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Name Gender Religion Occupation Address
: Mr. Jumardin : Male : Islam : Army/Prada
Room : XI Age
: 20 years old
: United dormitory of Pusdik Armed - Cimahi
Sent by Date of examination (Co. ass) Date of treatment Date of Exit
: His Batallyon : May 22th 2011 : May 19th 2011 : May 26th 2011 : 17.30 p.m
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.
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.
a. General complaint Fever Sleep Edema Icteric Thirst Appetite Weight : Present : Present : Absent : Present : Absent : Present : Absent
e. Stomach compliant Local pain Pain with pressure : Absent : Present
Pain in the entire stomach : Absent Pain associated with - Food - Defecation - Menstruation : : Absent : Absent : Absent
Sense of stomach tumor : Absent b. Head complaint Sight Nose Tongue : Absent : Absent : Absent Vomiting Diarrhea Obstipation Tenesmi ad ani Change in defecation Change in Urine : Absent : Absent : Absent : Absent : Absent : Absent
Swallow dysfunction : Absent Hearing Mouth Teeth Voice : Absent : Absent : Absent : Absent
Change in menstruation : Absent
c. Neck Complaint Suffocate in neck Gland enlargement Stiffness neck : Absent : Absent : Absent
f. Arm and Leg complaint Stiffness Fatigue Joint/muscle pain Numbness : Absent : Absent : Absent : Absent : Absent : Absent : Absent : Absent : Absent
d. Chest complaint Shortness of breath Chest pain Wheezing Cough Palpitate : Absent : Absent : Absent : Absent : Absent
Fractures Pain behind the knee Pain with pressure Wound/scar swollen
Addiction e.M . Other Complaint Skin Armpit Lymph node complaint : Absent : Absent : Absent Additional History Taking a.g. Contagious disease : Absent c.D.Thyroid . Venereal disease : Absent : Absent Endocrine gland complaint : .Others : : Absent : Absent : Absent 4 . Nutrition : Quality : Sufficient Quantity : Sufficient b.Menstruation . Hereditary disease : Absent d.
General Awareness Character Impression illness Movement Sleep Height Weight : Composmentis : Cooperatif : Moderate : Unlimited : Supine with one pillow : 173 cm : 65 kg Nutrition condition : BMI= 21. Respiratory condition Type Frequency Pattern : Abdominothoracal : 20x/ minute : Normal 5 .equal. GENERAL IMPRESSION a. adequate : 35.equal. adequate Left :72x/second.7 Skin nutrition Muscle nutrition Body shape Estimated age Skin : Sufficient : Sufficient : Athleticus : Appropriate : anemic (+). icteric (-) b. regular. Circulation Blood Pressure Pulse rate : Right :100/60 mmHg Left : 100/60 mmHg : Right :72x/second.B.50C : Present : Absent Body temperature Cold sweat Cyanosis c. regular. STATUS PRAESEN I.
anemic (+). Eyes Location Eyelids Cornea Cornea reflex Pupils : Symetric : No abnormalities : No abnormalities : +/+ : Circle . Head 1. Ears Inspection Palpation Hearing : Symetric : No abnormalities : No abnormalities 5. Nose Inspection : No abnormalities 6 . Face Inspection Palpation : Symetric. icteric (-) : No abnormalities 3. Indirect +/+ : Examination is not conducted : Examination is not conducted 4. Breath Smell Breath sound : No abnormalities : No abnormalities II. Skull Inspection Palpation : Symetric : No abnormalities 2. SPECIAL EXAMINATION a. Ishokor Convergence Reaction : +/+ Sclera Conjunctiva Iris Movement Light Reaction Visus Funduskopi : Sub icteric : Anemic : No abnormalities : Normal to every direction : Direct+/+.
Obstruction Snot : Absent : Absent 6. Mouth Cavity Hyperemic Lichen Aphtea Spots : Absent : Absent : Absent : Absent 10. Neck 1. Neck Cavity Mucous Membrane : No abnormalities : T1 – T1 quite Pharyng posterior wall : No hyperemic Tonsils : Deviation not seen : Enlargement not seen 7 . Inspection Trachea Glandula thyroid Size Shape Movement Surface Frenulum lingue : Normal : No abnormalities : No abnormalities : anemic (-) : ikterik (-) 9. Lips Cyanosis Kheilitis Stomatitis angularis Rhagaden Perleche : Absent : Absent : Absent : Absent : Absent : Gums : No abnormalities 1 2 3 4 5 6 7 8 1 2 3 4 5 6 78 O = Caries 7. Tongue b. Teeth and Gums 8 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1 X: Toothless 8.
Venous expantion Neck venous pulsation Jugular venous pressure : Absent : Absent : 5 + 1 cmH2O. not increase 2. Palpation Lymph nodes Tumor : No enlargement : Absent d. Inspection General shape ØAnteroposterior &Sagital Epigastric Angle Intercostals Space Movement Skin Musculatur Tumor Ictus cordis : Symetric : ØAnteroposterior < Ø transversal : < 900 : Not widening nor narrowing : Symetric : anemic (+). Palpation Lymph nodes Glandula Thyroid Tumor Neck muscle Neck stiffness : No enlargement : No enlargement : Absent : No abnormalities : Absent c. Axilla 1. icteric (-) : No abnormalities : Absent : Not seen 8 . Inspection Armpit hair Tumor : No abnormalities : Absent 2. Thorax Examination Anterior thorax 1.
Palpation Skin Musculatur Mammae Intercostals Space Lung Movement Vocal fremitus : No abnormalities : No abnormalities : No abnormalities : Not widening nor narrowing Right : Symetric : Normal : : ICS V Linea midclavicularis sinistra : not bounding : not present : not present Left Symetric Normal Ictus cordis Location Intensity Widening Thriil 3. Percussion Lung Percussion sound Liver lung border Right : Sonor Left Sonor : ICS V Linea midclavicula dextra Diafragmatic displacement : 1 intercostal space (2 cm) Heart Up border Right Border Left Border : ICS II Linea sternalis sinistra : Linea sternalis dextra : ICS V linea midclavicularis sinistra 4. Other pulsation Venectation : Absent : Absent 2. Auscultation Lung Main breath sound Right : Vesicular Left Vesicular 9 .
Palpation Intercostal space Musculatur Vocal fremitus : Not widening nor narrowing : No abnormalities No abnormalities : Normal Normal 3. Percussion Lower border Diafragmatic displacement : Vertebra Th-X Vertebra Th-XI : 1 intercostal space (2 cm) 4. A2 > P2 Posterior Thorax 1.- Additional breath sound : Ronkhi(-) Wheezing(-) Ronkhi(-) Wheezing(-) Normal - Vocal resonance : Normal Heart Rhythm Main heart Sound : regular : M1 > M2. Auscultation Main breath sound Additional breath sound : Vesicular : Rhonchi (-) Wheezing (-) Vocal resonance : Normal Vesicular Rhonchi (-) Wheezing (-) Normal 10 . Additional heart sound Obsteperous of heart Pericardial friction rub : Absent : Absent : Absent P1 < P2 A1 < A2. T1 > T2. Inspection Shape Movement Skin Musculatur : Symetric : Symetric : ikterik (-) anemic (-) : No abnormalities Right Left 2.
Palpation Abdomen Local palpation pressure Diffuse palpation pressure Detached pain Defance musculair Liver Enlargement Consitence Surface Edge Pain With Presure : Soft : present a/r hipokondrium dextra : Absent : Absent : Absent : Palpable : 3 cm BAC. Abdomen 1.e. Inspection Shape Abdomen muscle Skin Movement in breathing Intestines movement Pulsation Venectation : Flat : No abnormalities : icteric (-) : No abnormalities : Unseen : Absent : Absent 2. 5 cm BPX : expansible : witness : sharp : present : Palpable : Schuffner I-II : soft : witness : difficult in value : absent : Not palpable : Not palpable Pain with pressure : -/- Spleen Enlargement Consistence Surface Incisura Pain with pressure Tumour/mass Ren 11 .
3. Femoralis : Examination is not conducted : Examination is not conducted : No abnormalities : Examination is not conducted Upper Lower h. Sacrum j. Percussion Percussion sound Ascites Side dullness Shifting dullness Fluid wave : Tympany. Inspection Tumor Lymph nodes Hernia : Absent : Unseen enlargement : Absent 2. Auscultation Bowel sound Bruit Others : (+) Normal : Absent : No abnormalities : Knocking pain -/- f. Inspection Shape Movement : No abnormalities No abnormalities : Unlimited Unimited 12 . Auscultation A. Groin 1. Anus& Rectum k. Palpassion Tumor Lymph node Hernia Pulsasi A. Traube`s space (+) : : (-) : (-) : (-) 4. Femoralis : Absent : No enlargement : Absent : Palpable 3. CVA(Costo vertebral angel) g. Genitalia i. Extremities 1. dull .
Articulatio 1. Neurologic Physiologic ReflexKPR Physiologic ReflexAPR Pathologic reflex Meningen reflex Sensoric : +/+ normal : +/+ normal : -/: absent : +/+ III. LABORATORY FINDINGS BLOOD Hemoglobin Leucocyte Erythrocyte : 8.000 cell/mm3 13 .5 g/dl : 5500 cell/mm3 : 3. Palpation Pain with pressure Fluctuation Others : Absent : Absent : No abnormalities m.500. Skin Muscle Edema Clubbing finger Palmar eritem : No abnormalities No abnormalities : No abnormalities No abnormalities : Absent : Absent : Absent : : Absent : Absent : Absent : Present Absent Absent Absent Present Absent Absent Absent 2. Inspection Deformity Inflamation sign Others : No abnormalities : Absent : No abnormalities 2. Palpation Pain with pressure Tumour Edema (pitting/non pitting) Artery pulsation l.
