. Auscultation

A. Femoralis : Examination is not conducted

h. Genitalia : Examination is not conducted

i. Sacrum : No abnormalities

j. Anus& Rectum : Examination is not conducted

k. Extremities Upper Lower

1. Inspection

Shape : No abnormalities No abnormalities

Movement : Unlimited Unimited

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Skin : No abnormalities No abnormalities

Muscle : No abnormalities No abnormalities

Edema : Absent Absent

Clubbing finger : Absent Absent

Palmar eritem : Absent Absent

2. Palpation :

Pain with pressure : Absent Absent

Tumour : Absent Absent

Edema (pitting/non pitting) : Absent Absent

Artery pulsation : Present Present

l. Articulatio

1. Inspection

Deformity : No abnormalities

Inflamation sign : Absent

Others : No abnormalities

2. Palpation

Pain with pressure : Absent

Fluctuation : Absent

Others : No abnormalities

m. Neurologic

Physiologic ReflexKPR : +/+ normal

Physiologic ReflexAPR : +/+ normal

Pathologic reflex : -/-

Meningen reflex : absent

Sensoric : + / +

III.LABORATORY FINDINGS

BLOOD

Hemoglobin : 8,5 g/dl

Leucocyte : 5500 cell/mm3

Erythrocyte : 3.500.000 cell/mm3

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Trombocyte : 138.000 cell/mm3

Differential count :

- Basophils : 0 %

- Eosinophils : 1 %

- Band Neutrophils : 2 %

- Segmented Neutrophils : 60 %

- Lymphocytes : 25 %

- Monocytes : 12 %

Erythrocyte Sedimentation Rate

- 1st hour : 30 mm

- 2nd hour : 65 mm

Blood Smears

Erythrocyte : Hipochrom normosyter, DDR (+) P.falcifarum

stadium trofozoit

Leucocyte : No abnormalities

Groups of trombocyte : Deficient

Impression : Anemia hipochromic ec malaria

URINE

Color : Yellow

Muddiness : Clear

Odor : Amoniak

Density : 1.015

Reaction : Acid

Albumin : -

Reduction : -

Urobilin : -

Bilirubin : -

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Sediment

- Leucocyt : 5-8/ HPF

- Erythrocyte : 6-9/HPF

- Crystal : -

- Bactery : -

- Epithelium : 2-4/HPF

FAECES

Colour : Brown

Odor : Indol skatol

Consistency : Slack

Mucus : -

Blood : -

Parasite : -

Erithrocyt : -

Leucocyt : -

Worm Eggs : -

Food remaining : +

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RESUME

A man, 20 years old,occupation: army, single, came with complaint of fever.

9 days ago patient complained of a suddenly high fever. Fever complaint was

preceded by rigoris then followed by caloris and sudoris after the fever get down.

Fever complaint was accompanied by weakness, headache, nausea without

vomiting and poor appetite.

Fever complaint was accompanied by that looks yellow eyes and a face that

looks pale.

Fever complaint was not accompanied by a decrease in consciousness or

convulsions.

Fever complaint was not accompanied by decreasement of urination, change of

urines color that get blackish. And complaint of defecation wasn’t found.

Fever complaint was not accompanied by severe pain in the calf or to make the

patient unable to walk, bleeding in the eye, and do not live in flood zones.

Fever complaint was not accompanied by a cough for more than three weeks,

sweat out in the evenings or drastic weight loss.

Fever complaints was not accompanied by rapid breathing and or shortness of

breath in time.

Patients had been visiting and living in malaria endemic area in Papua, from 1

January to 15 April 2011 to carry out tamtama education. patients did not drink malaria

prevention medication before going to the venue. While in Papua patients have never

experienced such complaints.

This is the first complaint that experienced by the patient, and family no one has

suffered from this disease.

16

Before the patient entered the hospital, the patient had previously been treated at

the unit physician, the patient was given paracetamol tablets and amoxicillin in the drink

3 times a day. but complaint of patients is not reduced and eventually the patient was

taken to the emergency room with dustira unity.

Further examination :

a. General

Awareness : Composmentis

Impression illness : Moderate

Skin : anemic (+), icteric (-)

b. Vital sign

Blood Pressure : 100/60 mmHg

Breathing : 20x/ second

Pulse rate : 72x/second, regular,equal, adequate

Temperature : 35,50C

Cyanosis : Absent

Cold sweat : Present

c. Special Examination

Head : Symetric

Sclera : Sub icteric

Conjunctiva : Anemic

Thorax : Shape and movement are symmetric

Skin : anemic (+), icteric (-)

Heart : Heart border Normal

1st Heart Sound &2nd heart sound: reguler

Lung : Vesikuler Right lung = Left Lung,

Ronchi -/-, wheezing -/-

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Abdomen : Tympany, dull

Hepar : Palpable, 3 cm BAC 5 cm BPX

- Consitence expansible

- Surface witness

- Edge sharp

- Pain With Presure present

Lien : palpable, schuffner I-II Traube’s space was filled

- Consitence soft

- Surface witness

- Incisura difficult in value

- Pain With Presure absent

Ren : No palpable, Knocking pain -/-

Ekstremity : No abnormality

Laboratory Findings

BLOOD :Erythrocyte sedimentation rate was high, leucopenia and trombocytopenia

Erythrocyte Sedimentation Rate

- 1st hour : 30 mm

- 2nd hour : 65 mm

Leucocyte : 5500 cell/mm3

Erythrocyte : 3.500.000 cell/mm3

Trombocyte : 138.000 cell/mm3

Blood Smears

Erythrocyte : Hipochrom Normosyter, DDR (+) P.falcifarum

stadium trofozoit

Leucocyte : No abnormalities

Groups of trombocyte : Deficient

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Impression : Anemia hipochromic ec malaria

URINE : Within normal limits

FAECES : Within normal limits

IV. DIFFERENTIAL DIAGNOSIS

Tropical Malaria

Tertiana Malaria

Typhoid fever with hepatitis Tifosa

V. DIAGNOSIS

Tropical Malaria

VI. EXAMINATION SUGGESTED :

1. DDR tests (repeated at the 3rd, 7th, 14th, 21th, and 28th day)

2. PfHRP2 and PfLDH test

3. AST, ALT, bilirubin total, bilirubin direct, bilirubin indirest test

4. Widal test I dan II, Gall Kulture

VII. TREATMENT

IVFD Ringer Lactat maintenance 2L/24 hour

Inj. Artem - 1st day 2x2 amp (160 mg) im

- 2nd until 5th 2x1 amp (80 mg) im

Dokxiciklin 2x100 mg (1 week)

Kina tab 3x1 (1 week)

Folic acid 1x1

PCT 3x500 mg

Vitamin B complex 3x1 tab

VIII.PROGNOSE

Quo ad vitam : Ad Bonam

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Quo ad functionam : Dubia Ad Bonam

CASE DISCUSSION

Discussion of Chief Complaint

patients come to rs dustira with chief complaint of fever

I. fever of less than seven days include :

Chikungunya, avian influenza, dengue fever

II. fever for more than seven days include :

Typhoid fever, malaria, leptospirosis, tbc, malignancy, hiv aids

Discussion of patients illness

Fever complaint was preceded by shivering then followed by sweathing after the fever

get down.

The classic symptoms of malaria which is known as trias malaria are frigoris

(shivering), calories (fever),sudoris (sweathing) that happen consecutively.

Frigoris period (15-60 minutes) : begin to shiver, patient usually wrap his body

with blanket. His body will vibrate until the teeth stumble to each other. then this

period followed by calories period :characterized by red face, tachycardia, and the fever

stays in few hours. After that patient will get into sudoris period: patient get sweathing a

lot, the temperature goes down, and patient feel healthy.

Fever complaint was accompanied by severe headache without followed by

unconsciousness decreasement and seizure. Complaint was accompanied with body’s

weakness, appetite decreasement and pain at both of leg. Fever complaint was also

accompanied by nausea but not until get throw up.

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The most happen prodormal sign of malaria tropika are headache, pain at the

leg, cold feeling, nausea , vomitus and diarrhea but in this patient is not until vomitus

and diarrhea copmplaint wasn’t found.

Fever complaint was accompanied by severe headache without followed by

unconsciousness decreasement and seizure.

To detect any possibility of cerebral malaria complication, such as

consciousness decreasement thet stay more than 30 minutes and seizures attack.

Fever complaint was not accompanied by decreasement of urination, change of

urines color that get blackish. And complaint of defecation wasn’t found.

To detect any possibilities of kidney complications such as acute renal failure

and black water fever.

Fever complaint was not accompanied by swallow pain, cough and cold.

To eliminate the possibility of fever caused by upper respiratory tractus

infection

Complaints body heat is not accompanied by cough more than 3 weeks, night

sweats or weight loss drastically.

To rule out the possibility of pulmonary tuberculosis in patients

Fever complaint was not accompanied with pain at leg which hurt when it is

pushed, yellow eyes, and bloody eyes. Patient hasn’t visited any floody area in few

months before.

To eliminate fever caused by leptospirosis. Leptospirosis is characterized by

pain at leg which hurt when it is pushed, yellow eyes, bloody eyes and patient has ever

visited floody area before.

Complaint of defecation wasn’t found.

In malaria sometimes we can find diarrhea.

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Patients had been visiting and living in malaria endemic area in Papua, from 1

January to 15 April 2011 to carry out tamtama education. patients did not drink

malaria prevention medication before going to the venue

History of traveling and staying in endemic malaria area support straighten of

malarial diagnosis.

Complaints like this the first time experienced by the patient, and family no

one is suffering from a disease like this.

To get rid of malaria disease recurrence in

Discussion of physical examination

1. General condition

Patient’s awareness was compos mentis means patient absolutely awaken and

gives an adequate respond to the stimulus that is given. This condition eliminates

possibility of malaria cerebral. People with malaria cerebral usually come in apathy,

somnolen until coma condition. Impression illness of this patient was moderate means

patient has disturbtion in his activities and need people’s help to do his activities.

2. Vital signs :

- Temperature :35,5° C

Patient with malaria usually comes with fever complaint that’s why in his

examination usually gives a febris temperature. But in this patient, there is an

irregular temperature which is one of malaria tropikan’s characteristic.

- Blood pressure: 100/60 mmHg, right=left

Patient’s blood pressure has a decreasement. Hypotension is a poorprognostic sign

only when associated with poor perfusion, as evidenced by cool peripheries and

poor capillary refill.

- Pulse : 72x/minutes, right = left, reguler, equal, adequate

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Patient’s pulse is normal

- Respiration : 20 x/menit type thorakoabdominal

Patient’s respiration rate is normal. Respiration could be followed by pathologic

sounds when there is a complication in the lung such as bronchitis or lobaric

pneumonia.

3. Special Examination

a. Head

i. Sclera : Sub icteric

ii. Conjunctiva : Anemic

In some cases of malaria there could be complications. In malaria with liver

dysfunction we can find jaundice and icteric at sclera. Severe jaundice is

associated with P. falciparum infection is more common among adults than

among children, and results from hemolysis, hepatocyte injury and cholestasis.

In severe malaria, both infected and uninfected red cells show reduced

deformabolity, which correlates with prognosis and development of anemia.

b. Neck

i. Lymph nodes : No enlargement

ii. Jugular venous pressure: 5 + 1 cmH2O, not increase

Usually any abnormalities is not found

c. Thoraks : Shape and movement are symmetric

i. Cor : Heart sounds are pure regular

ii. Pulmo : VBS right = left

Ronkhi - / - Wheezing - / -

Lung could be normal or found any abnormal sounds.

d. Abdomen : flat and soft

i. Hepar : palpable 3 cm BAC 5 cm BPX

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ii. Lien : palpable schuffner I-II, Traube’s space was filled

Presence of hepatomegaly could be found in malaria.

Spleenomegaly is a typical sign of malaria. The spleen get enlarge because there

is accumulation of parasyte’s erythrocyte pigment.

Discussion of laboratory examination

a. Blood test

- Hb : acquired anemia

- Leukosit : within normal limits

- Counts : found that decreased lymphocytes and monocytes increasedthin smear morphology was found plasmodium vivax stage trofozoit

b. Urine : within normal limitIn general, if no complications then obtained from macroscopic examination of urine

will get the normal, clear yellow color, the smell of ammonia, and acid reaction.

c. Faeces : within normal limit

f. Blood smear:

a. Erythrocyte : Hipochrom normocyt, DDR (+) P. Falcifarum stadium

trofozoit

b. Leucocyte : no abnormalities

c. Thrombocyte : deficient

d. Impression : anemia hipochromic ec malaria

Sensitivity and specifity depend to a great extent on the experience of the microscopist,

the quality of the slides, atands and microscope, and the time spent examining the slide.

Artefacts are common and often confusing.

Diagnosis:

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In this patient the differential diagnosis is to determine the etiology of primary

or secondary

Diagnosis

Based on the history taking, physical examination and laboratory examination, can

be concluded that patient suffer of tropical malaria.

Things that support the diagnosis:

History taking:

- From history taking was found classic symptoms of malaria which is known as trias

malaria are frigoris (shivering), calories (fever),sudoris (sweathing) that happen

consecutively.