015 : Acid : : : : - 14 . DDR (+) P.falcifarum stadium trofozoit Leucocyte : No abnormalities Groups of trombocyte : Deficient Impression : Anemia hipochromic ec malaria URINE Color Muddiness Odor Density Reaction Albumin Reduction Urobilin Bilirubin : Yellow : Clear : Amoniak : 1. Trombocyte Differential count Basophils Eosinophils Band Neutrophils : 138.000 cell/mm3 : : 0 % : 1 % : 2 % Segmented Neutrophils : 60 % Lymphocytes Monocytes : 25 % : 12 % Erythrocyte Sedimentation Rate 1st hour 2nd hour : 30 mm : 65 mm Blood Smears Erythrocyte : Hipochrom normosyter.
Sediment Leucocyt Erythrocyte Crystal Bactery Epithelium : 5-8/ HPF : 6-9/HPF : : : 2-4/HPF FAECES Colour Odor Consistency Mucus Blood Parasite Erithrocyt Leucocyt Worm Eggs Food remaining : Brown : Indol skatol : Slack : : : : : : : + 15 .
Fever complaint was not accompanied by a decrease in consciousness or convulsions. This is the first complaint that experienced by the patient. And complaint of defecation wasn’t found. came with complaint of fever. and do not live in flood zones. Fever complaint was accompanied by that looks yellow eyes and a face that looks pale. patients did not drink malaria prevention medication before going to the venue. Fever complaint was not accompanied by a cough for more than three weeks.RESUME A man.occupation: army. and family no one has suffered from this disease. single. 16 . Patients had been visiting and living in malaria endemic area in Papua. headache. nausea without vomiting and poor appetite. sweat out in the evenings or drastic weight loss. 20 years old. Fever complaints was not accompanied by rapid breathing and or shortness of breath in time. bleeding in the eye. Fever complaint was accompanied by weakness. Fever complaint was not accompanied by decreasement of urination. Fever complaint was preceded by rigoris then followed by caloris and sudoris after the fever get down. 9 days ago patient complained of a suddenly high fever. Fever complaint was not accompanied by severe pain in the calf or to make the patient unable to walk. change of urines color that get blackish. While in Papua patients have never experienced such complaints. from 1 January to 15 April 2011 to carry out tamtama education.
Vital sign Blood Pressure Breathing Pulse rate Temperature Cyanosis Cold sweat : 100/60 mmHg : 20x/ second : 72x/second.Before the patient entered the hospital. Special Examination Head Sclera Conjunctiva : Symetric : Sub icteric : Anemic Thorax : Shape and movement are symmetric Skin Heart : anemic (+). regular. General Awareness Impression illness Skin : Composmentis : Moderate : anemic (+).equal. the patient had previously been treated at the unit physician. adequate : 35. Further examination : a. Ronchi -/-. icteric (-) : Heart border Normal 1st Heart Sound &2nd heart sound: reguler Lung : Vesikuler Right lung = Left Lung. but complaint of patients is not reduced and eventually the patient was taken to the emergency room with dustira unity. the patient was given paracetamol tablets and amoxicillin in the drink 3 times a day.50C : Absent : Present c. icteric (-) b. wheezing -/- 17 .
DDR (+) P.Pain With Presure absent Ren Ekstremity : No palpable.Incisura difficult in value .000 cell/mm3 : 138. schuffner I-II Traube’s space was filled .000 cell/mm3 Leucocyte Erythrocyte Trombocyte Blood Smears Erythrocyte : Hipochrom Normosyter. Knocking pain -/- : No abnormality Laboratory Findings BLOOD :Erythrocyte sedimentation rate was high.Pain With Presure present Lien : palpable.Surface witness .Surface witness . Abdomen : Tympany. dull Hepar : Palpable.Consitence expansible .Consitence soft . 3 cm BAC 5 cm BPX .Edge sharp . leucopenia and trombocytopenia Erythrocyte Sedimentation Rate 1st hour 2nd hour : 30 mm : 65 mm : 5500 cell/mm3 : 3.falcifarum stadium trofozoit Leucocyte : No abnormalities Groups of trombocyte : Deficient Impression : Anemia hipochromic ec malaria 18 .500.
PROGNOSE Quo ad vitam Quo ad functionam : Ad Bonam : Dubia Ad Bonam 19 . Widal test I dan II. ALT. bilirubin direct. TREATMENT IVFD Ringer Lactat maintenance 2L/24 hour Inj. DIFFERENTIAL DIAGNOSIS Tropical Malaria Tertiana Malaria Typhoid fever with hepatitis Tifosa V. AST.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. EXAMINATION SUGGESTED : 1. DDR tests (repeated at the 3rd. Gall Kulture VII. bilirubin indirest test 4. bilirubin total.URINE FAECES : Within normal limits : Within normal limits IV. DIAGNOSIS Tropical Malaria VI. PfHRP2 and PfLDH test 3. 7th. 21th. Artem .1st day 2x2 amp (160 mg) im . 14th. and 28th day) 2.
Fever complaint was accompanied by severe headache without followed by unconsciousness decreasement and seizure. and patient feel healthy. nausea . then this period followed by calories period :characterized by red face. tbc. pain at the leg. After that patient will get into sudoris period: patient get sweathing a lot. calories (fever). Fever complaint was also accompanied by nausea but not until get throw up. and the fever stays in few hours.sudoris (sweathing) that happen consecutively. The most happen prodormal sign of malaria tropika are headache. Complaint was accompanied with body’s weakness. malignancy.CASE DISCUSSION Discussion of Chief Complaint patients come to rs dustira with chief complaint of fever I. patient usually wrap his body with blanket. hiv aids Discussion of patients illness Fever complaint was preceded by shivering then followed by sweathing after the fever get down. tachycardia. Frigoris period (15-60 minutes) : begin to shiver. fever of less than seven days include : Chikungunya. The classic symptoms of malaria which is known as trias malaria are frigoris (shivering). the temperature goes down. vomitus and diarrhea but in this patient is not until vomitus and diarrhea copmplaint wasn’t found. appetite decreasement and pain at both of leg. malaria. Fever complaint was accompanied by severe headache without followed by unconsciousness decreasement and seizure. fever for more than seven days include : Typhoid fever. His body will vibrate until the teeth stumble to each other. leptospirosis. avian influenza. 20 . dengue fever II. cold feeling.
Complaint of defecation wasn’t found. such as consciousness decreasement thet stay more than 30 minutes and seizures attack. Patient hasn’t visited any floody area in few months before.To detect any possibility of cerebral malaria complication. yellow eyes. bloody eyes and patient has ever visited floody area before. To detect any possibilities of kidney complications such as acute renal failure and black water fever. In malaria sometimes we can find diarrhea. change of urines color that get blackish. night sweats or weight loss drastically. 21 . Fever complaint was not accompanied by swallow pain. Leptospirosis is characterized by pain at leg which hurt when it is pushed. To eliminate fever caused by leptospirosis. 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. cough and cold. and bloody eyes. yellow eyes. And complaint of defecation wasn’t found. from 1 January to 15 April 2011 to carry out tamtama education. Fever complaint was not accompanied by decreasement of urination. 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. To eliminate the possibility of fever caused by upper respiratory tractus infection Complaints body heat is not accompanied by cough more than 3 weeks. Patients had been visiting and living in malaria endemic area in Papua.
right=left Patient’s blood pressure has a decreasement. 2. adequate Patient’s pulse is normal Respiration : 20 x/menit type thorakoabdominal Patient’s respiration rate is normal. Hypotension is a poorprognostic sign only when associated with poor perfusion. To get rid of malaria disease recurrence in Discussion of physical examination 1. there is an irregular temperature which is one of malaria tropikan’s characteristic. 22 . Blood pressure: 100/60 mmHg. Vital signs : Temperature :35. But in this patient. equal. right = left. Pulse : 72x/minutes. as evidenced by cool peripheries and poor capillary refill. This condition eliminates possibility of malaria cerebral. and family no one is suffering from a disease like this. Respiration could be followed by pathologic sounds when there is a complication in the lung such as bronchitis or lobaric pneumonia. People with malaria cerebral usually come in apathy. General condition Patient’s awareness was compos mentis means patient absolutely awaken and gives an adequate respond to the stimulus that is given. somnolen until coma condition.Complaints like this the first time experienced by the patient.5° C Patient with malaria usually comes with fever complaint that’s why in his examination usually gives a febris temperature. reguler. Impression illness of this patient was moderate means patient has disturbtion in his activities and need people’s help to do his activities.
23 . Head i. Thoraks : Shape and movement are symmetric i. which correlates with prognosis and development of anemia./ Lung could be normal or found any abnormal sounds. not increase Usually any abnormalities is not found c. Spleenomegaly is a typical sign of malaria. Traube’s space was filled Presence of hepatomegaly could be found in malaria. hepatocyte injury and cholestasis.3. Abdomen : flat and soft i. Conjunctiva : Sub icteric : Anemic In some cases of malaria there could be complications. d. In severe malaria. and results from hemolysis. Neck i.Wheezing . Pulmo : VBS right = left Ronkhi . b. Jugular venous pressure: 5 + 1 cmH2O. Cor : Heart sounds are pure regular ii. In malaria with liver dysfunction we can find jaundice and icteric at sclera. The spleen get enlarge because there is accumulation of parasyte’s erythrocyte pigment. Special Examination a. Lien : palpable schuffner I-II. both infected and uninfected red cells show reduced deformabolity. Lymph nodes : No enlargement ii. Sclera ii. Hepar : palpable 3 cm BAC 5 cm BPX ii./ . Severe jaundice is associated with P. falciparum infection is more common among adults than among children.
Diagnosis: In this patient the differential diagnosis is to determine the etiology of primary or secondary Diagnosis Based on the history taking. DDR (+) P. atands and microscope. Blood test Hb : acquired anemia Leukosit : within normal limits Counts : found that decreased lymphocytes and monocytes increased thin smear morphology was found plasmodium vivax stage trofozoit b. Erythrocyte : Hipochrom normocyt. Thrombocyte : deficient d.Discussion of laboratory examination a. Falcifarum stadium trofozoit b. Urine : within normal limit In general. 24 . Blood smear: a. the quality of the slides. can be concluded that patient suffer of tropical malaria. Leucocyte : no abnormalities c. Faeces : within normal limit f. Artefacts are common and often confusing. c. and acid reaction. clear yellow color. and the time spent examining the slide. Impression : anemia hipochromic ec malaria Sensitivity and specifity depend to a great extent on the experience of the microscopist. physical examination and laboratory examination. the smell of ammonia. if no complications then obtained from macroscopic examination of urine will get the normal.
vivax. pain at the leg. Widal test I dan II. Total bilirubin and indirect bilirubin director test To assess the causes of jaundice in both eyes. rapid. falciparum or by p. 2. Examination Suggested : 1.Things that support the diagnosis: History taking: . 4. 14th. heart or liver posts. and 28th day To evaluate the effectivity of the teraphy and medication ressistancy. .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.Prodormal sign of malaria tropika such as severe headache.From history taking was found classic symptoms of malaria which is known as trias malaria are frigoris (shivering). whether prehepatik. calories (fever). PfHRP2 and PfLDH test PfHRP2 to detect plasmodium falciparum in a rapid way and PfLDH is to differ between the infection caused by p. 21th. DDR tests (repeated at the 3rd. highly specific and increasingly affordable dipstick or card tests for the diagnosis of malaria has been a major advance in recent years 3. Gall Kulture Untuk menghilangkan DD/ Demam Tifoi 25 . nausea and appetite decreasement. . sensitive. The spleen get enlarge because there is accumulation of parasyte’s erythrocyte pigment. The introduction of simple. body’s weakness.sudoris (sweathing) that happen consecutively. 7th.
Treatment First line medication for tropical malaria with complication IVFD Ringer Lactat maintenance 2L/24 hour Inj. falciparum but there was accompanied complications found. 26 .1st day 2x2 amp (160 mg) im . Artem . Even patient had previous history of malaria but there was no complications found.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. Quo ad functionam : dubia ad bonam Quo ad functionam of this patient is dubia ad bonam because even patient was suffered by p.
South-east Asia and Oceania. North Africa. This encodes a vestigial plastid (the apicoplast) that is an evolutionary homologue of the chloroplast of plants and algal cells. P. Four species of the genus Plasmodium infect humans. Almost all deaths and severe diseases are cause by P. The three ‘benigh’ malarias. P. all lie close together on the evolutionary tree near the other primate malarias. whereas P. as it does in Papua New Guinea and Haiti. P. P.LITERATURE REVIEW MALARIA THE PARASITE The malaria parasite is a mosquito-transmitted protozoan. GEOGRAPHICAL ASPECTS Distribution Malaria is endemic in 109 countries and is found throughout the tropics (Figure 73. ovale and P. falciparum predominates. vivax is rare in sub-Saharan Africa (except for the horn of Africa). Severe disease with these species is relatively unusual. is an important cause of human malaria on the island of Burneo and peninsular Malaysia.1). malariae is found in most areas. 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. malariae. falciparum. although on the island of New Guinea Plasmodium vivax is associated with significant mortality. The prevalent of both species is approximately equal in other parts of South America. knowlesi. Occasionally patients with vivax malaria will die from rupture of an enlarge spleen. whereas P. although infection with a fifth parasite P. vivax is more common in Central and parts of South America. bird. and P. the Middle East and the Indian subcontinent. Plasmodia are sporozoan parasites of red blood cells transmitted to animals (mammals. but is relatively uncommon outside Africa. reptiles) by the bites of mosquitoes. Malaria was once endemic in Europe and Northern Asia.. vivax. P. ovale is common only in West Africa. In Africa. a malaria of long-tailed and pig-tailed macaque monkeys. vivax infection in pregnancy reduce birth weight. which predisposes to neonatal death. and 27 .
was introduced to North America.19 28 . The most important pertain to the anopheline mosquito vector. In Northern China and North Korea.33 and the high hemoglobin F content of the infants erythrocytes which retards parasite development. vivax hibernans) with long incubation periods and long intervals (10-12 months) between relapses may still be found. The factors responsible for this include passive transfer of maternal immunity. if malaria is to be transmitted. Malaria transmission to man depends on several interrelated factors. but the blood stage infection is seldom severe.vivax strains (P.16 The epidemiology of malaria is complex and may vary considerably even within relatively small geographical areas. but it has been eradicated from these areas. EPIDEMIOLOGY The mosquito vector Malaria is transmitted by some species of anopheline mosquitoes.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). and at altitudes >2000m because development conditions for transmission are high humidity and an ambient temperature between 20 and 30 º C. P. or above 33 º C.34 In holoendemic areas the baby is inoculated repeatedly with sporozoites during the first year of life. and in particular is longevity. Malaria transmission does not occur at temperatures below 16º C. As sporogony (development of the sporozoite parasites in the vector) takes over a week (depending on ambient temperatures). excessive rainfall may wash away mosquito larvae and pupae. the mortality is high). Clinical epidemiology Babies develop severe malaria relatively infrequently (although. the mosquito must survive for longer than this after feeding on a gametocyte-carrying human. Although rainfall provides breeding sites for mosquitoes. if they do.
e. symptomatic infections are more common. unless they leave the transmission area and return years later (and even then malaria is seldom life-threatening). the introduction of new vectors. and severe disease is common when non-immune individuals enter these areas (e. the intensity of transmission or ‘endemicity’ can change. Symptomatic disease occurs at any age. the transmission of malaria varies considerably over short distances. or changes in the habits of the 29 . markedly seasonal. population migration.g. In Europe. but the majority of cases still do occur during the west season. and was termed ‘aestivo-autumnal malaria’. Epidemics are caused by migration (i. it remains substantial until EIR falls well below one. This is termed ‘unstable’ malaria. falciparum malaria was common in spring and in late summer and autumn. and cerebral malaria becomes a more prominent manifestation of severe diseases. Malaria is usually a ‘rainy seasons disease’ coinciding with increased mosquito abundance.2).people may receive up to three infectious bite per day. parasite rates (i. introduction of susceptible hosts). the proportion of people with positive blood smears) are relatively constant throughout the year. 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). before eradication. In some areas. and changes in agricultural practice have profound effects on malaria transmission. or focal. with less intense or more variable or unstable transmission the age range affected by severe malaria extends to older children. In this epidemiological context. Deforestation.. Most infections in adult are asymptomatic. Where transmission of malaria is low. and cerebral malaria is a prominent manifestation of severe diseases at all ages. A state of premonition is often not attained. Urban malaria is becoming an increasing problem in many countries. In hyper endemic and holoendemic areas indigenous adults never develop severe malaria. In many areas. erratic. Immunity is constantly boosted and effective premonition prevents parasite burdens reaching dangerous levels.e. In low transmission settings malaria can behave as an epidemic disease carrying a high mortality.35-37 although mortality falls with decreasing transmission intensity. the main clinical impact of falciparum malaria is to cause severe anemia in the 1-3-year ago group (figure 73.
Malaria may also be transmitted by blood transfusion. travelers and immigrants. leading to delays in treatment and severe presentations of falsiparum malaria are not uncommon. 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. but up to 100 may be introduced in some instance.mosquito vector or the human host. transplantation. they enter the circulation. all sporozoites have either entered the hepatocytes and there begins a phase of a sexual reproduction. and thus the potential. this has not led to the reintroduction of malaria to areas from where it had earlier been eradicated (although the vector. and Bangladesh over recent decades. India. After injection.5 (P.43The small motile sporozoites are injected during the phase of probing as the mosquitoes searches for a vascular space before aspirating blood.4445 Most sporozoites come from the large salivary ducts and represent only a small fraction of the total number in the salivary gland. This stage last on average between 5. Imported malaria is often misdiagnosed. relatively few sporozoites are injected (appromaxmately 8-15). Increasing international air travel and worsening antimalarial drug resistance have led to an increase in imported cases of malaria in tourists. or through needle-sharing among intravenous drug addicts. malariae) before the hepatic schizont ruptures to release meroaoites into the bloodstream Plosmodium Prepatent period (days) Incubation period (days) 30 . remains). In most cases. and rapidly target the hepatic parenchymal cells. Within 45 min of the bite. falciparum) and 15 days (P. either directly or via lymph channels (approximately 20%). With the recent exception of some of the former Soviet republics in East Europe and West Asia. The incidence of malaria has risen markedly in several African countries.
4) 13.0 14. to awaken weeks or months later. vivax and P.1 (2. orientation so that the apical complex (which protrudes slightly from one and of the merozoites and containts the rophtries. but instead rest inert as sleeping forms or ‘hypnozoites’.vivax 12. However.falciparum 11. and cause yhe relapses which of characterize infection whit these two species.4 (2.1 Naturally acquaried infections are considered to have an incubation period of between 13 – 28 days in some instances. 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. The process of invasion involves attachment to the erythrocyte surface.malariae 32. the micronemes.7) P.7a 34. Asexual blood – stage development The metozoites liberated into the bloodstream closely resemble sporozoites.3) 13. and dense granules) abuts the red cells.P.ovale 12. In P.8) P. this phase is asymptomatic for the human host.0 (2. the parasite lies within the erythrocyte cytosol enveloped by its own plasma membrane and a surrounding parasiteophorous vacuolar membrane. 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. the primary incubation period can be much longer. ovale infections a proportions of the intrahepatic parasites do not develop. as only a few liver cells are infected.2 (2. localized to the micronemes of the merozoite apical 31 .7a P. and then interiorization takes places by a wriggling boring motion inside a vacuole composed of the invaginated arytrhocyte. They are motile ovoid forms which invade red cells rapidly.