- Prodormal sign of malaria tropika such as severe headache, pain at the leg, body’s

weakness, nausea and appetite decreasement.

- Patient has history of traveling and staying in endemic malaria area

Physical examination:

- Hepatomegaly

- Skin and conjunctiva anemis

- Sclera yellow jaundice

- Traube’s space was filled

Spleenomegaly schuffner I-II is a typical sign of malaria. The spleen get enlarge

because there is accumulation of parasyte’s erythrocyte pigment.

Examination Suggested :

1. DDR tests (repeated at the 3rd, 7th, 14th, 21th, and 28th day

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To evaluate the effectivity of the teraphy and medication ressistancy.

2. PfHRP2 and PfLDH test

PfHRP2 to detect plasmodium falciparum in a rapid way and PfLDH is to differ

between the infection caused by p. falciparum or by p. vivax.

The introduction of simple, rapid, sensitive, highly specific and increasingly

affordable dipstick or card tests for the diagnosis of malaria has been a major

advance in recent years

3. Total bilirubin and indirect bilirubin director test

To assess the causes of jaundice in both eyes, whether prehepatik, heart or liver

posts.

4. Widal test I dan II, Gall Kulture

Untuk menghilangkan DD/ Demam Tifoi

Treatment

First line medication for tropical malaria with complication

IVFD Ringer Lactat maintenance 2L/24 hour

Inj. Artem - 1st day 2x2 amp (160 mg) im

- 2nd until 5th 2x1 amp (80 mg) im

Dokxiciklin 2x100 mg (1 week)

Kina tab 3x1 (1 week)

Folic acid 1x1

PCT 3x500 mg

Vitamin B complex 3x1 tab

Prognose

Quo ad vitam : ad bonam

Because the patient can still do daily activities and this patient has good vital sign. Even

patient had previous history of malaria but there was no complications found.

Quo ad functionam : dubia ad bonam

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Quo ad functionam of this patient is dubia ad bonam because even patient was suffered

by p. falciparum but there was accompanied complications found.

LITERATURE REVIEW

MALARIA

THE PARASITE

The malaria parasite is a mosquito-transmitted protozoan. Plasmodia are

sporozoan parasites of red blood cells transmitted to animals (mammals, bird, reptiles)

by the bites of mosquitoes. Protozoan parasites of the phylum Apicomplexa contain

three genetic elements: the nuclear and mitochondrial genomes characteristic of

virtually all eukaryotic cells and a 35-kilobase circular extra chromosomal DNA. This

encodes a vestigial plastid (the apicoplast) that is an evolutionary homologue of the

chloroplast of plants and algal cells. Four species of the genus Plasmodium infect

humans, although infection with a fifth parasite P. knowlesi, a malaria of long-tailed and

pig-tailed macaque monkeys, is an important cause of human malaria on the island of

Burneo and peninsular Malaysia.. Almost all deaths and severe diseases are cause by P.

falciparum. The three ‘benigh’ malarias, P. vivax, P. ovale and P. malariae, all lie close

together on the evolutionary tree near the other primate malarias. Severe disease with

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these species is relatively unusual, although on the island of New Guinea Plasmodium

vivax is associated with significant mortality. Occasionally patients with vivax malaria

will die from rupture of an enlarge spleen, and P. vivax infection in pregnancy reduce

birth weight, which predisposes to neonatal death.

GEOGRAPHICAL ASPECTS

Distribution

Malaria is endemic in 109 countries and is found throughout the tropics (Figure

73.1). In Africa, P. falciparum predominates, as it does in Papua New Guinea and Haiti,

whereas P. vivax is more common in Central and parts of South America, North Africa,

the Middle East and the Indian subcontinent. The prevalent of both species is

approximately equal in other parts of South America, South-east Asia and Oceania. P.

vivax is rare in sub-Saharan Africa (except for the horn of Africa), whereas P. ovale is

common only in West Africa. P. malariae is found in most areas, but is relatively

uncommon outside Africa. Malaria was once endemic in Europe and Northern Asia, and

was introduced to North America, but it has been eradicated from these areas. In

Northern China and North Korea. P.vivax strains (P. vivax hibernans) with long

incubation periods and long intervals (10-12 months) between relapses may still be

found.

EPIDEMIOLOGY

The mosquito vector

Malaria is transmitted by some species of anopheline mosquitoes. Malaria

transmission does not occur at temperatures below 16º C, or above 33 º C, and at altitudes

>2000m because development conditions for transmission are high humidity and an

ambient temperature between 20 and 30 º C. Although rainfall provides breeding sites

for mosquitoes, excessive rainfall may wash away mosquito larvae and pupae.16

28

The epidemiology of malaria is complex and may vary considerably even

within relatively small geographical areas.17-20 Intensities of malaria transmission vary

from very low (on average one infectious bite per person every 10 years) to extremely

high (three infectious bites per person per day). Malaria transmission to man depends on

several interrelated factors. The most important pertain to the anopheline mosquito

vector, and in particular is longevity. As sporogony (development of the sporozoite

parasites in the vector) takes over a week (depending on ambient temperatures), the

mosquito must survive for longer than this after feeding on a gametocyte-carrying

human, if malaria is to be transmitted.

Clinical epidemiology

Babies develop severe malaria relatively infrequently (although, if they do, the

mortality is high). The factors responsible for this include passive transfer of maternal

immunity,33 and the high hemoglobin F content of the infants erythrocytes which retards

parasite development.34 In holoendemic areas the baby is inoculated repeatedly with

sporozoites during the first year of life, but the blood stage infection is seldom severe.19

people may receive up to three infectious bite per day. In this epidemiological context,

the main clinical impact of falciparum malaria is to cause severe anemia in the 1-3-year

ago group (figure 73.2). with less intense or more variable or unstable transmission the

age range affected by severe malaria extends to older children, and cerebral malaria

becomes a more prominent manifestation of severe diseases.35-37 although mortality falls

with decreasing transmission intensity, it remains substantial until EIR falls well below

one. In hyper endemic and holoendemic areas indigenous adults never develop severe

malaria, unless they leave the transmission area and return years later (and even then

malaria is seldom life-threatening). Immunity is constantly boosted and effective

premonition prevents parasite burdens reaching dangerous levels. Most infections in

adult are asymptomatic.

Where transmission of malaria is low, erratic, markedly seasonal, or

focal, symptomatic infections are more common. A state of premonition is often not

29

attained. Symptomatic disease occurs at any age, and cerebral malaria is a prominent

manifestation of severe diseases at all ages. This is termed ‘unstable’ malaria. In many

areas, the transmission of malaria varies considerably over short distances, and severe

disease is common when non-immune individuals enter these areas (e.g. woodcutters in

South America and South-east Asia where malaria is of the ‘forest fringe’ type or

highland refugees in Burundi descending into malarious low-land).

Malaria is usually a ‘rainy seasons disease’ coinciding with increased

mosquito abundance. In some areas, parasite rates (i.e. the proportion of people with

positive blood smears) are relatively constant throughout the year, but the majority of

cases still do occur during the west season. In Europe, before eradication, falciparum

malaria was common in spring and in late summer and autumn, and was termed

‘aestivo-autumnal malaria’. the intensity of transmission or ‘endemicity’ can change..

Deforestation, population migration, and changes in agricultural practice have profound

effects on malaria transmission. Urban malaria is becoming an increasing problem in

many countries.

In low transmission settings malaria can behave as an epidemic disease

carrying a high mortality. Epidemics are caused by migration (i.e. introduction of

susceptible hosts), the introduction of new vectors, or changes in the habits of the

mosquito vector or the human host. Increasing international air travel and worsening

antimalarial drug resistance have led to an increase in imported cases of malaria in

tourists, travelers and immigrants. With the recent exception of some of the former

Soviet republics in East Europe and West Asia, this has not led to the reintroduction of

malaria to areas from where it had earlier been eradicated (although the vector, and thus

the potential, remains). The incidence of malaria has risen markedly in several African

countries, India, and Bangladesh over recent decades. Imported malaria is often

misdiagnosed, leading to delays in treatment and severe presentations of falsiparum

malaria are not uncommon. Malaria may also be transmitted by blood transfusion,

transplantation, or through needle-sharing among intravenous drug addicts.

30

MALARIA PARASITE LIFE CYCLE

Pre-erythrocytic development

Infection with human malaria begins when the feeding female anopheline

mosquito inoculates plasmodial sporozoites at the time of feeding.43The small motile

sporozoites are injected during the phase of probing as the mosquitoes searches for a

vascular space before aspirating blood. In most cases, relatively few sporozoites are

injected (appromaxmately 8-15), but up to 100 may be introduced in some instance.44-

45Most sporozoites come from the large salivary ducts and represent only a small

fraction of the total number in the salivary gland. After injection, they enter the

circulation, either directly or via lymph channels (approximately 20%), and rapidly

target the hepatic parenchymal cells. Within 45 min of the bite, all sporozoites have

either entered the hepatocytes and there begins a phase of a sexual reproduction. This

stage last on average between 5.5 (P. falciparum) and 15 days (P. malariae) before the

hepatic schizont ruptures to release meroaoites into the bloodstream

PlosmodiumPrepatent period

(days)

Incubation period

(days)

P.falciparum 11.0 (2.4) 13.1 (2.8)

P.vivax 12.2 (2.3) 13.4 (2.7)

P.malariae 32.7a 34.7a

P.ovale 12.0 14.1

Naturally acquaried infections are considered to have an incubation period of between 13 – 28 days

in some instances, the primary incubation period can be much longer. In P.

vivax and P. ovale infections a proportions of the intrahepatic parasites do not develop,

31

but instead rest inert as sleeping forms or ‘hypnozoites’, to awaken weeks or months

later, and cause yhe relapses which of characterize infection whit these two species.

During the pre-erytrhocytic or hepatic phase of development considerable asexual

multiplication takes and many thousand of merozoites are released from aech ruptured

infect hepatocyte. However, as only a few liver cells are infected, this phase is

asymptomatic for the human host.

Asexual blood – stage development

The metozoites liberated into the bloodstream closely resemble sporozoites.

They are motile ovoid forms which invade red cells rapidly. The process of invasion

involves attachment to the erythrocyte surface, orientation so that the apical complex

(which protrudes slightly from one and of the merozoites and containts the rophtries, the

micronemes, and dense granules) abuts the red cells, and then interiorization takes

places by a wriggling boring motion inside a vacuole composed of the invaginated

arytrhocyte, the parasite lies within the erythrocyte cytosol enveloped by its own plasma

membrane and a surrounding parasiteophorous vacuolar membrane. The attachment of

the merozoite to the red cells is mediated by the attachment of one or more of a family

of erythrocyte binding proteins, localized to the micronemes of the merozoite apical

complex, to a specific erythrocyte rereceptor. In P.vivax this is related to the duffy blood

group antigen Fya or Fyb.The absence of these phenotypes in west affrican, or people

who originate from that region, explains their resistance to infection with P.falciparum

the merozoite protein EBA 175, a product of the ‘Duffy binding like (DBL)

superfamilyof genes encoding ligands for hodt cell receptors, is clearly important.48,49

this bind to sialic acid and the peptide backbone of the red cell membrane

sialoglycoprotein glycophorin A. But other, sialic acid dependent and independent

pathways of invasion also occur indicating considerable reserver in the invasion

system.48,50 Blinding is linked to activation of a parasite actin motor which provides the

mechanical energy for the invasion process. The red cells surface receptor for

P.malariae and P.ovale are not known.

32

During the early stage of intraerytrhocytic development (<12h), the small ‘ring

forms’ of the four pasite species appear similar under light microscopy. The young

developing parasite looks like a signetring or , in yhe case of P.falciparum like a pair of

stereo-headphones, with darkly staining chromatin in the nucleus, a circularrim of

citoplasma, and a pale central food vacuole ( figures 73.3. 73.4). Parasite are freely

motile within the erythrocyte. As they grow, they increase in size logarithmically and

consume the erythrocye’s contents (most of which is haemoglobin). With this increase

in size, P.falciparum-infected erythrocytes become spherical and less deformable.51,52

Proteolysis of haemoglobin within the digestive vacuole of the growing parasites

realeses for protein synthesis, but the liberated haem process a problem. When haem is

freed from its protein scaffold, is oxidizesto the toxic ferric form. Intraparasitic toxicity

is avoided by spontaneous dimerization to an inert crystalline substance, haemozoin.

This may be facilitated nonenzymatically by parasite proteins. Non-polymerized haem

exits the food vacuole but its then degraded in the cytosol by glutathione. Too much

non-polymerizedhaem overwhealms the defence mechanism and toxic. The digested

product, mainly the brown or black insolunle pigment haemozoin, can be readily seen

within the digestive vacuole of the growing parasite. To abtain amino acids and other

nutrients and to control the electrolytic milieu in the infected arythrocyte the parasite

inserts specific transporters and other proteins in the red cell membrane.55

At approximately 12 – 14 of development, P.falciparum parasites begin

to exhibit a high molecular weight strain-specific varian antigen, plasmodium

falciparum erythrocyte membrane protein 1 (PfEMP1) on the exterior surface of the

infected red cell which mediates attachment of the infected erythrocyte to vascular

endothelium.56,57 This is associated with knob-like projection from the erythrocyte

membrane. Expression increases towards the middle of the cycle (24h). these ‘knobby’

or K + red cells progressively disappear from the circulation by attachment or

‘cytoadherence’ to the walls of venules and capillaries in the vital organs. This process

is called ‘sequestration’. The other there ‘benign’ human malarias do not cytoadhere in

systemic blood vessels and all stages of development circulate in bloodstream.