But other.48.49 this bind to sialic acid and the peptide backbone of the red cell membrane sialoglycoprotein glycophorin A.malariae and P. is oxidizesto the toxic ferric form. they increase in size logarithmically and consume the erythrocye’s contents (most of which is haemoglobin). Non-polymerized haem exits the food vacuole but its then degraded in the cytosol by glutathione. or people who originate from that region. When haem is freed from its protein scaffold.3. mainly the brown or black insolunle pigment haemozoin.50 Blinding is linked to activation of a parasite actin motor which provides the mechanical energy for the invasion process.52 Proteolysis of haemoglobin within the digestive vacuole of the growing parasites realeses for protein synthesis.falciparum the merozoite protein EBA 175. This may be facilitated nonenzymatically by parasite proteins. a product of the ‘Duffy binding like (DBL) superfamilyof genes encoding ligands for hodt cell receptors.falciparum-infected erythrocytes become spherical and less deformable.vivax this is related to the duffy blood group antigen Fya or Fyb. in yhe case of P.4). but the liberated haem process a problem. to a specific erythrocyte rereceptor. During the early stage of intraerytrhocytic development (<12h).51. a circularrim of citoplasma. Parasite are freely motile within the erythrocyte.falciparum like a pair of stereo-headphones. with darkly staining chromatin in the nucleus. sialic acid dependent and independent pathways of invasion also occur indicating considerable reserver in the invasion system. As they grow.48. Too much non-polymerizedhaem overwhealms the defence mechanism and toxic.ovale are not known. The digested product. In P. can be readily seen within the digestive vacuole of the growing parasite. and a pale central food vacuole ( figures 73. the small ‘ring forms’ of the four pasite species appear similar under light microscopy.complex.55 32 . The young developing parasite looks like a signetring or . The red cells surface receptor for P. 73. haemozoin. is clearly important. P.The absence of these phenotypes in west affrican. With this increase in size. explains their resistance to infection with P. 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. Intraparasitic toxicity is avoided by spontaneous dimerization to an inert crystalline substance.
In Thailand.At approximately 12 – 14 of development. It then ruptures. leads to an increase in deformability as the parasite matures.malariae pruduces characteristic ‘band forms’ as the parasite grows. The other there ‘benign’ human malarias do not cytoadhere in systemic blood vessels and all stages of development circulate in bloodstream.57 This is associated with knob-like projection from the erythrocyte membrane. so that between 6 and 36 merozoites are realesed. Expression increases towards the middle of the cycle (24h). Apporoximately nuclear division takes place to form a ‘segmenter’ or schizont (the term ‘meront’ is etymologically more correct). P. P.falciparum schizogony the residual cytoadherent erythrocyte membrane and associated malaria pigment often remain attached to the vascular endhotelium for many hours. and full of merozoites.falciparum22. This process is called ‘sequestration’. Eventually the growing parasite occupies the entire red cell which has become spherical. Thus. which also distrost the shape of the infected erythrocyte (hence its name). Red granules known as schuffner’s dots appear throughtout the erythrocyte.59 only a sub-population of erythrocytes can be invaded. The released merozoites rapidly re-invade other red cells and start a new asexual cycle. 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. Following P. This is determined largely by red cell age. malariae58. As P. depleted in haemoglobin.vivax can invade red cells for up to 2 weeks after emergence from the bone marrow.56. Similar dots are also prominent in P.falciparum. Knowlestsi it also produces band forms. When humans are infected with the potentially lethal monkey malaria p. destroying the remmants of the red cell. P. 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.vivax grows it enlarges the infected red cell. the infection expands logarithmically at approximately 10-fold per cycle. High parasitaemias (over 2%) are usually caused by P.falciparum parasites causing severe malaria showed unselective invasion.falciparum parasites begin to exhibit a high molecular weight strain-specific varian antigen. and had a graeter multiplication potential at high densities than those which 33 . and is therefore often mistaken for P. P. It is usually present at low parasitaemias. which in contrast to P.ovale .
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.10 datys in P. In contrast P. These are the stages which transmit in infection. in 1894) . 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). P. The motile male microgametes separate and seek the female macrogametes. 48 h for P. For a brief period. falciparum. Symptomatic P. The process of gametocytogony takes about 7.64 One male (containing 8 microgametes) and one female (macrogamete) are required per mosquito blood meal (apporoximately 2µL) for infection to occur. the male and female gametocytes become activated in the mosquito’s gut.vivax infection are tgerefore more likely to present whit patent gametocytaemia and to transmit before treatment then acute P.ovale. Thus gametocyte densities of 1 per µL theorerically sufficient to infect mostquitoes.falciparum.falciparum is apporoximately 1:4. The male gametocytes undergo rapid nuclear division and each of the eight nuclei formed associates whit a flagellum (20-25 µm long). a sub-populatioon of parasites develops into sexual forms (gamethocytes) which are long lived and motile. and the process of gametocytogony in the blood srage infection takes only 4 days. The male-to-female gametocyte sex ratio for P. Thus there is an interval of approximately 1 week between the peaks of asexual and sexual stage parasitaemia in acute falciparum malaria.60. Fusion and meiosis then take place to form a zygote. Malariae Sexual stages and development in the mostquito After a series of sexual cycle in plasmodium falciparum. but these patterns become obscured by by the time the oocyst has matured to contain thousands of fusiform motile sporozoites.61 The asexual life cycle is apporoximately 24 h for P.caused uncomplicated malaria. Ronald Ross. The oocyts finally bursts to liberate myriads of sporozoites into the coelomic cavity of mosquito. and 72 h for P. Following ingestion in the blood meal of a biting female anopheline mosquito.knowlesi. vivax begins gametocytogenesis immediately. vivax and P. a density beneath the limit of detection for most routine for microscopy.falciiparum infection. The sporozoites then migrate to the 34 .
Haploid and diploid generations alternate. 65 immune selection also provides the selective pressure to maintain diversity in T. falciparum but more evenly balanced in the other malaria parasites genomes. the variant surface protein which mediates cytoadherence (PfEMP1) appears the main antigen determining the parasites population structure during chronic falciparum malaria infections. On a large scale . Molecular Genetics Inheritance in plasmodium is similar to that in other eukaryotes. This switching occurs at different rates. It has been suggested that the diversity of these immunodominant variant repeat sequences interferes with the selection of high affinity antibody responses. A large number of individual genes were cloned and sequenced on the long and winding (and as yet unfinished) road towards the development of a malaria vaccine. The progeny of single drug resistant parasites ( 35 . 64 Variation in surface antigenicity result from the activation of the different ‘var’ gene. drug resisrance has had a profound effect on the malaria parasite population structure. some of which exceed 2% per asexual cycle. are also located close to each other near the telomeres. For example. The development of the parasite in the mosquito is termed sporogony. Codon composition is extremely biased to adenine and thymidine in P. P. This ‘confusion of the immune response’ delays the development of effective immunity. (see above). and takes between 8 and 35 days depending on the ambient temperature and species of parasite and mosquito. falciparum has approximately 6000 genes in its 14 chromosomes and extrachromosomal elements compared with the 31.000 of its natural host. There appear to be some groupings of genes relared to function. and perpetuates low affinity responses in malaria. The ‘var’ gene product. the genes encoding the merozoite surface proteins are grouped. and in the fast few years the entire genome of several a malaria parasites have been sequenced.and B cell epitopes through a high frequency of nonsynonymous base mutations during the asexual development of malaria parasites. The longevity of the mosquito is a critical factor in determining its vectorial capacity. which contribute to the antigenic diversity necessary for the parasite to elude the host immune system.salivary glands to await inoculation into the next human host during feeding. The many genes encoding the variant red cell surface anrigens (‘var’ and ‘rif’ families).
and the host reaction to these events. These products of malaria parasites.120.66 some of the polymorphic antigens identified are encoded by single gene copies in the haploid genome. As these repeat sequences are also antibody targets.119 A glycolipid material with many of the proper-ties of bacterial endotoxin is released on meront rupture. is often positive in acute malaria. the liberation of parasite and erythrocyte material into the circulation. but malaria parasites do induce release of cytokines in much the same way as bacterial endotoxin. PATHOPHYSIOLOGY The pathophysiology of malaria results from destruction of erythrocytes. and the crude malaria pigment which is released at 36 .111 Malaria antigen-related IgE complexes also activate cytokine release.their variation provides antigenic diversity. and caused the symptoms of the paroxysm. These polypeptide antigens are characterized by tandem repeat sequences. 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."' This material is associated with the glycosylphosphatidylinositol anchor which covalently links proteins including the malaria parasite surface antigens to the cell membrane lipid bilayer. falciparum malaria infected erythrocytes sequester in the microcirculation of vital organs.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. P. The limulus lysate assay. No toxin in the strict sense of the word has ever been identified. 118. Toxicity and cytokines For many years malariologists hypothesized that parasites contained a toxin which was liberated at schizont rupture. interfering with microcirculatory flow and host tissue metabolism. The mechanisms maintaining genetic diversity within the parasite genome are many and complex. Unequal crossing over during recombination can generate completely different sequences of these repeats. a test of endotoxin-like activity.
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+ 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 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. 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
but that its body has been missed in the section. red blood cell suspensions exhibit Newtonian behaviour. capillary values are lower) have major effects on cytoadherence. Under experimental conditions.) 40 . they do not enter the circulation again. electron dense deposits are evident on the cell membranes indicating the red cell does contain a parasite.144 B Figure 73. shear rates fall by approximately half allowing greater time for contact between cells and endothelium. the more that cells roll along the endothelial surface. and a higher proportion of these adhere to the vascular endothelium. Note that even when no intracellular parasite is seen.7 Two electron micrographs (x4320) showing densely packed parasitized erythrocytes sequestered in cerebral venules of a fatal case of cerebral malaria. severe anaemia). Rolling increased five-fold as haematocrit rose from 10% to 20% and cytoadhesion rose 12-fold between 100/b and 30%.e. 10-30%.143 Once infected red cells adhere. the viscosity of blood approximately doubles. The higher the haematocrit. remaining stuck until they rupture at merogony (schizogony). and so if shear stress is held constant.non-linearly under the different shear rates encountered in the circulation (non-Newtonian behaviour). (Courtesy of Emsrii Pongponratn. Over this range. changes in haematocrit over the range commonly encountered in severe malaria (venous haematocrit. At haematocrits <12% (i. The packing of red cells is much tighter than in normal conditions.
and often indicate serious infection.7). As a consequence. intestines and adipose tissue.144 possibly reflecting differences in the expression of endothelial receptors (Figure 73. spherical cytoadherent parasitized erythrocytes to maintain flow. It is not distributed uniformly throughout the body. but recent pathological and laboratory studies show that that they do. liver. particularly the white matter. Cytoadherence and the related phenomena of rosetting and autoagglutination lead to microcirculatory obstruction in falciparum malaria (Figure 73. being greatest in the brain. these forms are rare in falciparum malaria." It was thought that ring stage-infected erythrocytes do not cytoadhere at all.8). This is compromised by the reduced cleformability of uninfected red cells in severe malaria and the intererythrocytic adhesive forces that mediate rosetting. Adherence is essentially complete in the second half of the parasites' 48-h asexual life cycle.146 Even within the brain the distribution of sequestered erythrocytes varies markedly from vessel to vessel. and least in the skin. raising the intriguing possibility that the entire asexual cycle could take place away from the peripheral circulation.8 Uninfected red cells must squeeze past the static. although much less so than more mature stages.140. rigid. eyes. Under febrile conditions cytoadherence begins at approximately 12 h after merozoite invasion.Figure 73. kidneys. prominent in the heart. Sequestration occurs predominantly in the venules of vital organs (Figure 73.7). whereas in the other malarias of man mature parasites are commonly seen on blood smears.147 The gross microcirculatory obstruction caused by cytoadherent erythrocytes has recently been clearly visualized in vivo using polarised light imaging (in the buccal 41 .145 Ring form-infected parasites are also concentrated in the spleen and placenta. and reaches 50% of maximum after 14-16 h.144.
and parasites can be selected in culture which are knob negative (K-) but still cytoadhere. A small subpopulation of naturally occurting parasites do not induce surface knobs. together with reduced oxygen and substrate supply.9).111. and varies between different parasites and different PfEMP-1 genes. or in internal clusters. endothelial dysfunction. a process which is tightly controlled at the transcriptional level. PfEMP-1 protrudes from the red cell surface offering several Duffy binding-like (DBL) domains each capable of binding to particular vascular 'receptors' Analysis of multiple PfEMP-1 sequences has revealed common antigenic determinants in the DBL-1 domain. it is then exported to the surface of the infecting erythrocyte. The protuberances are not essential for cytoadherence (Figure 73."' These accretions cause humps or knobs on the surface of the red cell. which leads to anaerobic glycolysis.and rectal microcirculation) and by high resolution fluoroscein angiography of the retinal circulation.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. high molecular weight parasite-derived proteins termed P.141. close to a telomeric Ivaf gene. lactic acidosis and cellular dysfunction.152 PfEMP-1 is transcribed. However.151 Each parasitized red cell expresses the product of a single gene. which are the points of attachment to vascular endothelium (Figure 73. natural parasite isolates are nearly always knob positive (K+).10). Beginning at around 12 h of development. a 42 . falciparu?n erythrocyte membrane protein I or PfEMP-1. synthesized.150 These variant surface antigen (VSA) proteins (molecular mass 240-20 kDa) are encoded by 'var' genes.149 The consequences of microcirculatory obstruction are activation of the vascular endothelium.57. a family of -60 genes distributed in three general locations within the haploid genome: either immediately adjacent to the telomere. The most important parasite ligands are a family of strain-specific. and stored within the parasite. Cytoadherence Cytoadherence is mediated by several different processes.
constituent of the so-called 'head structure common to all PfEMP. In vivo. also called Pfalhesiti). reflecting the effects of host immune response on parasite antigenic variation. 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. falciparum.159 In the chronic phase of untreated infections. The central role of parasite derived proteins in cytoadherence is not accepted by all. the immmodominant surface antigen undergoes antigenic variation to 'change its coat’ and avoid immune mediated attack. In addition to the 'var'.the Rifins and the Surfins. PfEMP. genome sequencing has revealed the 'vir' gene superfamily in Plasmodium vivax. the PfEMP-1 gene expressed shows some dependence on previous variant expression.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. These could play a role in ring stage cytoadherence. faiciparum var gene appears to have different rates of switching on and off. this antigenic variation results in small waves of parasitaemia approximately every three weeks.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). 43 .I variants that is involved in the formation of rosettes and in cytoadherence. PfEMP1 is an important adhesion molecule and as it is a parasite protein exposed to immune recognition. 'rifin’ and 'surfin’ variant surface antigen gene superfamilies of P. it is also a major antigenic determinant for the blood stage parasite. As in other protozoal parasites.I expression is greatest in the middle of the asexual cycle. Two other variant surface antigeps encoded by different gene families have been identified .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. Each P. Interestingly. It has been suggested that cytoadherence is mediated by altered red cell membrane components such as a modified form of the red cell cytoskeleton protein band 3 (the major erythrocyte anion transporter. most parasites lose the ability to cytoadhere after several cycles of replication.162 In culture. with a net result that the infecting parasite population 'switches.
On the red cell side. Parasite modified band 3 (the major anion transporter) contributes to 44 .g. Probably the most important of these proteins is the leukocyte differentiation antigen CD36 165. human umbilical vein/dermal microvascular or cerebral enclothelial cells or transfected COS cells) or with the immobilized purified candidate ligand proteins. 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. Figure 73.164 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. and stabilized by PfEMP3. It is anchored beneath tolthe knob associated histicline rich protein (KAHRP).falciparum.166. The interaction between these proteins and the variant surface adhesin of the parasitize red cell is complex. 10). The property of cytoadherence can be studied in vitro with cells expressing the potential ligands on their surface (e.cytoadherence maybe modulated by the spleen. The rifin and CLAG gene products are not directly involved in adhesion but CLAG does appear to be required for cytoadherence. Parasitized erythrocytes do not cytoadhere in s mized monkeys. the principal ligand is the variant antigen pla5modium falciporum erythrocyte membrane protein I (PfEMPl).10 Schematic representation of cytoadherence in falciparum malaria.163 This has been shown in Saimiri monkeys infected with P. This is expressed on the surface of 'knobs' which protrude from the red cell surface.
appears to be the major cytoadherence receptor in the brain. Intercellular adhesion molecule I (ICAM 1) is important particularly in the brain.171 ICAM-1.e. At physiological shear rates (i. those likely to be encountered in the human microcirculation) the binding forces (c. heparan sulphate (HS) and P-selectin. E-selectin and the integrin alpha. Chondroitin sulphate A (CSA) attached to thrombomodulin (TM). Sequestrin is a distinct parasite derived protein also mediating adhesion. and provides a plausible pathological scenario whereby cytokine release enhances cytoadherence. is upregulated by cytokines (notably TNF(x).172. Binding to the two ligands is synergistic."' CD36 is constitutionally expressed on vascular endothelium. have also been shown to bind in some circumstances.ding PfEMPI. The other identified adhesion molecules are vascular cell adhesion molecule 1 (VCAMl). The ring stage adhesion"' (not shown) is distinct from NEW.167 Binding is increased at low pH (<7."' although it has been suggested that parasitized erythrocytes could bind via CD36 to platelets adherent to cerebral vascular endothelium. Nearly all freshly obtained parasites bind to CD36.01 and in the presence of high calcium concentrations. platelet enclothelial cell adhesion molecule I (PECAMI). platelets. but not CD36. PECAM/CD31. 174 Thrombospondin (a natural ligand for CD36) will also bind to some parasitized red cells (probably to modified band 3). Hyaluronic acid (HA) has also been implicated as a receptor for placental sequestration.-beta. and expressed in the first third of the asexual cycle. P. and monocytes/ macrophages but is usually not present on the surface of cerebral vessels.142. 169.10-"N) are similar for CD36 and ICAM-1.173 For both." The intercellular adhesion molecule (ICAM-1 or CD54). integrin. are very important for placental sequestration. E-selectin.adhesion probably by binding to thrombosponclin (TSA).111 P-selectin has been shown to mediate 45 . On the vascular endothelial side. Other proteins including VCAM-I. many molecules facilitate adhesion by bir. m. which suggests post-attachment alterations to increase adhesion. elsewhere it synergises with CD36. which is also the receptor for rhinovirus attachment. The most important is the cellular differentiation antigen: CD36. the forces of attachment are lower than those required for detachment. but the evidence for this has weakened as it has emerged that HA is usually contaminated with CSA.