33

As P.vivax grows it enlarges the infected red cell, which in contrast to

P.falciparum, leads to an increase in deformability as the parasite matures. Red granules

known as schuffner’s dots appear throughtout the erythrocyte. Similar dots are also

prominent in P.ovale , which also distrost the shape of the infected erythrocyte (hence

its name). P.malariae pruduces characteristic ‘band forms’ as the parasite grows. It is

usually present at low parasitaemias. When humans are infected with the potentially

lethal monkey malaria p. Knowlestsi it also produces band forms, and is therefore often

mistaken for P. malariae58. High parasitaemias (over 2%) are usually caused by

P.falciparum22. Apporoximately nuclear division takes place to form a ‘segmenter’ or

schizont (the term ‘meront’ is etymologically more correct). Eventually the growing

parasite occupies the entire red cell which has become spherical, depleted in

haemoglobin, and full of merozoites. It then ruptures, so that between 6 and 36

merozoites are realesed, destroying the remmants of the red cell. Following

P.falciparum schizogony the residual cytoadherent erythrocyte membrane and

associated malaria pigment often remain attached to the vascular endhotelium for many

hours. The released merozoites rapidly re-invade other red cells and start a new asexual

cycle. Thus, the infection expands logarithmically at approximately 10-fold per cycle.59

only a sub-population of erythrocytes can be invaded. This is determined largely by red

cell age. P.vivax can invade red cells for up to 2 weeks after emergence from the bone

marrow. In Thailand, P.falciparum parasites causing severe malaria showed unselective

invasion, and had a graeter multiplication potential at high densities than those which

caused uncomplicated malaria.60,61 The asexual life cycle is apporoximately 24 h for

P.knowlesi, 48 h for P.falciparum, P. vivax and P.ovale, and 72 h for P. Malariae

Sexual stages and development in the mostquito

After a series of sexual cycle in plasmodium falciparum, a sub-populatioon of

parasites develops into sexual forms (gamethocytes) which are long lived and motile.

These are the stages which transmit in infection. The process of gametocytogony takes

about 7- 10 datys in P. falciparum. Thus there is an interval of approximately 1 week

between the peaks of asexual and sexual stage parasitaemia in acute falciparum

34

malaria. In contrast P. vivax begins gametocytogenesis immediately, and the process of

gametocytogony in the blood srage infection takes only 4 days. Symptomatic P.vivax

infection are tgerefore more likely to present whit patent gametocytaemia and to

transmit before treatment then acute P.falciiparum infection. The male-to-female

gametocyte sex ratio for P.falciparum is apporoximately 1:4.64 One male (containing 8

microgametes) and one female (macrogamete) are required per mosquito blood meal

(apporoximately 2µL) for infection to occur. Thus gametocyte densities of 1 per µL

theorerically sufficient to infect mostquitoes, a density beneath the limit of detection for

most routine for microscopy. Following ingestion in the blood meal of a biting female

anopheline mosquito, the male and female gametocytes become activated in the

mosquito’s gut. The male gametocytes undergo rapid nuclear division and each of the

eight nuclei formed associates whit a flagellum (20-25 µm long). The motile male

microgametes separate and seek the female macrogametes. Fusion and meiosis then take

place to form a zygote. For a brief period, the malaria parasite genome is diploid within

24 h the enlarging zygote becomes motile and this form (the ookinete) penetrates the

wall of the mosquito mid-gut (stomach) where it encysts (as an oocyst). This spherical

bag of parasites expands by asexsual division to reach diameter of approximately stage

of oocyst development there is a characteristic pigment pattern and colour that allows

specification (it was this that caught the eye of its discoverer, Ronald Ross, in 1894) ,

but these patterns become obscured by by the time the oocyst has matured to contain

thousands of fusiform motile sporozoites. The oocyts finally bursts to liberate myriads

of sporozoites into the coelomic cavity of mosquito. The sporozoites then migrate to the

salivary glands to await inoculation into the next human host during feeding. The

development of the parasite in the mosquito is termed sporogony, and takes between 8

and 35 days depending on the ambient temperature and species of parasite and

mosquito. The longevity of the mosquito is a critical factor in determining its vectorial

capacity. (see above).

Molecular Genetics

Inheritance in plasmodium is similar to that in other eukaryotes. Haploid and

diploid generations alternate. A large number of individual genes were cloned and

35

sequenced on the long and winding (and as yet unfinished) road towards the

development of a malaria vaccine, and in the fast few years the entire genome of several

a malaria parasites have been sequenced. P. falciparum has approximately 6000 genes

in its 14 chromosomes and extrachromosomal elements compared with the 31.000 of its

natural host. Codon composition is extremely biased to adenine and thymidine in P.

falciparum but more evenly balanced in the other malaria parasites genomes. There

appear to be some groupings of genes relared to function. For example, the genes

encoding the merozoite surface proteins are grouped. The many genes encoding the

variant red cell surface anrigens (‘var’ and ‘rif’ families), which contribute to the

antigenic diversity necessary for the parasite to elude the host immune system, are also

located close to each other near the telomeres. The ‘var’ gene product, the variant

surface protein which mediates cytoadherence (PfEMP1) appears the main antigen

determining the parasites population structure during chronic falciparum malaria

infections. 64 Variation in surface antigenicity result from the activation of the different

‘var’ gene. This switching occurs at different rates, some of which exceed 2% per

asexual cycle. It has been suggested that the diversity of these immunodominant variant

repeat sequences interferes with the selection of high affinity antibody responses, and

perpetuates low affinity responses in malaria. This ‘confusion of the immune response’

delays the development of effective immunity. 65 immune selection also provides the

selective pressure to maintain diversity in T- and B cell epitopes through a high

frequency of nonsynonymous base mutations during the asexual development of malaria

parasites. On a large scale , drug resisrance has had a profound effect on the malaria

parasite population structure. The progeny of single drug resistant parasites ( first

bearing chloroquine resistence and later sulfadoxine – pyrimethamine resistence) which

otiginated in south-east asia have swept across India and then spread across southern

and eastern Africa.

The mechanisms maintaining genetic diversity within the parasite genome are

many and complex.66 some of the polymorphic antigens identified are encoded by

single gene copies in the haploid genome. These polypeptide antigens are characterized

by tandem repeat sequences. Unequal crossing over during recombination can generate

36

completely different sequences of these repeats. As these repeat sequences are also

antibody targets,their variation provides antigenic diversity.

PATHOPHYSIOLOGY

The pathophysiology of malaria results from destruction of erythrocytes, the liberation

of parasite and erythrocyte material into the circulation, and the host reaction to these

events. P. falciparum malaria infected erythrocytes sequester in the microcirculation of

vital organs, interfering with microcirculatory flow and host tissue metabolism.

Toxicity and cytokines

For many years malariologists hypothesized that parasites contained a toxin which was

liberated at schizont rupture, and caused the symptoms of the paroxysm. No toxin in the

strict sense of the word has ever been identified, but malaria parasites do induce release

of cytokines in much the same way as bacterial endotoxin. 118,119 A glycolipid

material with many of the proper-ties of bacterial endotoxin is released on meront

rupture."' This material is associated with the glycosylphosphatidylinositol anchor

which covalently links proteins including the malaria parasite surface antigens to the

cell membrane lipid bilayer.120, 121 This activates host inflammatory responses in

macrophages by signal ling through toll-like receptor (TLR) 2 and to a lesser extent

TLR 4,121,111 Malaria antigen-related IgE complexes also activate cytokine release. The

limulus lysate assay, a test of endotoxin-like activity, is often positive in acute malaria.

These products of malaria parasites, and the crude malaria pigment which is released at

schizont rupture, induce activation of the cytokine cascade in a similar manner to the

endotoxin of bacteria. But they are consider ably less potent. For example an Lcoli

bacteraernia of I bacterium/mL carries an approximate mortality of 20% whereas in

falciparum malaria only parasite densities of well over 10'/mL produce such a lethal

effect. Clearly, compared with bacteria, malaria parasites are notable for their lack of

toxicity! Cells of the macrophage monocyte series, 7/5 T cells, (x/P T cells, CD14+

37

cells and endothelium are stimulated to release cytokines in a mutually amplifying chain

reaction. Initially tumour necrosis factor (TNF), which plays a pivotal role, interleukin

(IL)-I, and gamma interferon (TFN) are prodbred and these in turn induce release of a

cascade of other 'pro-inflammatory' cytokines including IL-6, IL-8, IL-12, IL-18.121-127

These are balanced by production of the 'anti inflammatory' cytokines, notably IL-IO."'

Cytokines are responsible for many of the symptoms and signs of the infection,

particularly fever and malaise. Plasma concentrations of cytokines are elevated in both

acute vivax and falcipanim malaria.121-111,129,130

In established vivax malaria, which tends to synchronize earlier than P, falciparum, a

pulse release of TNF occurs at the time of schizont rupture and this is followed by the

characteristic symptoms and signs of the 'paroxysm', i.e. shivering, cooll extremities,

headache, chills, a spike of fever, and sometimes rigors followed by sweating,

vasodilatation and defervescence."' For a given number of parasites Plasmodium vivax

is a more potent inducer of TNF release than P. falciparum, which may explain its lower

pyrogenic density.

It has been proposed that severe malaria and bacterial septicaemia may have a

common cytokine-mediated pathology, despite considerable differences in their clinical,

metabolic and haemodynamic manifestations. Cytokine concentrations in the blood

fluctuate widely over a short period of t; me, and are high in both P. tdwx and P.

falciparum; indeed some of the highest TNF concentrations recorded in malaria occur

during the paroxysms of synchronous P. Pit= infections."' Nearly all the TNF measured

in these assays is bound to soluble receptors; there is usually little or no bioactivity.

Nevertheless, in most series there is a positive correlation between cytokine levels and

prognosis in severe falciparum malaria. Acute malaria is associated with high levels of

most cytokines but the balance differs in relation to severity. IL- 12 and TGF-P I, which

may regulate the balance between pro-and antiinflammatory cytokines, are higher in

uncomplicated than severe malaria. "I IL-12 is inversely correlated with plasma lactate -

a measure of disease severity IL-10, a potent antiinflammatory cytokine, increases

markedly in severe malaria but, in fatal cases, does not increase sufficiently to restrain

the production of TNE"' A reduced IL-I0/TNF ratio has also been associated with

38

childhood malarial anaemia in areas of high transmission.""' All this points to a

disturbed balance of cytokine production in severe malaria.

The first studies to associate elevations in plasma cytokine levels with disease

severity focused on TNF and cerebral malaria, and led to the suggestion that TNF

played a causal role in coma and cerebral dysfunction. Genetic studies from Africa

indicated that children with the (308A) TNF2 allele, a polymorphism in the TNF

promoter region, had a relative risk of 7 for death or neurological sequelae from

cerebral malaria .7' This finding was not confirmed in studies from South-east Asia. A

separate polymorphism in this region which affects gene expression was associated with

a four-fold increased risk of cerebral malaria." On the other hand, the clinical studies in

cerebral malaria with anti-TNF antibodies, and other strategies to reduce TNF

production reported to date have shown no convincing effects other than reduction in

fever."' in contrast to contradictory evidence in severe falciparum malaria, there is good

evidence that cytokines do play a causal role in the pathogenesis of cerebral symptoms

in murine models of severe malaria."' Numerous interventions have been beneficial in

this model, but the clinical relevance of these observations is uncertain as Murine

'cerebral malaria' is clinically and pathologically unlike human cerebral malaria. There

is no direct evidence that systemic release of TNF or other cytokines causes coma in

humans (although mechanisms involving local release of nitric oxide and other

medicators within the central nervous system and consequent inhibition of

neurotransmission can be hypothesized). In a large prospective study in adults with

severe malaria, elevated plasma TNF concentrations were associated specifically with

renal dysfunction,130 and TNF levels were actually lower in patients with pure cerebral

malaria than those with other manifestations of severe disease. Severe malarial anaemia

has been associated with yet another TNF promoter polymorphism (238A; odds ratio,

OR 2,5).80 Taken together, these various finding do not support a cytokine mediated

pathology that is common to sepsis and malaria, although they do suggest some role for

TNF and other cytokines in severe disease, (but not encephalopathy perse). The extent

to which these cytokine abnormalities are a cause or an effect of severe disease remains

to be determined.

39

Cytokines are probably involved in placental dysfunction, suppression of

erythropoiesis and inhibition of gluconeogenesis, and certainly do cause fever in

malaria. Tolerance to malaria, or premunition, reflects both immune regulation of the

infection and also reduced production of cytokines in response to mal toxic immunity).

Cytokines upregulate the endothelial expression of vascular ligands for P.

falciparum-infected erythrocytes, notably ICAM-1, and thus promote cytoadherence.

They may also be important mediators of parasite killing by activating leukocytes, and

possibly other cells, to release toxic oxygen sped oxide, and by generating parasiticidal

lipid peroxides and causing fever. Thus, whereas high concentrations cytokines appear

to be harmful, lower levels probably benefit the host.