182.179 Thus."' This probably explains why the adverse effects of pregnancy on birth weight are greater in primigravidae. The relationship between cytoadherence.175-177 Binding is mediated by a particular PfEMPI (var2CSA) which gives hope for a specific vaccine against malaria in pregriancy. measured ex-vivo. and the severity of infection or clinical manifestations has been inconsistent between studies. Chondroitin sulphate A (CSA) appears to be the major receptor for cytoadherence in the placenta. as all parasitized erythrocytes cytoadhere.178. but not primigravidae. Severity is related to the number of parasites in the body and distribution of cytoadherence within the vital organs. CSA is the major ligand in the placenta.11). Rosetting Erythrocytes containing mature parasites also adhere to uninfected erythrocytes. 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. Antibodies which inhibit parasitized red cell cytoadherence by binding var2CSA are generally present in multigraviclae in endemic areas. as sequestration also occuffs in vessels expressing none of the potential ligands identified so far. This is not particularly surprising. The relative importance of these molecules and their interactions in vivo is still not clear. 46 .rolling.181 Ibis process leads to the formation of 'rosettes' when suspensions of parasitized erythrocytes are viewed under the microscope (Figure 73. the placenta selects a parasite subpopulation expressing this epitope.183 it starts at around 16 h of asexual life cycle development (slightly after cytoadherence begins)184 and it is trypsin-sensitive. Rosetting shares some characteristics of cytoadherence. In summary ICAM-1 appears to be a major vascular ligand in the brain involved in cerebral sequestration. But parasite species which do not sequester do rosette"' and unlike cytoadherence. Other as yet unidentified vascular receptors are also present. and CD36 is probably the major ligand in the other organs.
Attachment is facilitated by serum components recently identified as Complement factor D. 47 . not all rosette.188-191 it has been suggested that rosetting might enwurage cytoadherence by reducing flow (shear rate).187 Rosetting has been associated with severe malaria in some studies but not in others. and associated with disease severity. and probably other red cell surface molecules.195 This is the platelet mediated aggregation of parasitized erythrocytes and is mediated via platelet CD36. When known rosetting parasite lines (K+R+) are perfused through the rat mesocaecum. reduce pH and facilitate adherence of infected erythrocytes to venular endothelium. Aggregation could also contribute to vascular occlusion. These cells clump together in ex vivo cultures. an ex vivo model for the study of vascular perfusion. 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. heparan sulphate. Aggregation Recently a new adherence property of parasitized red cells has been characterized.192. and circulating parasitized red cells.9).194. albumin. Rosetting tends to ' start in venules. which would enhance anaerobic glycolysis. and this could certainly reduce flow. and IgG anti-band 3 antibodies. falciparum cytoadhere. although shearing forces may still be effective in disrupting rosettes in vivo. Rosetting is mediated by attachment of specific domains of PfEMP1 to the complement receptor CRI. blood group A antigen.193 The mechanical obstruction or 'static hindrance' would be compounded by the lack of deformability of the adherent. they cause significantly more microvascular obstruction than isolates which cytoadhere but do not rosette (K+R-)139.rosetting is inhibited by certain heparin subfiactions and calcium-chelators. whereas all fresh isolates of P."' The forces required to separate a rosette are approximately five times greater than those required to separate cytoadherent cells. Furthermore.
Ferguson.".e.147 Increased erythrocyte rigidity measu low shear stresses encountered in capillaries and venules is corelated closely with outcome in severe malaria. However.Red cell deformability As Plasmodium vivax matures inside the erythrocyte. falciparuminfected erythrocyte. indeed it has been argued that sequestration is an adaptive response to escape B Figure 73."' The reduction in deformability results from reduced membrane fluidiM increasing sphericity. it is not found in sepsis. Infected red cells are less filterable than uninfected cells. (Courtesy of D.11 Rosetting.193. This phenomenon is specific to severe falciparum malaria.) splenic filtration. the cell enlarges and becomes more deformable. reduced deformability alone cannot account for microvascular obstruction as it would lead to obstruction at the mid-capillary (i. the smallest internal diameter in the vasculature) and could not explain sequestration in venules. (A) Uninfected red bl9od cells bind to a P.197 48 . and the enlarging and relatively rigid intraerythrocytic parasite." Plasmodium falciparum does exactly the opposite. reduced red cell deformability correlates with anaernia. the normally flexible biconcave disc becomes progressively more spherical and rigid. and readily removed by the spleen.196 When assessed at the higher shear rates encountered on the arterial side. vivax-infected erythrocyte. and importantly in the spleen. (Courtesy of R.)N Transmission electron micrograph of a rosette around a P. A reduction of uninfected red cell deformabifity hal been recognized as a major contributor to disease severrity and outcome.193 Even in severe malaria the majority of red cells are still unifected. Udomsangpetch.
Malaria has been found to cause cognitive impairments. Malariae. hemoglobinuria. Severe malaria is almost exclusively caused by P. and usually arises 6–14 days after infection. falciparum can have recurrent fever every 36–48 hours or a less pronounced and almost continuous fever. Renal failure is a feature of blackwater fever. vomiting. children with malaria frequently exhibit abnormal posturing. even with intensive care and treatment. cerebral ischemia. where hemoglobin from lysed red blood cells leaks into the urine.SIGNS AND SYMPTOMS Symptoms of malaria include fever. fatality rates can exceed 20%. In the most severe cases of the disease. For reasons that are poorly understood. and convulsions. a sign indicating severe brain damage. ovale infections. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours. It causes widespread anemia during a period of rapid brain development and also direct brain damage. falciparum infection. which may be a useful clinical sign in distinguishing malaria from other causes of fever. anemia (caused by hemolysis). occurring every two days in P. developmental impairments have been documented in children who have suffered episodes of severe malaria 49 . vivax and P. hepatomegaly (enlarged liver). while every three days for P. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Cerebral malaria is associated with retinal whitening. Splenomegaly (enlarged spleen). shivering. hypoglycemia. In endemic areas. Severe malaria can progress extremely rapidly and cause death within hours or days. and hemoglobinuria with renal failure may occur. especially in children. but that may be related to high intracranial pressure. This neurologic damage results from cerebral malaria to which children are more vulnerable. P. Over the longer term. retinal damage. arthralgia (joint pain). severe headache. treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten.
Findings in severe malaria may include metabolic acidosis. urate. with low plasma concentration of glucose. muscle and liver enzymes. creatinine. sodium. and urinalysis usually gives normal results. normocytic anemia is usually documented. and conjugated and unconjugated bilirubin. severe infections maybe accompanied by prolonged prothrombin and partial thromboplastin times and by severe thrombocytopenia. the following tests are instrumental for accurate diagnosis: Laboratory findings Normochromic. Levels of antithrombin III are reduced even in mild infection. The leucocyte count is generally low to normal. calcium. blood urea nitrogen. The erythrocyte sedimentation rate. although it maybe raised in very severe onfections. In adults and children with cerebral malaria.Main symptoms of malaria EXAMINATION In addition to a physical examination and the assessment of health history. Hypergammaglobinemia is usual in immune amd semi immune sunjects. blood urea nitrogen. the mean 50 . and creatinine are usually normal. bicarbonate. and albumin together with elevation on lactate. phosphate. degree of plasma viscosity. and level of C-reactive protein are high. In uncomplicated malaria. plasma concentration of electrolytes. The platelet count is usually reduced to ~105 /µL.
Speciation of malaria at the trophozoite stage is easier on the thin film. grease free glass slides. 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). and the glucose maybe slightly low relative to blood. In malaria endemic areas where malaria is the most common cause of fever. and the stage of parasite development should be assessed on the film. then it is reasonable to treat for malaria if rapid test or microscopy are not readily available. atands and microscope.e.0 g/L (100 mg/dL)] and cell count (<20/µL). or preferably 500 white cells is noted. The thick film is approximately 30 times more sensitive than the thin film. mature trophozyte and schizonts) should be counted. Diagnosis Malaria is dignosed by microscopic examination of the blood. In patient who have already received antimalarial treatment.. the quality of the slides. At low parasitemias (<5/10000 on the thin folm) the thick film should be counted. the CSF is usually normal or has a slightly elevated total protein level [<1. and the time spent examining the slide. this is counted as one. It is not a clinical diagnosis. although sensitivity and specifity depend to a great extent on the experience of the microscopist. an alternative os to count all parasites in fixed volume of blood. The number of parasitized red cells per 1000 red cells should be counted.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. In severe malaria parasotemias are usually high. the number of parasites per 200. Artefacts are common and often confusing. although gametocytes and schizonts are more likely to be seen on the thick film. The proportion of asexual parasites containing visible pigment (i. pigment may still be present in 51 . The thin film is more accurate for parasite counting. Of the white count is not available then the count is assumed to be 8000 µL. The presence of pigment in neutrophils and monocyte should also be noted and counted. Of there are two parasites in one red cell. The CSF lactate concentration is reaised in cerebral malaria. Blood Smears Thick and thin blood film are made on clean.
rapid. highly specific and increasingly affordable dipstick or card tests for the diagnosis of malaria has been a major advance in recent years. and a serum creatinine of more 52 . iron deficiency and thalassaemia/haemoglobinopathy must be exclude. Aparasitaemia of >100000/ µL might be a more appropriate threshold. and adolase. provide a diagnostic sensitivity for plasmodium falciparum similar to train microscopists. Rapid Diagnostic Test The introduction of simple. Cerebral malaria – unrousable coma not attributable to any other cause in a patient with falciparum malaria. Renal failure – defined as a urine output of<400 mL 24 h in adults.. currently histidine rich protein 2 (PfHRP2). failing to improve after rehydration. if anaemia is hypochromic and/or microcytic. Coma should be assessed using Blantyre coma scale in children of the Glasgow coma scale in adults. sensitive. Severe anaemia – normocytic anaemia with haematocrit <15% or haemoglobin <5 g/dL in the presence of parasitaemia more tha 10. and would include many children in high transmission areas. (These criteria are rather generous. Current PfHRP2 and PfLDH tests.) 3. note that finger prick samples may underestimate the heaemolobn concentration by up to 1 g if the finger is squeezed. 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 1. parasite lactate dehydogenase (which is antigenically distinct from the host enzyme). Monocytes containinbg pigment are cleared more slowly than pigment containing neutrophils.leukocytes after clearance of parasitemia. 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. or 12 mL/kg in 24 h in children.000/µL. These are based on antibody detection of malaria specific antigens in blood samples. and this is an important clue to the diagnosis. 2. based on color reactions.
nose. 9.) 4. these may be febrile convulsions. Pulmonary oedemaor adult respiratory distress syndrome. 5. 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.) 8. Spotaneous bleeding from gums.449 7.) 11. Acidaemia – defined as an arterial or capillary pH <7. 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.than 256 µmol/L (>3. Abnormal breathing patterns are a sign of severity indicating severe acidosis. (In practice for initial assessment. pulmonary oedema or pneumonia. gas \trointestinal tract. with cold clammy skin or core – skin temperature difference > 10 C. The clinical presentation of ‘respiratory distress’ or ‘acidotic breathing’ is focused upon in the 2000 recommendations. (This is relatively unusual. Found especially grey matter. y\this part of the definition is not very useful.35 (note temperature corrections are needed as most patient are hotter than 37 C) or acidosis defined as a plasma bicarbonate concertration <15 mol/L or a base excess >10. etc. Hypocaemia – defined as a whole blood glucose concentration of less tha 2. tonic clonic eye movenments.g. Postmortem confirmation of diagnosis. (The more recent review declined to give precise definitions. profuse salivation. (Operationally. and the other clinical and parasitological features need to be taken into account.) Clinical evidence of seizure activity may be subtle (e. are venules/capillaries packed with erythrocyte containing mature 53 .2 mmol. (This is difficult to ascertain in practice: if the G6PD deficiency. and /or substantial laboratory evidence of DIC.) 10. 6. Circulatory collapse or shock – hypotension (syntolic blood pressu<50 mmHgin children aged 1-5 years or <70 mmHg in adult). the serum creatinine alone is used. (In young children. In fatal cases a diagnosis of severe falciparum malaria can be confirmed by histogicalexamination of a postmortem needle necroscopy of the brain. Reoeated generalized convulsions – more than two observed within 24 h despite 24 cooling.L (40mg/dL).0 mg/dL). delayed coma recovery). The characteristic features.
but the Blantyre Scale needs careful local standartdization particularly in younger children. Drugs which are used for prophylaxis. In a child not old enough to sit. faciparum. Assessment using the Glasgow Coma Scale is straightforward. Many use a threshould definition of 10% parasitaemia n higher transmission settings. This is defined as an inability to feed. (Any impairment of consciousness must be treated seriously.0 mg/dL). Prostration: Inability to sit unassisted in a child who is normally able to do so. (these features may not be presents who die several days after the tart of treatment. Impairment of consciousness less marked than unrousable coma.) 13. Hyperpyrexia – a rectal temperature above 40 C in adults and children is no longer considered a sigh of severity. e. In nonimmune children studied in Thailand a parasitaemia ≥4% carried a 3% mortality (30 tim higher than in all uncomplicated malaria) but in areas of high transmission value mush higher may be tolerated well. 54 . But in general very high parasite densities are associated with increased risk of severe disease. treatment & in the prevention for malaria are called antimalarials. although there is usually some residual pigment in the cerebral vessels. TREATMENT Antimalarial medication Antimalarial medications are designed to prevent or cure malaria. This only marker of severe malaria when combined with evidence of other vital organ dysfunction such as coma or renal failure. This definition is based on examination not history. The following were not considered criteria of severe malaria: Jaundice – detected clinically or defined by a serum bilirubin concentration >50 µmol/L (3.g.trophozoites and schizonts of P. Hyperparasitaemia – the relation of parasitaemia to severity of illness different in different populations and age groups. But may be well tolerated in semi – immune children.) 12. >4% parasitaemia is dangerous in non-immunes. 14.
thus facilitating an aggregation of cytotoxic heme. Quinine is less effective and more toxic as a blood schizonticidal agent than chloroquine. however. It is especially useful in areas where there is known to be a high level of resistance to chloroquine. since this offers several advantages . reduced risk of developing resistance. mefloquine. It is practical to consider antimalarials by chemical structure since this is associated with important properties of each drug. Current practice in treating cases of malaria is based around the concept of combination therapy. it is still very effective and widely used in the treatment of acute cases of severe P. and the discovery of the cinchona tree. especially Plasmodium falciparum. As an alkaloid. enhanced convenience and reduced sideeffects. Quinine is an alkaloid that acts as a blood schizonticidal and weak gametocide against Plasmodium vivax and Plasmodium malariae. 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. 55 . such as mechanism of action. 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). to the current day and a collection of derivatives that are still frequently used in the prevention and treatment of malaria. it is accumulated in the food vacuoles of Plasmodium species. Routine Intermittent treatment of certain groups in endemic regions. and sulfa drug combinations with pyrimethamine. and the potential uses of its bark. falciparum. Prompt parasitological confirmation by microscopy or alternatively by RDTs is recommended in all patients suspected of malaria before treatment is started.reduced risk of treatment failure. Quinine is also used in post-exposure treatment of individuals returning from an area where malaria is endemic. It acts by inhibiting the hemozoin biocrystallization.
Quinimax is a combination of four alkaloids (quinine. sterilised needles for IV or IM injections). 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. rashes. Repeated or over-dosage can result in renal failure and death through depression of the respiratory system. vomiting and abdominal pain are the most common symptoms. Quinidine is recommended only for the treatment of severe cases of malaria. this occurs in therapeutic doses and therefore it is advised that glucose levels are monitored in all patients every 4–6 hours.e. These actions are mediated through the interactions of Quinine causing a decrease in the excitability of the motor neuron end plates. Chloroquine Chloroquine was until recently the most widely used anti-malarial. Quinidine is a direct derivative of quinine. The emergence of drug-resistant 56 . Quinine can cause hypoglycaemia through its action of stimulating insulin secretion. quinidine. best tested and safest of all available drugs. It is a distereoisomer. acute treatment or prophylaxis). Use of quinine is characterised by a frequently experienced syndrome called cinchonism. intravenous or intramuscular routes. It is also the least expensive. cinchoine and cinchonidine). It was the original prototype from which most methods of treatment are derived. This combination has been shown in several studies to be more effective than quinine. delirium and coma.e. thus having similar anti-malarial properties to the parent compound. Doses can be given by oral. vertigo. This effect can be exaggerated in pregnancy and therefore additional care in administering and monitoring the dosage is essential. combined with doxycycline. Tinnitus (a hearing impairment). This often results in functional impairment of the eighth cranial nerve. Neurological effects are experienced in some cases due to the drug's neurotoxic properties. tetracycline or clindamycin.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. nausea. resulting in confusion. supposedly due to a synergistic action between the four cinchona derivatives. The recommended method depends on the urgency of treatment and the available resources (i. Quinimax and quinidine are the two most commonly used alkaloids related to quinine in the treatment or prevention of malaria.
ovale as well as the immature gametocytes of P. 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. falciparum and P. falciparum strains.parasitic strains is rapidly decreasing its effectiveness. However. P. which. it is still the first-line drug of choice in most sub-Saharan African countries. vivax strains) and the gametocytes of P. falciparum. due to its alkaline nature. Chloroquine also has a significant anti-pyretic and anti-inflammatory effect when used to treat P. It controls the conversion of toxic heme to hemozoin by inhibiting the biocrystallization of hemozoin. It is believed to reach high concentrations in the vacuoles of the parasite. Chloroquine has been used in the treatment of malaria for many years and no abortifacient or teratogenic effects have been reported during this time. it is considered very safe to use during pregnancy. For chemoprophylaxis: 5 mg/kg/week (single dose) or 10 mg/kg/week divided into 6 daily doses is advised. Amodiaquine has tended to be administered in areas of chloroquine resistance while some patients prefer its tendency to cause less itching than chloroquine. vivax and sensitive P. and thus it may still remain useful even when resistance is more widespread. however. thus poisoning the parasite through excess levels of toxicity. involves giving an initial dose of 10 mg/kg followed 6–8 hours later by 5 mg/kg. malariae. A pharmacokinetically superior regime. therefore. Chloroquine is only recommended as a prophylactic drug in regions only affected by P. then 5 mg/kg on the following 2 days. It is now suggested that it is used in combination with other antimalarial drugs to extend its effective usage. raises the internal pH. vivax. Amodiaquine Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure and mechanism of action to chloroquine. Children and adults should receive 25 mg of chloroquine per kg given over 3 days. The most significant level of activity found is against all forms of the schizonts (with the obvious exception of chloroquine-resistant P. itching can occur at intolerable level and Chloroquinine can be a provocation factor of psoriasis. P. Amodiaquine is now available in a combined formulation with 57 . vivax infections. recommended by the WHO. Chloroquine is a 4-aminoquinolone compound with a complicated and still unclear mechanism of action.
chloroquine combination does not provide effective protection against resistant strains of P. P. It has no known effect against hypnozoites therefore is not used in the prevention of relapse. Adverse reactions are generally similar in severity and type to that seen in chloroquine treatment. Proguanil Proguanil (chloroguanide) is a biguanide. vivax and P. It was developed in 1945 by a British Antimalarial research group. There are very few side effects to 58 .artesunate (ASAQ) and is among the artemisinin-combination therapies recommended by the World Health Organisation. This inhibits the malarial dihydrofolate reductase enzyme. Combination with sulfadoxine=pyrimethamine is no longer recommended (WHO guidelines 2010). It has a weak blood schizonticidal activity and is not recommended for therapy of acute infection. 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. It acts primarily on the schizonts during the erythrocytic phase. vomiting and some abdominal pain have been recorded. twice daily maintains the plasma levels with a greater level of consistency. The proguanil. In addition. a synthetic derivative of pyrimidine. It has many mechanisms of action but primarily is mediated through conversion to the active metabolite cycloguanil pamoate. itching. falciparum. Its most prominent effect is on the primary tissue stages of P. Pyrimethamine Pyrimethamine is used in the treatment of uncomplicated malaria. falciparum strains when combined with sulfadoxine. falciparum. thereby halting the processes of DNA synthesis. Some blood and hepatic disorders have also been seen in a small number of patients. 3 mg/kg is the advised dosage per day. bradycardia. ovale. nausea. It acts by inhibiting dihydrofolate reductase in the parasite thus preventing the biosynthesis of purines and pyrimidines. However it is useful in prophylaxis when combined with atovaquone or chloroquine (in areas where there is no chloroquine resistance). cell division and reproduction. and nowadays is only used in concert with a sulfonamide. The pharmacokinetic profile of the drugs indicates that a half dose. It is particularly useful in cases of chloroquine-resistant P. thus giving a greater level of protection. (hence approximate adult dosage is 200 mg).