Sequestration

Erythrocytes containing mature forms of P. falciparum adhere to microvascular

endothelium ('cytoadherence') and thus from the circulation, This process is known as

sequestration (Figure 73.7). The simian malaria parasites P. coatneyi and P. fragile

infecting rhesus monkeys also sequester, but this does not occur to a significant extent

with the other three human malaria parasites. Sequestration is thought to be central to

the pathophysiology of falciparum malaria.139-141

The mechanics of cytoadhefence are similar to leukocyte endothelial

interactions. Tethering (the initial contact) is followed by rolling and then firm

adherence (stasis). Once adherent, the parasitized cell remains stuck until schizogony

and even aftewards the residual membranes (and often the attached pigment body)

remain attached to the vascular endothelium. Rolling is probably the rate-limiting factor

determining cytoadherence.142

Blood is a complex soup of deformable cells suspended in plasma proteins,

electrolytes, and a variety of small organic molecules. its effective viscosity changes

non-linearly under the different shear rates encountered in the circulation

(non-Newtonian behaviour). At haematocrits <12% (i.e. severe anaemia), red blood cell

suspensions exhibit Newtonian behaviour. Under experimental conditions, changes in

40

haematocrit over the range commonly encountered in severe malaria (venous

haematocrit, 10-30%, capillary values are lower) have major effects on cytoadherence.

Rolling increased five-fold as haematocrit rose from 10% to 20% and cytoadhesion rose

12-fold between 100/b and 30%. Over this range, the viscosity of blood approximately

doubles, and so if shear stress is held constant, shear rates fall by approximately half

allowing greater time for contact between cells and endothelium. The higher the

haematocrit, the more that cells roll along the endothelial surface, and a higher

proportion of these adhere to the vascular endothelium.143

Once infected red cells adhere, they do not enter the circulation again, remaining

stuck until they rupture at merogony (schizogony).144

B

Figure 73.7 Two electron micrographs (x4320) showing densely packed parasitized

erythrocytes sequestered in cerebral venules of a fatal case of cerebral malaria. Note that

even when no intracellular parasite is seen, electron dense deposits are evident on the

cell membranes indicating the red cell does contain a parasite, but that its body has been

missed in the section. The packing of red cells is much tighter than in normal

conditions. (Courtesy of Emsrii Pongponratn.)

41

Figure 73.8 Uninfected red cells must squeeze past the static, rigid, spherical

cytoadherent parasitized erythrocytes to maintain flow. This is compromised by the

reduced cleformability of uninfected red cells in severe malaria and the intererythrocytic

adhesive forces that mediate rosetting.

Under febrile conditions cytoadherence begins at approximately 12 h after merozoite

invasion, and reaches 50% of maximum after 14-16 h. Adherence is essentially

complete in the second half of the parasites' 48-h asexual life cycle. As a consequence,

whereas in the other malarias of man mature parasites are commonly seen on blood

smears, these forms are rare in falciparum malaria, and often indicate serious infection."

It was thought that ring stage-infected erythrocytes do not cytoadhere at all, but recent

pathological and laboratory studies show that that they do, although much less so than

more mature stages.144,145 Ring form-infected parasites are also concentrated in the

spleen and placenta, raising the intriguing possibility that the entire asexual cycle could

take place away from the peripheral circulation. Sequestration occurs predominantly in

the venules of vital organs (Figure 73.7). It is not distributed uniformly throughout the

body, being greatest in the brain, particularly the white matter, prominent in the heart,

eyes, liver, kidneys, intestines and adipose tissue, and least in the skin.140,146 Even within

the brain the distribution of sequestered erythrocytes varies markedly from vessel to

vessel,144 possibly reflecting differences in the expression of endothelial receptors

(Figure 73.8). Cytoadherence and the related phenomena of rosetting and

autoagglutination lead to microcirculatory obstruction in falciparum malaria (Figure

73.7).147 The gross microcirculatory obstruction caused by cytoadherent erythrocytes

42

has recently been clearly visualized in vivo using polarised light imaging (in the buccal

and rectal microcirculation) and by high resolution fluoroscein angiography of the

retinal circulation.111,149

The consequences of microcirculatory obstruction are activation of the vascular

endothelium, endothelial dysfunction, together with reduced oxygen and substrate

supply, which leads to anaerobic glycolysis, lactic acidosis and cellular dysfunction.

Cytoadherence

Cytoadherence is mediated by several different processes. The most important

parasite ligands are a family of strain-specific, high molecular weight parasite-derived

proteins termed P. falciparu?n erythrocyte membrane protein I or PfEMP-1.57,141,150

These variant surface antigen (VSA) proteins (molecular mass 240-20 kDa) are encoded

by 'var' genes, a family of -60 genes distributed in three general locations within the

haploid genome: either immediately adjacent to the telomere, close to a telomeric Ivaf

gene, or in internal clusters.151

Each parasitized red cell expresses the product of a single gene, a process which

is tightly controlled at the transcriptional level, and varies between different parasites

and different PfEMP-1 genes.152 PfEMP-1 is transcribed, synthesized, and stored within

the parasite. Beginning at around 12 h of development, it is then exported to the surface

of the infecting erythrocyte.153 There it is apposed by an electrostatic interaction through

the membrane to a submembranous accretion of parasite-derived knob-associated

histicline-rich protein (KAHRP) which is in turn anchored to the red cell via the

cytoskeleton protein ankryn."' These accretions cause humps or knobs on the surface of

the red cell, which are the points of attachment to vascular endothelium (Figure 73.9).

The protuberances are not essential for cytoadherence (Figure 73.10). A small

subpopulation of naturally occurting parasites do not induce surface knobs, and

parasites can be selected in culture which are knob negative (K-) but still cytoadhere.

However, natural parasite isolates are nearly always knob positive (K+). PfEMP-1

protrudes from the red cell surface offering several Duffy binding-like (DBL) domains

43

each capable of binding to particular vascular 'receptors' Analysis of multiple PfEMP-1

sequences has revealed common antigenic determinants in the DBL-1 domain, a

constituent of the so-called 'head structure common to all PfEMP- I variants that is

involved in the formation of rosettes and in cytoadherence. PfEMP- I expression is

greatest in the middle of the asexual cycle. PfEMP1 is an important adhesion molecule

and as it is a parasite protein exposed to immune recognition, it is also a major antigenic

determinant for the blood stage parasite. Two other variant surface antigeps encoded by

different gene families have been identified - the Rifins and the Surfins,155-156 Their

function is uncertain. Proteins expressed only on the younger ring stage infected red

cells have also been identified in parasite lines which subsequently develop a

chondroitin-sulphate A binding phenotype. These could play a role in ring stage

cytoadherence.

As in other protozoal parasites, the immmodominant surface antigen undergoes

antigenic variation to 'change its coat’ and avoid immune mediated attack. Each P.

faiciparum var gene appears to have different rates of switching on and off, with a net

result that the infecting parasite population 'switches, to a new variant of PfEMP I at an

average rate of about 2% per asexual cycle in culture158 although this may be

considerably higher in vivo. Interestingly, the PfEMP-1 gene expressed shows some

dependence on previous variant expression, reflecting the effects of host immune

response on parasite antigenic variation.159

In the chronic phase of untreated infections, this antigenic variation results in

small waves of parasitaemia approximately every three weeks. In addition to the 'var',

'rifin’ and 'surfin’ variant surface antigen gene superfamilies of P. falciparum, genome

sequencing has revealed the 'vir' gene superfamily in Plasmodium vivax.160 A protein

similar to PfEMP-I named sequestrin (molecular mass 270 kDa) has been identified on

the surface of infected red cells using anti-idiotypic antibodies raised against ont

putative vascular receptors CD36 (see below).161 The protein MESA may also be

partially expressed on the surface of the red cell and has been suggested as a contributor

to cytoadherence. The central role of parasite derived proteins in cytoadherence is not

accepted by all. It has been suggested that cytoadherence is mediated by altered red cell

44

membrane components such as a modified form of the red cell cytoskeleton protein

band 3 (the major erythrocyte anion transporter, also called Pfalhesiti).162 In culture,

most parasites lose the ability to cytoadhere after several cycles of replication. In vivo,

cytoadherence maybe modulated by the spleen.163 This has been shown in Saimiri

monkeys infected with P.falciparum. Parasitized erythrocytes do not cytoadhere in s

mized monkeys. Rare patients who have had a splenectodevelop falciparum malaria and

in some of these all stages of the parasite are seen in peripheral blood smears.164

Vascular enclothelial ligands

A number of different cell adhesion molecules expressed on the surface of

vascular endothelium have been shown to bind parasitized red cells (Figure 73. 10). The

interaction between these proteins and the variant surface adhesin of the parasitize red

cell is complex. The property of cytoadherence can be studied in vitro with cells

expressing the potential ligands on their surface (e.g. human umbilical vein/dermal

microvascular or cerebral enclothelial cells or transfected COS cells) or with the

immobilized purified candidate ligand proteins. Probably the most important of these

proteins is the leukocyte differentiation antigen CD36 165,166;

Figure 73.10 Schematic representation of cytoadherence in falciparum malaria. On the

red cell side, the principal ligand is the variant antigen pla5modium falciporum

45

erythrocyte membrane protein I (PfEMPl). This is expressed on the surface of 'knobs'

which protrude from the red cell surface. It is anchored beneath tolthe knob associated

histicline rich protein (KAHRP), and stabilized by PfEMP3. The rifin and CLAG gene

products are not directly involved in adhesion but CLAG does appear to be required for

cytoadherence. Parasite modified band 3 (the major anion transporter) contributes to

adhesion probably by binding to thrombosponclin (TSA). Sequestrin is a distinct

parasite derived protein also mediating adhesion. The ring stage adhesion"' (not shown)

is distinct from NEW, and expressed in the first third of the asexual cycle. On the

vascular endothelial side, many molecules facilitate adhesion by bir;ding PfEMPI. The

most important is the cellular differentiation antigen: CD36. Intercellular adhesion

molecule I (ICAM 1) is important particularly in the brain, elsewhere it synergises with

CD36. Chondroitin sulphate A (CSA) attached to thrombomodulin (TM), are very

important for placental sequestration. Hyaluronic acid (HA) has also been implicated as

a receptor for placental sequestration, but the evidence for this has weakened as it has

emerged that HA is usually contaminated with CSA. The other identified adhesion

molecules are vascular cell adhesion molecule 1 (VCAMl), E-selectin, platelet

enclothelial cell adhesion molecule I (PECAMI), m, P, integrin, heparan sulphate (HS)

and P-selectin.

Nearly all freshly obtained parasites bind to CD36.167 Binding is increased at low pH

(<7.01 and in the presence of high calcium concentrations."' CD36 is constitutionally

expressed on vascular endothelium, platelets, and monocytes/ macrophages but is

usually not present on the surface of cerebral vessels,"' although it has been suggested

that parasitized erythrocytes could bind via CD36 to platelets adherent to cerebral

vascular endothelium."

The intercellular adhesion molecule (ICAM-1 or CD54), which is also the

receptor for rhinovirus attachment, appears to be the major cytoadherence receptor in

the brain. 169,171 ICAM-1, but not CD36, is upregulated by cytokines (notably

TNF(x), and provides a plausible pathological scenario whereby cytokine release

enhances cytoadherence. At physiological shear rates (i.e. those likely to be encountered

in the human microcirculation) the binding forces (c.10-"N) are similar for CD36 and

46

ICAM-1.142,172,173 For both, the forces of attachment are lower than those required for

detachment, which suggests post-attachment alterations to increase adhesion. Binding to

the two ligands is synergistic. 174 Thrombospondin (a natural ligand for CD36) will

also bind to some parasitized red cells (probably to modified band 3). Other proteins

including VCAM-I, PECAM/CD31, E-selectin and the integrin alpha,-beta, have also

been shown to bind in some circumstances.111 P-selectin has been shown to mediate

rolling. The relative importance of these molecules and their interactions in vivo is still

not clear.

Chondroitin sulphate A (CSA) appears to be the major receptor for

cytoadherence in the placenta.175-177 Binding is mediated by a particular PfEMPI

(var2CSA) which gives hope for a specific vaccine against malaria in pregriancy.178,179

Thus, the placenta selects a parasite subpopulation expressing this epitope. Antibodies

which inhibit parasitized red cell cytoadherence by binding var2CSA are generally

present in multigraviclae in endemic areas, but not primigravidae."' This probably

explains why the adverse effects of pregnancy on birth weight are greater in

primigravidae.

Other as yet unidentified vascular receptors are also present, as sequestration

also occuffs in vessels expressing none of the potential ligands identified so far. In

summary ICAM-1 appears to be a major vascular ligand in the brain involved in

cerebral sequestration, CSA is the major ligand in the placenta, and CD36 is probably

the major ligand in the other organs. The relationship between cytoadherence, measured

ex-vivo, and the severity of infection or clinical manifestations has been inconsistent

between studies. This is not particularly surprising, as all parasitized erythrocytes

cytoadhere. Severity is related to the number of parasites in the body and distribution of

cytoadherence within the vital organs. The relative importance of parasite phenotype

and the various potential vascular ligands in the pathophysiology of severe falciparum

malaria and the precise role of the spleen as a modulator of cytoadherence still remains

to be determined.

47

Rosetting

Erythrocytes containing mature parasites also adhere to uninfected

erythrocytes.181 Ibis process leads to the formation of 'rosettes' when suspensions of

parasitized erythrocytes are viewed under the microscope (Figure 73.11). Rosetting

shares some characteristics of cytoadherence.182,183 it starts at around 16 h of asexual life

cycle development (slightly after cytoadherence begins)184 and it is trypsin-sensitive.

But parasite species which do not sequester do rosette"' and unlike cytoadherence,

rosetting is inhibited by certain heparin subfiactions and calcium-chelators.

Furthermore, whereas all fresh isolates of P. falciparum cytoadhere, not all rosette.

Rosetting is mediated by attachment of specific domains of PfEMP1 to the complement

receptor CRI, heparan sulphate, blood group A antigen, and probably other red cell

surface molecules. Attachment is facilitated by serum components recently identified as

Complement factor D, albumin, and IgG anti-band 3 antibodies."' The forces required to

separate a rosette are approximately five times greater than those required to separate

cytoadherent cells, although shearing forces may still be effective in disrupting rosettes

in vivo. When known rosetting parasite lines (K+R+) are perfused through the rat

mesocaecum, an ex vivo model for the study of vascular perfusion, they cause

significantly more microvascular obstruction than isolates which cytoadhere but do not

rosette (K+R-)139,187 Rosetting has been associated with severe malaria in some studies

but not in others.188-191 it has been suggested that rosetting might enwurage

cytoadherence by reducing flow (shear rate), which would enhance anaerobic

glycolysis, reduce pH and facilitate adherence of infected erythrocytes to venular

endothelium. Rosetting tends to ' start in venules, and this could certainly reduce flow.

The adhesive forces involved in rosetting could impede forward flow of uninfected

erythrocytes as they squeeze past sticky cytoadherent parasitized red cells in cap illaries

and venules (Figure 73.9).192,193 The mechanical obstruction or 'static hindrance' would

be compounded by the lack of deformability of the adherent, and circulating parasitized

red cells.

48

Aggregation

Recently a new adherence property of parasitized red cells has been

characterized, and associated with disease severity.194,195 This is the platelet mediated

aggregation of parasitized erythrocytes and is mediated via platelet CD36. These cells

clump together in ex vivo cultures. Aggregation could also contribute to vascular

occlusion.

Red cell deformability

As Plasmodium vivax matures inside the erythrocyte, the cell enlarges and

becomes more deformable." Plasmodium falciparum does exactly the opposite; the

normally flexible biconcave disc becomes progressively more spherical and rigid.","'

The reduction in deformability results from reduced membrane fluidiM increasing

sphericity, and the enlarging and relatively rigid intraerythrocytic parasite. Infected red

cells are less filterable than uninfected cells, and readily removed by the spleen. indeed

it has been argued that sequestration is an adaptive response to escape

B

Figure 73.11 Rosetting. (A) Uninfected red bl9od cells bind to a P. vivax-infected

erythrocyte. (Courtesy of R. Udomsangpetch.)N Transmission electron micrograph of a

rosette around a P. falciparuminfected erythrocyte. (Courtesy of D. Ferguson.)

49

splenic filtration. However, reduced deformability alone cannot account for

microvascular obstruction as it would lead to obstruction at the mid-capillary (i.e. the

smallest internal diameter in the vasculature) and could not explain sequestration in

venules.193

Even in severe malaria the majority of red cells are still unifected. A reduction

of uninfected red cell deformabifity hal been recognized as a major contributor to

disease severrity and outcome. This phenomenon is specific to severe falciparum

malaria; it is not found in sepsis.147 Increased erythrocyte rigidity measu low shear

stresses encountered in capillaries and venules is corelated closely with outcome in

severe malaria.193,196 When assessed at the higher shear rates encountered on the arterial

side, and importantly in the spleen, reduced red cell deformability correlates with

anaernia.197

SIGNS AND SYMPTOMS

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting,

anemia (caused by hemolysis), hemoglobinuria, retinal damage, and convulsions. The

classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor

and then fever and sweating lasting four to six hours, occurring every two days in P.

vivax and P. ovale infections, while every three days for P. Malariae, P. falciparum can

have recurrent fever every 36–48 hours or a less pronounced and almost continuous

fever. For reasons that are poorly understood, but that may be related to high

intracranial pressure, children with malaria frequently exhibit abnormal posturing, a

sign indicating severe brain damage. Malaria has been found to cause cognitive

impairments, especially in children. It causes widespread anemia during a period of

rapid brain development and also direct brain damage. This neurologic damage results

from cerebral malaria to which children are more vulnerable. Cerebral malaria is

associated with retinal whitening, which may be a useful clinical sign in distinguishing

malaria from other causes of fever.

Severe malaria is almost exclusively caused by P. falciparum infection, and

usually arises 6–14 days after infection.[18] Consequences of severe malaria include

50

coma and death if untreated—young children and pregnant women are especially

vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia,

hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure

may occur. Renal failure is a feature of blackwater fever, where hemoglobin from lysed

red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and

cause death within hours or days.[18] In the most severe cases of the disease, fatality rates

can exceed 20%, even with intensive care and treatment.[19] In endemic areas, treatment

is often less satisfactory and the overall fatality rate for all cases of malaria can be as

high as one in ten.[20] Over the longer term, developmental impairments have been

documented in children who have suffered episodes of severe malaria

Main symptoms of malaria

EXAMINATION

In addition to a physical examination and the assessment of health history, the

following tests are instrumental for accurate diagnosis:

Laboratory findings

51

Normochromic, normocytic anemia is usually documented. The leucocyte count

is generally low to normal, although it maybe raised in very severe onfections. The

erythrocyte sedimentation rate, degree of plasma viscosity, and level of C-reactive

protein are high. The platelet count is usually reduced to ~105 /µL. severe infections

maybe accompanied by prolonged prothrombin and partial thromboplastin times and by

severe thrombocytopenia. Levels of antithrombin III are reduced even in mild infection.

In uncomplicated malaria, plasma concentration of electrolytes, blood urea nitrogen, and

creatinine are usually normal. Findings in severe malaria may include metabolic

acidosis, with low plasma concentration of glucose, sodium, bicarbonate, calcium,

phosphate, and albumin together with elevation on lactate, blood urea nitrogen,

creatinine, urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin.

Hypergammaglobinemia is usual in immune amd semi immune sunjects, and urinalysis

usually gives normal results. In adults and children with cerebral malaria, the mean

opening pressure at lumbar puncture is ±160 mm of CSF but because the normal range

in children is lower (<100 mm) most values in children are elevated.; the CSF is usually

normal or has a slightly elevated total protein level [<1.0 g/L (100 mg/dL)] and cell

count (<20/µL). The CSF lactate concentration is reaised in cerebral malaria, and the

glucose maybe slightly low relative to blood.

Diagnosis

Malaria is dignosed by microscopic examination of the blood. It is not a clinical

diagnosis. In malaria endemic areas where malaria is the most common cause of fever,

then it is reasonable to treat for malaria if rapid test or microscopy are not readily

available.

Blood Smears

Thick and thin blood film are made on clean, grease free glass slides. The thick

film is approximately 30 times more sensitive than the thin film, although sensitivity and

specifity depend to a great extent on the experience of the microscopist, the quality of

the slides, atands and microscope, and the time spent examining the slide. Artefacts are

52

common and often confusing. Speciation of malaria at the trophozoite stage is easier on

the thin film, although gametocytes and schizonts are more likely to be seen on the thick

film. The thin film is more accurate for parasite counting. The number of parasitized red

cells per 1000 red cells should be counted. Of there are two parasites in one red cell, this

is counted as one. At low parasitemias (<5/10000 on the thin folm) the thick film should

be counted; the number of parasites per 200, or preferably 500 white cells is noted.

These figures can then be corrected by the total red cell and white cell counts to give the

number of parasites per unit blood volume (µL). Of the white count is not available then

the count is assumed to be 8000 µL. an alternative os to count all parasites in fixed

volume of blood. In severe malaria parasotemias are usually high, and the stage of

parasite development should be assessed on the film. The proportion of asexual parasites

containing visible pigment (i.e. mature trophozyte and schizonts) should be counted. The

presence of pigment in neutrophils and monocyte should also be noted and counted. In

patient who have already received antimalarial treatment, pigment may still be present in

leukocytes after clearance of parasitemia, and this is an important clue to the diagnosis.

Monocytes containinbg pigment are cleared more slowly than pigment containing

neutrophils.

Rapid Diagnostic Test

The introduction of simple, rapid, sensitive, highly specific and increasingly

affordable dipstick or card tests for the diagnosis of malaria has been a major advance in

recent years. These are based on antibody detection of malaria specific antigens in blood

samples; currently histidine rich protein 2 (PfHRP2), parasite lactate dehydogenase

(which is antigenically distinct from the host enzyme), and adolase. Current PfHRP2

and PfLDH tests, based on color reactions, provide a diagnostic sensitivity for

plasmodium falciparum similar to train microscopists..

COMPLICATION OF MALARIA DISEASE

World Health Organisation (WHO) had defined severe malaria while it is found

Plasmodium falciparum in asexual form with one or some of complication below:

1990 WHO definition of severe malaria

53

1. Cerebral malaria – unrousable coma not attributable to any other cause in a patient

with falciparum malaria. The coma should persist for at least 30 min (I h in the 2000

definition) after a generalized convulsion to make the distinction from transient

postictal coma. Coma should be assessed using Blantyre coma scale in children of

the Glasgow coma scale in adults.

2. Severe anaemia – normocytic anaemia with haematocrit <15% or haemoglobin <5

g/dL in the presence of parasitaemia more tha 10.000/µL. note that finger prick

samples may underestimate the heaemolobn concentration by up to 1 g if the finger

is squeezed, if anaemia is hypochromic and/or microcytic, iron deficiency and

thalassaemia/haemoglobinopathy must be exclude. (These criteria are rather

generous; and would include many children in high transmission areas.

Aparasitaemia of >100000/ µL might be a more appropriate threshold.)

3. Renal failure – defined as a urine output of<400 mL 24 h in adults, or 12 mL/kg in

24 h in children, failing to improve after rehydration, and a serum creatinine of more

than 256 µmol/L (>3.0 mg/dL). (In practice for initial assessment, the serum

creatinine alone is used.)

4. Pulmonary oedemaor adult respiratory distress syndrome.

5. Hypocaemia – defined as a whole blood glucose concentration of less tha 2.2

mmol.L (40mg/dL).

6. Circulatory collapse or shock – hypotension (syntolic blood pressu<50 mmHgin

children aged 1-5 years or <70 mmHg in adult), with cold clammy skin or core – skin

temperature difference > 10⁰C. (The more recent review declined to give precise

definitions, but noted the lack of sensitivity or specificity of core-peripheral

measurements.) Capillary refill time is not mentioned but recent studies indicate this

simple test provides a good assessment of severity.449

7. Spotaneous bleeding from gums, nose, gas \trointestinal tract, etc. and /or substantial

laboratory evidence of DIC. (This is relatively unusual.)

8. Reoeated generalized convulsions – more than two observed within 24 h despite 24

cooling. (In young children, these may be febrile convulsions, and the other clinical

and parasitological features need to be taken into account.) Clinical evidence of

54

seizure activity may be subtle (e.g. tonic clonic eye movenments, profuse salivation,

delayed coma recovery).

9. Acidaemia – defined as an arterial or capillary pH <7.35 (note temperature

corrections are needed as most patient are hotter than 37⁰C) or acidosis defined as a

plasma bicarbonate concertration <15 mol/L or a base excess >10. (Operationally.

The clinical presentation of ‘respiratory distress’ or ‘acidotic breathing’ is focused

upon in the 2000 recommendations. Abnormal breathing patterns are a sign of

severity indicating severe acidosis, pulmonary oedema or pneumonia.)

10. Macroscopic haemoglobinuria – if definitely associated with acute malaria infection

and not merely the result of oxidant anti malarial drugs in patiens with erythrocyte

enzyme defects such as G6Pd\D deficiency. (This is difficult to ascertain in practice:

if the G6PD deficiency. y\this part of the definition is not very useful.)

11. Postmortem confirmation of diagnosis. In fatal cases a diagnosis of severe

falciparum malaria can be confirmed by histogicalexamination of a postmortem

needle necroscopy of the brain. The characteristic features. Found especially grey

matter, are venules/capillaries packed with erythrocyte containing mature

trophozoites and schizonts of P. faciparum. (these features may not be presents who

die several days after the tart of treatment, although there is usually some residual

pigment in the cerebral vessels.)

12. Impairment of consciousness less marked than unrousable coma. (Any impairment of

consciousness must be treated seriously. Assessment using the Glasgow Coma Scale

is straightforward, but the Blantyre Scale needs careful local standartdization

particularly in younger children.)

13. Prostration: Inability to sit unassisted in a child who is normally able to do so. In a

child not old enough to sit. This is defined as an inability to feed. This definition is

based on examination not history.

14. Hyperparasitaemia – the relation of parasitaemia to severity of illness different in

different populations and age groups. But in general very high parasite densities are

associated with increased risk of severe disease, e.g. >4% parasitaemia is dangerous

in non-immunes. But may be well tolerated in semi – immune children. In non-

immune children studied in Thailand a parasitaemia ≥4% carried a 3% mortality (30

55

tim higher than in all uncomplicated malaria) but in areas of high transmission value

mush higher may be tolerated well. Many use a threshould definition of 10%

parasitaemia n higher transmission settings.

The following were not considered criteria of severe malaria:

Jaundice – detected clinically or defined by a serum bilirubin concentration >50

µmol/L (3.0 mg/dL). This only marker of severe malaria when combined with

evidence of other vital organ dysfunction such as coma or renal failure.

Hyperpyrexia – a rectal temperature above 40⁰C in adults and children is no longer

considered a sigh of severity.

TREATMENT              

Antimalarial medication

Antimalarial medications are designed to prevent or cure malaria. Drugs which

are used for prophylaxis, treatment & in the prevention for malaria are called

antimalarials.

Treatment of malaria in individuals with suspected or confirmed

infection

Prevention of infection in individuals visiting a malaria-endemic region

who Have no immunity (prophylaxys).

Routine Intermittent treatment of certain groups in endemic regions.

Current practice in treating cases of malaria is based around the concept of

combination therapy, since this offers several advantages - reduced risk of treatment

failure, reduced risk of developing resistance, enhanced convenience and reduced side-

effects.

It is practical to consider antimalarials by chemical structure since this is

associated with important properties of each drug, such as mechanism of action.

Prompt parasitological confirmation by microscopy or alternatively by RDTs is

recommended in all patients suspected of malaria before treatment is started.[1]

56

Treatment solely on the basis of clinical suspicion should only be considered when a

parasitological diagnosis is not accessible

Medications

Quinine and related agents

Quinine has a long history stretching from Peru, and the discovery of the

cinchona tree, and the potential uses of its bark, to the current day and a collection of

derivatives that are still frequently used in the prevention and treatment of malaria.

Quinine is an alkaloid that acts as a blood schizonticidal and weak gametocide against

Plasmodium vivax and Plasmodium malariae. As an alkaloid, it is accumulated in the

food vacuoles of Plasmodium species, especially Plasmodium falciparum. It acts by

inhibiting the hemozoin biocrystallization, thus facilitating an aggregation of cytotoxic

heme. Quinine is less effective and more toxic as a blood schizonticidal agent than

chloroquine; however, it is still very effective and widely used in the treatment of acute

cases of severe P. falciparum. It is especially useful in areas where there is known to be

a high level of resistance to chloroquine, mefloquine, and sulfa drug combinations with

pyrimethamine. Quinine is also used in post-exposure treatment of individuals returning

from an area where malaria is endemic.

The treatment regimen of quinine is complex and is determined largely by the

parasite's level of resistance and the reason for drug therapy (i.e. acute treatment or

prophylaxis). The World Health Organization recommendation for quinine is 20 mg/kg

first times and 10 mg/kg 8 hr for 5days where parasites are sensitive to quinine,

combined with doxycycline, tetracycline or clindamycin. Doses can be given by oral,

intravenous or intramuscular routes. The recommended method depends on the urgency

of treatment and the available resources (i.e. sterilised needles for IV or IM injections).

Use of quinine is characterised by a frequently experienced syndrome called

cinchonism. Tinnitus (a hearing impairment), rashes, vertigo, nausea, vomiting and

abdominal pain are the most common symptoms. Neurological effects are experienced

in some cases due to the drug's neurotoxic properties. These actions are mediated

through the interactions of Quinine causing a decrease in the excitability of the motor

neuron end plates. This often results in functional impairment of the eighth cranial

57

nerve, resulting in confusion, delirium and coma. Quinine can cause hypoglycaemia

through its action of stimulating insulin secretion; this occurs in therapeutic doses and

therefore it is advised that glucose levels are monitored in all patients every 4–6 hours.

This effect can be exaggerated in pregnancy and therefore additional care in

administering and monitoring the dosage is essential. Repeated or over-dosage can

result in renal failure and death through depression of the respiratory system.

Quinimax and quinidine are the two most commonly used alkaloids related to

quinine in the treatment or prevention of malaria. Quinimax is a combination of four

alkaloids (quinine, quinidine, cinchoine and cinchonidine). This combination has been

shown in several studies to be more effective than quinine, supposedly due to a

synergistic action between the four cinchona derivatives. Quinidine is a direct derivative

of quinine. It is a distereoisomer, thus having similar anti-malarial properties to the

parent compound. Quinidine is recommended only for the treatment of severe cases of

malaria.

Chloroquine

Chloroquine was until recently the most widely used anti-malarial. It was the

original prototype from which most methods of treatment are derived. It is also the least

expensive, best tested and safest of all available drugs. The emergence of drug-resistant

parasitic strains is rapidly decreasing its effectiveness; however, it is still the first-line

drug of choice in most sub-Saharan African countries. It is now suggested that it is used

in combination with other antimalarial drugs to extend its effective usage.

Chloroquine is a 4-aminoquinolone compound with a complicated and still

unclear mechanism of action. It is believed to reach high concentrations in the vacuoles

of the parasite, which, due to its alkaline nature, raises the internal pH. It controls the

conversion of toxic heme to hemozoin by inhibiting the biocrystallization of hemozoin,

thus poisoning the parasite through excess levels of toxicity. Other potential

mechanisms through which it may act include interfering with the biosynthesis of

parasitic nucleic acids and the formation of a chloroquine-haem or chloroquine-DNA

complex. The most significant level of activity found is against all forms of the

schizonts (with the obvious exception of chloroquine-resistant P. falciparum and P.

58

vivax strains) and the gametocytes of P. vivax, P. malariae, P. ovale as well as the

immature gametocytes of P. falciparum. Chloroquine also has a significant anti-pyretic

and anti-inflammatory effect when used to treat P. vivax infections, and thus it may still

remain useful even when resistance is more widespread.

Children and adults should receive 25 mg of chloroquine per kg given over

3 days. A pharmacokinetically superior regime, recommended by the WHO, involves

giving an initial dose of 10 mg/kg followed 6–8 hours later by 5 mg/kg, then 5 mg/kg

on the following 2 days. For chemoprophylaxis: 5 mg/kg/week (single dose) or

10 mg/kg/week divided into 6 daily doses is advised. Chloroquine is only recommended

as a prophylactic drug in regions only affected by P. vivax and sensitive P. falciparum

strains. Chloroquine has been used in the treatment of malaria for many years and no

abortifacient or teratogenic effects have been reported during this time; therefore, it is

considered very safe to use during pregnancy. However, itching can occur at intolerable

level and Chloroquinine can be a provocation factor of psoriasis.

Amodiaquine

Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure and

mechanism of action to chloroquine. Amodiaquine has tended to be administered in

areas of chloroquine resistance while some patients prefer its tendency to cause less

itching than chloroquine. Amodiaquine is now available in a combined formulation with

artesunate (ASAQ) and is among the artemisinin-combination therapies recommended

by the World Health Organisation. Combination with sulfadoxine=pyrimethamine is no

longer recommended (WHO guidelines 2010).

The drug should be given in doses between 25 mg/kg and 35 mg/kg over 3 days

in a similar method to that used in chloroquine administration. Adverse reactions are

generally similar in severity and type to that seen in chloroquine treatment. In addition,

bradycardia, itching, nausea, vomiting and some abdominal pain have been recorded.

Some blood and hepatic disorders have also been seen in a small number of patients.

59

Pyrimethamine

Pyrimethamine is used in the treatment of uncomplicated malaria. It is

particularly useful in cases of chloroquine-resistant P. falciparum strains when

combined with sulfadoxine. It acts by inhibiting dihydrofolate reductase in the parasite

thus preventing the biosynthesis of purines and pyrimidines, thereby halting the

processes of DNA synthesis, cell division and reproduction. It acts primarily on the

schizonts during the erythrocytic phase, and nowadays is only used in concert with a

sulfonamide.

Proguanil

Proguanil (chloroguanide) is a biguanide; a synthetic derivative of pyrimidine. It

was developed in 1945 by a British Antimalarial research group. It has many

mechanisms of action but primarily is mediated through conversion to the active

metabolite cycloguanil pamoate. This inhibits the malarial dihydrofolate reductase

enzyme. Its most prominent effect is on the primary tissue stages of P. falciparum, P.

vivax and P. ovale. It has no known effect against hypnozoites therefore is not used in

the prevention of relapse. It has a weak blood schizonticidal activity and is not

recommended for therapy of acute infection. However it is useful in prophylaxis when

combined with atovaquone or chloroquine (in areas where there is no chloroquine

resistance). 3 mg/kg is the advised dosage per day, (hence approximate adult dosage is

200 mg). The pharmacokinetic profile of the drugs indicates that a half dose, twice daily

maintains the plasma levels with a greater level of consistency, thus giving a greater

level of protection. The proguanil- chloroquine combination does not provide effective

protection against resistant strains of P. falciparum. There are very few side effects to

proguanil, with slight hair loss and mouth ulcers being occasionally reported following

prophylactic use.

Sulfonamides

Sulfadoxine and sulfamethoxypyridazine are specific inhibitors of the enzyme

dihydropteroate synthetase in the tetrahydrofolate synthesis pathway of malaria

parasites. They are structural analogs of p-aminobenzoic acid (PABA) and compete

60

with PABA to block its conversion to dihydrofolic acid. Sulfonamides act on the

schizont stages of the erythrocytic (asexual) cycle. When administered alone

sulfonamides are not efficacious in treating malaria but co-administration with the

antifolate pyrimethamine, most commonly as fixed-dose sulfadoxine-pyrimethamine

(Fansidar), produces synergistic effects sufficient to cure sensitive strains of malaria.

Sulfonamides are not recommended for chemoprophylaxis because of rare but

severe skin reactions experienced. However it is used frequently for clinical episodes of

the disease.

Mefloquine

Mefloquine was developed during the Vietnam War and is chemically related to

quinine. It was developed to protect American troops against multi-drug resistant P.

falciparum. It is a very potent blood schizonticide with a long half-life. It is thought to

act by forming toxic heme complexes that damage parasitic food vacuoles. It is now

used solely for the prevention of resistant strains of P. falciparum despite being

effective against P. vivax, P. ovale and P. marlariae. Mefloquine is effective in

prophylaxis and for acute therapy. It is now strictly used for resistant strains (and is

usually combined with Artesunate). Chloroquine/proguanil or sufha drug-

pyrimethamine combinations should be used in all other Plasmodia infections.

A dose of 15–25 mg/kg is recommended, depending on the prevalence of

mefloquine resistance. The increased dosage is associated with a much greater level of

intolerance, most noticeably in young children; with the drug inducing vomiting and

oesophagitis. The effects during pregnancy are unknown, although it has been linked

with an increased number of stillbirths. It is not recommended for use during the first

trimester, although considered safe during the second and third trimesters. Mefloquine

frequently produces side effects, including nausea, vomiting, diarrhea, abdominal pain

and dizziness. Several associations with neurological events have been made, namely

affective and anxiety disorders, hallucinations, sleep disturbances, psychosis, toxic

encephalopathy, convulsions and delirium. Cardiovascular effects have been recorded

with bradycardia and sinus arrhythmia being consistently recorded in 68% of patients

treated with mefloquine (in one hospital-based study).

61

Mefloquine can only be taken for a period up to 6 months due to side effects.

After this, other drugs (such as those based on paludrine/nivaquine) again need to be

taken.

Atovaquone

Atovaquone is only available in combination with proguanil under the name

Malarone, albeit at a price higher than Lariam. It is commonly used in prophylaxis by

travellers and used to treat falciparum malaria in developed countries.

Primaquine

Primaquine is a highly active 8-aminoquinolone that is used in treating all types

of malaria infection. It is most effective against gametocytes but also acts on

hypnozoites, blood schizonticytes and the dormant plasmodia in P. vivax and P. ovale.

It is the only known drug to cure both relapsing malaria infections and acute cases. The

mechanism of action is not fully understood but it is thought to block oxidative

metabolism in Plasmodia.

For the prevention of relapse in P. vivax and P. ovale 0.15 mg/kg should be

given for 14 days. As a gametocytocidal drug in P. falciparum infections a single dose

of 0.75 mg/kg repeated 7 days later is sufficient. This treatment method is only used in

conjunction with another effective blood schizonticidal drug. There are few significant

side effects although it has been shown that primaquine may cause anorexia, nausea,

vomiting, cramps, chest weakness, anaemia, some suppression of myeloid activity and

abdominal pains. In cases of over-dosage granulocytopenia may occur.

Artemisinin and derivatives

Artemisinin is a Chinese herb (qinghaosu) that has been used in the treatment of

fevers for over 1,000 years,[4] thus predating the use of Quinine in the western world. It

is derived from the plant Artemisia annua, with the first documentation as a successful

therapeutic agent in the treatment of malaria is in 340 AD by Ge Hong in his book Zhou

Hou Bei Ji Fang (A Handbook of Prescriptions for Emergencies).[5] Ge Hong extracted

the artemesinin using a simple macerate, and this method is still in use today.[6] The

62

active compound was isolated first in 1971 and named artemsinin. It is a sesquiterpene

lactone with a chemically rare peroxide bridge linkage. It is this that is thought to be

responsible for the majority of its anti-malarial action, although the target within the

parasite remains controversial. At present it is strictly controlled under WHO guidelines

as it has proven to be effective against all forms of multi-drug resistant P. falciparum,

thus every care is taken to ensure compliance and adherence together with other

behaviors associated with the development of resistance. It is also only given in

combination with other anti-malarials.

Artemisinin has a very rapid action and the vast majority of acute

patients treated show significant improvement within 1–3 days of receiving treatment. It

has demonstrated the fastest clearance of all anti-malarials currently used and acts

primarily on the trophozite phase, thus preventing progression of the disease. Semi-

synthetic artemisinin derivatives (e.g. artesunate, artemether) are easier to use than the

parent compound and are converted rapidly once in the body to the active compound

dihydroartemesinin. On the first day of treatment 20 mg/kg should be given, this dose is

then reduced to 10 mg/kg per day for the 6 following days. Few side effects are

associated with artemesinin use. However, headaches, nausea, vomiting, abnormal

bleeding, dark urine, itching and some drug fever have been reported by a small number

of patients. Some cardiac changes were reported during a clinical trial, notably non

specific ST changes and a first degree atrioventricular block (these disappeared when

the patients recovered from the malarial fever).

Artemether is a methyl ether derivative of dihydroartemesinin. It is

similar to artemesinin in mode of action but demonstrates a reduced ability as a

hypnozoiticidal compound, instead acting more significantly to decrease gametocyte

carriage. Similar restrictions are in place, as with artemesinin, to prevent the

development of resistance, therefore it is only used in combination therapy for severe

acute cases of drug-resistant P. falciparum. It should be administered in a 7 day course

with 4 mg/kg given per day for 3 days, followed by 1.6 mg/kg for 3 days. Side effects of

the drug are few but include potential neurotoxicity developing if high doses are given.

Artesunate is a hemisuccinate derivative of the active metabolite

dihydroartemisin. Currently it is the most frequently used of all the artemesinin-type

63

drugs. Its only effect is mediated through a reduction in the gametocyte transmission. It

is used in combination therapy and is effective in cases of uncomplicated P. falciparum.

The dosage recommended by the WHO is a 5 or 7 day course (depending on the

predicted adherence level) of 4 mg/kg for 3 days (usually given in combination with

mefloquine) followed by 2 mg/kg for the remaining 2 or 4 days. In large studies carried

out on over 10,000 patients in Thailand no adverse effects have been shown.

Dihydroartemisinin is the active metabolite to which artemesinin is

reduced. It is the most effective artemesinin compound and the least stable. It has a

strong blood schizonticidal action and reduces gametocyte transmission. It is used for

therapeutic treatment of cases of resistant and uncomplicated P. falciparum. 4 mg/kg

doses are recommended on the first day of therapy followed by 2 mg/kg for 6 days. As

with artesunate, no side effects to treatment have thus far been recorded.

Arteether is an ethyl ether derivative of dihydroartemisinin. It is used in

combination therapy for cases of uncomplicated resistant P. falciparum. The

recommended dosage is 150 mg/kg per day for 3 days given by IM injections. With the

exception of a small number of cases demonstrating neurotoxicity following parenteral

administration no side effects have been recorded.

Halofantrine

Halofantrine is a relatively new drug developed by the Walter Reed Army

Institute of Research in the 1960s. It is a phenanthrene methanol, chemically related to

Quinine and acts acting as a blood schizonticide effective against all plasmodium

parasites. Its mechanism of action is similar to other anti-malarials. Cytotoxic

complexes are formed with ferritoporphyrin XI that cause plasmodial membrane

damage. Despite being effective against drug resistant parasites, halofantrine is not

commonly used in the treatment (prophylactic or therapeutic) of malaria due to its high

cost. It has very variable bioavailability and has been shown to have potentially high

levels of cardiotoxicity. It is still a useful drug and can be used in patients that are

known to be free of heart disease and are suffering from severe and resistant forms of

acute malaria. A popular drug based on halofantrine is Halfan. The level of

64

governmental control and the prescription-only basis on which it can be used

contributes to the cost, thus halofantrine is not frequently used.

A dose of 8 mg/kg of halofantrine is advised to be given in three doses at six

hour intervals for the duration of the clinical episode. It is not recommended for

children under 10 kg despite data supporting the use and demonstrating that it is well

tolerated. The most frequently experienced side-effects include nausea, abdominal pain,

diarrhea, and itch. Severe ventricular dysrhythmias, occasionally causing death are seen

when high doses are administered. This is due to prolongation of the QTc interval.

Halofantrine is not recommended for use in pregnancy and lactation, in small children,

or in patients that have taken mefloquine previously. Lumefantrine is a relative of

halofantrine that is used in some combination antimalarial regimens.[7]

Doxycycline

Probably one of the more prevalent antimalarial drugs prescribed, due to its

relative effectiveness and cheapness, doxycycline is a tetracycline compound derived

from oxytetracycline. The tetracyclines were one of the earliest groups of antibiotics to

be developed and are still used widely in many types of infection. It is a bacteriostatic

agent that acts to inhibit the process of protein synthesis by binding to the 30S

ribosomal subunit thus preventing the 50s and 30s units from bonding. Doxycycline is

used primarily for chemoprophylaxis in areas where chloroquine resistance exists. It can

also be used in combination with quinine to treat resistant cases of P. falciparum but has

a very slow action in acute malaria, and should not be used as monotherapy.

When treating acute cases and given in combination with quinine; 100 mg of

doxycycline should be given per day for 7 days. In prophylactic therapy, 100 mg (adult

dose) of doxycycline should be given every day during exposure to malaria.

The most commonly experienced side effects are permanent enamel hypoplasia,

transient depression of bone growth, gastrointestinal disturbances and some increased

levels of photosensitivity. Due to its effect of bone and tooth growth it is not used in

children under 8, pregnant or lactating women and those with a known hepatic

dysfunction.

Tetracycline is only used in combination for the treatment of acute cases of P.

falciparum infections. This is due to its slow onset. Unlike doxycycline it is not used in

65

chemoprophylaxis. For tetracycline, 250 mg is the recommended adult dosage (it should

not be used in children) for 5 or 7 days depending on the level of adherence and

compliance expected. Oesophageal ulceration, gastrointestinal upset and interferences

with the process of ossification and depression of bone growth are known to occur. The

majority of side effects associated with doxycycline are also experienced.

Clindamycin

Clindamycin is a derivative of lincomycin, with a slow action against blood

schizonticides. It is only used in combination with quinine in the treatment of acute

cases of resistant P. falciparum infections and not as a prophylactic. Being more

expensive and toxic than the other antibiotic alternatives, it is used only in cases where

the Tetracyclines are contraindicated (for example in children).

Clindamycin should be given in conjunction with quinine as a 300 mg dose (in

adults) four times a day for 5 days. The only side effects recorded in patients taking

clindamycin are nausea, vomiting and abdominal pains and cramps. However these can

be alleviated by consuming large quantities of water and food when taking the drug.

Pseudomembranous colitis (caused by Clostridium difficile) has also developed in some

patients; this condition may be fatal in a small number of cases.

Resistance

Antimalarial resistance is common.[8]

Anti-malarial drug resistance has been defined as: "the ability of a parasite to

survive and/or multiply despite the administration and absorption of a drug given in

doses equal to or higher than those usually recommended but within tolerance of the

subject. The drug in question must gain access to the parasite or the infected red blood

cell for the duration of the time necessary for its normal action." In most instances this

refers to parasites that remaining following on from an observed treatment. Thus

excluding all cases where anti-malarial prophylaxis has failed. In order for a case to be

defined as resistant, the patient under question must have received a known and

observed anti-malarial therapy whilst the blood drug and metabolite concentrations are

66

monitored concurrently. The techniques used to demonstrate this are: in vivo, in vitro,

animal model testing and the most recently developed molecular techniques.

Drug resistant parasites are often used to explain malaria treatment failure.

However, they are two potentially very different clinical scenarios. The failure to clear

parasitemia and recover from an acute clinical episode when a suitable treatment has

been given and anti-malarial resistance in its true form. Drug resistance may lead to

treatment failure, but treatment failure is not necessarily caused by drug resistance

despite assisting with its development. A multitude of factors can be involved in the

processes including problems with non-compliance and adherence, poor drug quality,

interactions with other pharmaceuticals, poor absorption, misdiagnosis and incorrect

doses being given. The majority of these factors also contribute to the development of

drug resistance.

The generation of resistance can be complicated and varies between plasmodium

species. It is generally accepted to be initiated primarily through a spontaneous mutation

that provides some evolutionary benefit, thus giving an anti-malarial used a reduced

level of sensitivity. This can be caused by a single point mutation or multiple mutations.

In most instances a mutation will be fatal for the parasite or the drug pressure will

remove parasites that remain susceptible, however some resistant parasites will survive.

Resistance can become firmly established within a parasite population, existing for long

periods of time.

The first type of resistance to be acknowledged was to chloroquine in Thailand

in 1957. The biological mechanism behind this resistance was subsequently discovered

to be related to the development of an efflux mechanism that expels chloroquine from

the parasite before the level required to effectively inhibit the process of haem

polymerization (that is necessary to prevent build up of the toxic by products formed by

haemoglobin digestion). This theory has been supported by evidence showing that

resistance can be effectively reversed on the addition of substances which halt the

efflux. The resistance of other quinolone anti-malarials such as amiodiaquine,

mefloquine, halofantrine and quinine are thought to have occurred by similar

mechanisms.

67

Plasmodium have developed resistance against antifolate combination drugs, the

most commonly used being sulfadoxine and pyrimethamine. Two gene mutations are

thought to be responsible, allowing synergistic blockages of two enzymes involved in

folate synthesis. Regional variations of specific mutations give differing levels of

resistance.

Atovaquone is recommended to be used only in combination with another anti-

malarial compound as the selection of resistant parasites occurs very quickly when used

in mono-therapy. Resistance is thought to originate from a single-point mutation in the

gene coding for cytochrome-b.

Spread of resistance

There is no single factor that confers the greatest degree of influence on the

spread of drug resistance, but a number of plausible causes associated with an increase

have been acknowledged. These include aspects of economics, human behaviour,

pharmokinetics, and the biology of vectors and parasites.

The most influential causes are examined below:

1. The biological influences are based on the parasites ability to survive the

presence of an anti-malarial thus enabling the persistence of resistance and the potential

for further transmission despite treatment. In normal circumstances any parasites that

persist after treatment are destroyed by the host's immune system, therefore any factors

that act to reduce the elimination of parasites could facilitate the development of

resistance. This attempts to explain the poorer response associated with

immunocompromised individuals, pregnant women and young children.

2. There has been evidence to suggest that certain parasite-vector

combinations can alternatively enhance or inhibit the transmission of resistant parasites,

causing 'pocket-like' areas of resistance.

3. The use of anti-malarials developed from similar basic chemical

compounds can increase the rate of resistance development, for example cross-

resistance to chloroquine and amiodiaquine, two 4-aminoquinolones and mefloquine

conferring resistance to quinine and halofantrine. This phenomenon may reduce the

usefulness of newly developed therapies prior to large-scale usage.

68

4. The resistance to anti-malarials may be increased by a process found in

some species of plasmodium, where a degree of phenotypic plasticity was exhibited,

allowing the rapid development of resistance to a new drug, even if the drug has not

been previously experienced.

5. The pharmokinetics of the chosen anti-malarial are key; the decision of

choosing a long-half life over a drug that is metabolised quickly is complex and still

remains unclear. Drugs with shorter half-life's require more frequent administration to

maintain the correct plasma concentrations, therefore potentially presenting more

problems if levels of adherence and compliance are unreliable, but longer-lasting drugs

can increase the development of resistance due to prolonged periods of low drug

concentration.

6. The pharmokinetics of anti-malarials is important when using

combination therapy. Mismatched drug combinations, for example having an

'unprotected' period where one drug dominates can seriously increase the likelihood of

selection for resistant parasites.

7. Ecologically there is a linkage between the level of transmission and the

development of resistance, however at present this still remains unclear.

8. The treatment regime prescribed can have a substantial influence on the

development of resistance. This can involve the drug intake, combination and

interactions as well as the drug's pharmokinetic and dynamic properties.

PREVENTION

The prevention of anti-malarial drug resistance is of enormous public health

importance. It can be assumed that no therapy currently under development or to be

developed in the foreseeable future will be totally protective against malaria. In

accordance with this, there is the possibility of resistance developing to any given

therapy that is developed. This is a serious concern, as the rate at which new drugs are

produced by no means matches the rate of the development of resistance. In addition,

the most newly developed therapeutics tend to be the most expensive and are required in

the largest quantities by some of the poorest areas of the world. Therefore it is apparent

69

that the degree to which malaria can be controlled depends on the careful use of the

current drugs to limit, insofar as it is possible, any further development of resistance.

Provisions essential to this process include the delivery of fast primary care

where staff are well trained and supported with the necessary supplies for efficient

treatment. This in itself is inadequate in large areas where malaria is endemic thus

presenting an initial problem. One method proposed that aims to avoid the fundamental

lack in certain countries health care infrastructure is the privatisation of some areas, thus

enabling drugs to be purchased on the open market from sources that are not officially

related to the health care industry. Although this is now gaining some support there are

many problems related to limited access and improper drug use, which could potentially

increase the rate of resistance development to an even greater extent.

There are two general approaches to preventing the spread of resistance:

preventing malaria infections and, preventing the transmission of resistant parasites.

Preventing malaria infections developing has a substantial effect on the potential

rate of development of resistance, by directly reducing the number of cases of malaria

thus decreasing the requirement for anti-malarial therapy. Preventing the transmission

of resistant parasites limits the risk of resistant malarial infections becoming endemic

and can be controlled by a variety of non-medical methods including insecticide-treated

bed nets, indoor residual spraying, environmental controls (such as swamp draining)

and personal protective methods such as using mosquito repellent. Chemoprophylaxis is

also important in the transmission of malaria infection and resistance in defined

populations (for example travellers).

A hope for future of anti-malarial therapy is the development of an effective

malaria vaccine. This could have enormous public health benefits, providing a cost-

effective and easily applicable approach to preventing not only the onset of malaria but

the transmission of gametocytes, thus reducing the risk of resistance developing. Anti-

malarial therapy could be also be diversified by combining a potentially effective

vaccine with current chemotherapy, thereby reducing the chance of vaccine resistance

developing.

70

COMBINATION TERAPHY

The problem of the development of malaria resistance must be weighed against

the essential goal of anti-malarial care; that is to reduce morbidity and mortality. Thus a

balance must be reached that attempts to achieve both goals whilst not compromising

either too much by doing so. The most successful attempts so far have been in the

administration of combination therapy. This can be defined as, 'the simultaneous use of

two or more blood schizonticidal drugs with independent modes of action and different

biochemical targets in the parasite'. There is much evidence to support the use of

combination therapies, some of which has been discussed previously, however several

problems prevent the wide use in the areas where its use is most advisable. These

include: problems identifying the most suitable drug for different epidemiological

situations, the expense of combined therapy (it is over 10 times more expensive than

traditional mono-therapy), how soon the programmes should be introduced and

problems linked with policy implementation and issues of compliance.

The combinations of drugs currently prescribed can be divided into two

categories: non-artemesinin-based combinations and artemesinin based combinations. It

is also important to distinguish fixed-dose combination therapies (in which two or more

drugs are co-formulated into a single tablet) from combinations achieved by taking two

separate antimalarials.

Non-artemisinin based combinations

Components Description Dose

Sulfadoxine-

pyrimethamine(SP)

(Fansidar)

This fixed-dose combination has been

used for many years, causes few adverse effects,

is cheap and effective in a single dose, thus

decreasing problems associated with adherence

and compliance. In technical terms Fansidar is not

generally considered a true combination therapy

since the components do not possess independent

curative activity.[1] Fansidar should no longer be

25 mg/kg of

sulfadoxine and

1.25 mg/kg of

pyrimethamine.

71

used alone for treatment of falciparum malaria.

SP plus chloroquine

High levels of resistance to one or both

components means this combination is effective in

few locations and it is no longer recommended by

WHO guidelines.[1]

Chloroquine

25 mg/kg over 3 days

with a single dose of

SP as described above.

SP plus amodiaquine

This combination has been shown to

produce a faster rate of clinical recovery than SP

and chloroquine, but is clearly inferior to

artemisinin-based combinations (ACTs) for the

treatment of malaria.[1]

10 mg/kg of

Amodiaquine per day

for 3 days with a single

standard dose of SP.

SP plus mefloquine

(Fansimef)

This single dose pill offered obvious

advantages of convenience over more complex

regimes but it has not been recommended for use

for many years owing to widespread resistance to

the components.

Quinine plus

tetracycline/doxycycline

This combination retains a high cure rate

in many areas. Problems with this regime include

the relatively complicated drug regimen, where

quinine must be taken every 8 hours for 7 days.

Additionally, there are significant side effects with

quinine ('cinchonism') and tetracyclines are

contraindicated in children and pregnant women

(these groups should use clindamycin instead).

With the advent of artemisinin-combination

therapies, quinine-based treatment is less popular

than previously.

Quinine

10 mg/kg doses every

8 hours and

tetracycline in 4 mg/kg

doses every 6 hours for

7 days.

According to WHO guidelines 2010, artemisinin-based combination therapies

should be used in preference to amodiaquine plus sulfadoxine-pyrimethamine for the

treatment of uncomplicated P. falciparum malaria.

Artemisinin-based combination therapies (ACTs)

Artemesinin has a very different mode of action than conventional anti-malarials

(see information above), this makes is particularly useful in the treatment of resistant

72

infections, however in order to prevent the development of resistance to this drug it is

only recommended in combination with another non-artemesinin based therapy. It

produces a very rapid reduction in the parasite biomass with an associated reduction in

clinical symptoms and is known to cause a reduction in the transmission of gametocytes

thus decreasing the potential for the spread of resistant alleles. At present there is no

known resistance to Artemesinin (though some resistant strains may be emerging)[9] and

very few reported side-effects to drug usage, however this data is limited.

Components Description Dose

Artesunate and

amodiaquine (Coarsucam and

ASAQ)

This combination has been tested

and proved to be efficacious in many areas

where amodiaquine retains some efficacy. A

potential disadvantage is a suggested link

with neutropenia. It's recommended by the

WHO for uncomplicated falciparum malaria.[1]

Dosage is as a

fixed-dose combination

(ASAQ) recommended

as 4 mg/kg of

Artesunate and

10 mg/kg of

Amodiaquine per day

for 3 days.

Artesunate and

mefloquine (Artequin and

ASMQ)

This has been used as an efficacious

first-line treatment regimen in areas of

Thailand for many years. Mefloquine is

known to cause vomiting in children and

induces some neuropsychiatric and

cardiotoxic effects, interestingly these

adverse reactions seem to be reduced when

the drug is combined with artesunate, it is

suggested that this is due to a delayed onset

of action of mefloquine. This is not

considered a viable option to be introduced

in Africa due to the long half-life of

mefloquine, which potentially could exert a

high selection pressure on parasites. It's

recommended by the WHO for

uncomplicated falciparum malaria.[1]

The standard

dose required is 4 mg/kg

per day of Artesunate

plus 25 mg/kg of

Mefloquine as a split

dose of 15 mg/kg on day

2 and 10 mg/kg on day

three.

Artemether and This combination has been

73

lumefantrine (Coartem

Riamet, Amatem and Lonart)

extensively tested in 16 clinical trials,

proving effective in children under 5 and has

been shown to be better tolerated than

artesunate plus mefloquine combinations.

There are no serious side effects documented

but the drug is not recommended in pregnant

or lactating women due to limited safety

testing in these groups. This is the most

viable option for widespread use and is

available in fixed-dose formulas thus

increasing compliance and adherence. It's

recommended by the WHO for

uncomplicated falciparum malaria.[1]

Artesunate and

sulfadoxine/pyrimethamine

(Ariplus and Amalar plus)

This is a well tolerated combination

but the overall level of efficacy still depends

on the level of resistance to sulfadoxine and

pyrimethamine thus limiting is usage. It is

recommended by the WHO for

uncomplicated falciparum malaria.[1]

It is

recommended in doses

of 4 mg/kg of

Artesunate per day for

3 days and a single dose

of 25 mg/kg of SP.

Dihydroartemisinin-

piperaquine (Duo-Cotecxin,

Artekin)

Has been studied mainly in China,

Vietnam and other countries in SEAsia. The

drug has been shown to be highly efficacious

(greater than 90%). It's recommended by the

WHO for uncomplicated falciparum malaria.

Pyronaridine and

artesunate (Pyramax)

Manufactured by Shin Poong

Pharmaceutical. Has been tested and

demonstrated a clinical response rate of

100% in one trial in Hainan (an area with

high levels of P. falciparum resistance to

Pyronaridine). A multi-centre phase III trial

conducted in Africa found a 99.5% response

rate.[10]

Other combinations

74

Several other anti-malarial combinations have been used or are in development.

For example, Chlorproguanil-dapsone and artesunate (CDA) appears efficacious but the

problem of haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD)

deficiency is likely to prevent widespread use.

PROGNOSTIC FACTORS

The prognostic factors listed in the table below

Biochemistry

Hypoglicaemia <2,2 mmol/L

Hyperlactatemia >5 mmol/L

Acidosis Arterial pH <7,3

Venous plasma HCO3 <15 mmol/L

Serum creatinine >265 µmol/L

Total bilirubin >50 µmol/L

Liver enzymes SGOT (AST) >3 upper limit of normal

SGPT (ALT) >3 upper limit of normal

5-Nucleatidase ↑

Muscle enzymes CPK ↑

Myoglobin ↑

Urate >600 µmol/L

Haematology

Leucocytosis >12000/µL

Severe anemia (PCV < 15 %)

Coagulopathy Platelets <50000/µL

Prothrombin time prolonged >3 s

Prolonged partial

Thromboplastin time

Fibrinogen: <200 mg/dL

Parasitology

Hyperparasitaemia >100000/µL – increased mortality

75

>500000/µL – high mortality

>20 % of parasites are pigment-contaonong thropozytes and schizonts

>5 % of neutrophils contain visible malaria pigment

The table reflect vital organ dysfunction and magnitude of the parasite burden.

They are not absolute and in fatal case, several factors usually co-exist. Some of the

apparently poor prognostic factors can have a benign explanation. Hyperventilation

(respiratory distress) is usually a bad sign (indicating metabolic acidosis, pulmonary

oedema, or pneumonia), but shallow tachipneu can result from high fever alone (the

tidal volume is lower). Upper gastrointestinal bleeding in cerebral malaria may also

occur spontaneously. The prognostic implocations of severe anemia depend on the rate

whoch haematocrit falls, the co-existing parasitemia and metabolic abnormalities and

the stage of the infection. If anemia develops gradually then even haemaglobin values

less thab 7 gr/dL (packed cell volume <20 %) can be surprisingly well tolerated as there

is time for homeostatic adaptation such as the right shift in the oxygen dissociation

curve, the increase in cardiac index and the fall in systemic vascular resistence.

Hypotension is a poorprognostic sign only when associated with poor perfusion, as

evidenced by cool peripheries and poor capillary refill. Patients particularly children,

with acute malaria often have very low blood pressures but they are warm and well

perfused.

The concentration of lactate in venous or arterial blood or CSF is linearly

proportional to the severity of disease. In terms of predictive prognostic values, the

admission venous bicarbonate concentration has the best sensitivity and specifity, and it

is available widely. Persistent acidosis with low plasma bicarbonate and elevated

plasma lactate 4 hours after admission indicates a poor prognosis.Although a deep

jaundice is often a bad sign, some adults patients develop a profound cholestatic

jaundice without other evidence of vital organ dysfunction. Parasitemia has traditionally

been used as a measure of severity. The sensivity and specificity of parasitemia alone is

limited, but can be improved by staging parasite development (more mature parasites –

worse prognosis) and counting the number of polymorphonuclear neutrophil leucocytes

which contain pigment (>5 % - poorer prognosis). For any parasitemia the prognosis is

76

worse if >20 % of parasites contain visible pigment and better if >50 % of parasites

are at the tiny ring stage. Recent studies indicate that measurement of plasmodium

falciparum Histidine Rich protein 2 (PfHRP2) in plasma or serum can be used to

estimate the sequestered parasite biomass in severe malaria.

BIBLIOGRAPHY

Fauci, A.S., Kasper, D.L., Longo, D.L., Braunwald, E., Hauser, S.L., Jameson, J.L., et al. 2008.

Acute Viral Hepatitis. In: Powers , A.C., Ed. Harrison’s Principal of Internal Medicine.

17th ed. New York Chicago San Fransisco Lisbon London Madrid Mexico City New Delhi

San Juan Seoul Singapore Sydney Toronto: Mc-Graw Hill Company Inc. 1932-

1948.Mcphee, J Stephen., Hammer D Garry.,et all : Renal disease .

Pathophysiology of Disease: An Introduction to Clinical Medicine, Sixth

Edition. 2010

Sudoyo, Aru W.et all.BUKU AJAR ILMU PENYAKIT DALAMjilid III., edisi IV. Jakarta

: Pusat penerbitan Departemen ilmu penyakit dalam Fakultas kedokteran

Universitas Indonesia, 2006.

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Perhimpunan Dokter Spesialis Penyakit Dalam Indonesia (PAPDI), Konsensus

Penanganan Malaria 2003, Agustus 2003.

Manson.2009. Tropical disease. Philadelphia : Elsevier Incorporation. 22th edition.

CASE RESPONSE

TROPICAL MALARIAE

Oleh:

78

Arief Fakhrizal

NIM. 41101125

Reported to :

Kol (P). Eddy Harjadi S. dr.SpPD

NRP 29886

INTERNAL MEDICINE DEPARTEMENT

DUSTIRA HOSPITAL / MEDICAL FACULTY OF

GENERAL ACHMAD YANI UNIVERSITY

CIMAHI

2011

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