A dose of 15–25 mg/kg is recommended. ovale and P. The increased dosage is associated with a much greater level of intolerance. depending on the prevalence of mefloquine resistance.proguanil. It is thought to act by forming toxic heme complexes that damage parasitic food vacuoles. It is not recommended for use during the first trimester. It was developed to protect American troops against multi-drug resistant P. falciparum despite being effective against P. vivax. Mefloquine frequently produces side effects. It is a very potent blood schizonticide with a long half-life. Mefloquine is effective in prophylaxis and for acute therapy. diarrhea. Mefloquine Mefloquine was developed during the Vietnam War and is chemically related to quinine. marlariae. most noticeably in young children. Sulfonamides act on the schizont stages of the erythrocytic (asexual) cycle. vomiting. with slight hair loss and mouth ulcers being occasionally reported following prophylactic use. most commonly as fixed-dose sulfadoxine-pyrimethamine (Fansidar). including nausea. The effects during pregnancy are unknown. P. However it is used frequently for clinical episodes of the disease. Chloroquine/proguanil or sufha drug- pyrimethamine combinations should be used in all other Plasmodia infections. abdominal pain 59 . It is now used solely for the prevention of resistant strains of P. Sulfonamides are not recommended for chemoprophylaxis because of rare but severe skin reactions experienced. falciparum. with the drug inducing vomiting and oesophagitis. They are structural analogs of p-aminobenzoic acid (PABA) and compete with PABA to block its conversion to dihydrofolic acid. produces synergistic effects sufficient to cure sensitive strains of malaria. although it has been linked with an increased number of stillbirths. Sulfonamides Sulfadoxine and sulfamethoxypyridazine are specific inhibitors of the enzyme dihydropteroate synthetase in the tetrahydrofolate synthesis pathway of malaria parasites. although considered safe during the second and third trimesters. It is now strictly used for resistant strains (and is usually combined with Artesunate). When administered alone sulfonamides are not efficacious in treating malaria but co-administration with the antifolate pyrimethamine.
75 mg/kg repeated 7 days later is sufficient. with the first documentation as a successful 60 . ovale 0. Primaquine Primaquine is a highly active 8-aminoquinolone that is used in treating all types of malaria infection. some suppression of myeloid activity and abdominal pains. It is derived from the plant Artemisia annua. convulsions and delirium.000 years. Artemisinin and derivatives Artemisinin is a Chinese herb (qinghaosu) that has been used in the treatment of fevers for over 1. Mefloquine can only be taken for a period up to 6 months due to side effects. sleep disturbances. blood schizonticytes and the dormant plasmodia in P.15 mg/kg should be given for 14 days. There are few significant side effects although it has been shown that primaquine may cause anorexia. vivax and P. It is the only known drug to cure both relapsing malaria infections and acute cases. vivax and P. In cases of over-dosage granulocytopenia may occur. toxic encephalopathy. namely affective and anxiety disorders. For the prevention of relapse in P. cramps. albeit at a price higher than Lariam. Atovaquone Atovaquone is only available in combination with proguanil under the name Malarone. This treatment method is only used in conjunction with another effective blood schizonticidal drug. 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). hallucinations. vomiting. After this. It is commonly used in prophylaxis by travellers and used to treat falciparum malaria in developed countries. As a gametocytocidal drug in P.and dizziness. chest weakness. Several associations with neurological events have been made. anaemia. thus predating the use of Quinine in the western world. The mechanism of action is not fully understood but it is thought to block oxidative metabolism in Plasmodia. It is most effective against gametocytes but also acts on hypnozoites. other drugs (such as those based on paludrine/nivaquine) again need to be taken. psychosis. ovale. nausea. falciparum infections a single dose of 0.
thus preventing progression of the disease. itching and some drug fever have been reported by a small number of patients. dark urine. 61 . artesunate. It is a sesquiterpene lactone with a chemically rare peroxide bridge linkage. and this method is still in use today. although the target within the parasite remains controversial.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). falciparum. Artemisinin has a very rapid action and the vast majority of acute patients treated show significant improvement within 1–3 days of receiving treatment. artemether) are easier to use than the parent compound and are converted rapidly once in the body to the active compound dihydroartemesinin. It is this that is thought to be responsible for the majority of its anti-malarial action. Few side effects are associated with artemesinin use. notably non specific ST changes and a first degree atrioventricular block (these disappeared when the patients recovered from the malarial fever).6 mg/kg for 3 days. falciparum. It has demonstrated the fastest clearance of all anti-malarials currently used and acts primarily on the trophozite phase. It should be administered in a 7 day course with 4 mg/kg given per day for 3 days. to prevent the development of resistance. headaches. abnormal bleeding. therefore it is only used in combination therapy for severe acute cases of drug-resistant P.g. instead acting more significantly to decrease gametocyte carriage. However. Ge Hong extracted the artemesinin using a simple macerate. nausea. this dose is then reduced to 10 mg/kg per day for the 6 following days. Semisynthetic artemisinin derivatives (e. The active compound was isolated first in 1971 and named artemsinin. thus every care is taken to ensure compliance and adherence together with other behaviors associated with the development of resistance. Some cardiac changes were reported during a clinical trial. as with artemesinin. Side effects of the drug are few but include potential neurotoxicity developing if high doses are given. Artemether is a methyl ether derivative of dihydroartemesinin. It is also only given in combination with other anti-malarials. At present it is strictly controlled under WHO guidelines as it has proven to be effective against all forms of multi-drug resistant P. On the first day of treatment 20 mg/kg should be given. Similar restrictions are in place. followed by 1. vomiting. It is similar to artemesinin in mode of action but demonstrates a reduced ability as a hypnozoiticidal compound.
falciparum. Its mechanism of action is similar to other anti-malarials.000 patients in Thailand no adverse effects have been shown. It is a phenanthrene methanol. The level of 62 . no side effects to treatment have thus far been recorded. falciparum. Dihydroartemisinin is the active metabolite to which artemesinin is reduced. It has very variable bioavailability and has been shown to have potentially high levels of cardiotoxicity. Despite being effective against drug resistant parasites. Halofantrine Halofantrine is a relatively new drug developed by the Walter Reed Army Institute of Research in the 1960s. A popular drug based on halofantrine is Halfan. halofantrine is not commonly used in the treatment (prophylactic or therapeutic) of malaria due to its high cost. Currently it is the most frequently used of all the artemesinin-type drugs. Cytotoxic complexes are formed with ferritoporphyrin XI that cause plasmodial membrane damage. 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. It is used in combination therapy and is effective in cases of uncomplicated P. It is used for therapeutic treatment of cases of resistant and uncomplicated P. Its only effect is mediated through a reduction in the gametocyte transmission. As with artesunate. 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. It is the most effective artemesinin compound and the least stable. Artesunate is a hemisuccinate derivative of the active metabolite dihydroartemisin. 4 mg/kg doses are recommended on the first day of therapy followed by 2 mg/kg for 6 days. Arteether is an ethyl ether derivative of dihydroartemisinin. In large studies carried out on over 10. It has a strong blood schizonticidal action and reduces gametocyte transmission. falciparum. The recommended dosage is 150 mg/kg per day for 3 days given by IM injections. It is used in combination therapy for cases of uncomplicated resistant P. chemically related to Quinine and acts acting as a blood schizonticide effective against all plasmodium parasites. With the exception of a small number of cases demonstrating neurotoxicity following parenteral administration no side effects have been recorded.
Tetracycline is only used in combination for the treatment of acute cases of P. falciparum but has a very slow action in acute malaria. transient depression of bone growth. Unlike doxycycline it is not used in chemoprophylaxis. 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 a tetracycline compound derived from oxytetracycline. The most commonly experienced side effects are permanent enamel hypoplasia. or in patients that have taken mefloquine previously. abdominal pain. 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 can also be used in combination with quinine to treat resistant cases of P. The tetracyclines were one of the earliest groups of antibiotics to be developed and are still used widely in many types of infection. Halofantrine is not recommended for use in pregnancy and lactation. In prophylactic therapy. thus halofantrine is not frequently used. The most frequently experienced side-effects include nausea. Due to its effect of bone and tooth growth it is not used in children under 8. 100 mg (adult dose) of doxycycline should be given every day during exposure to malaria. 100 mg of doxycycline should be given per day for 7 days. and itch. Doxycycline Probably one of the more prevalent antimalarial drugs prescribed. This is due to prolongation of the QTc interval. For tetracycline. diarrhea. falciparum infections. This is due to its slow onset. It is not recommended for children under 10 kg despite data supporting the use and demonstrating that it is well tolerated. Doxycycline is used primarily for chemoprophylaxis in areas where chloroquine resistance exists. due to its relative effectiveness and cheapness. in small children. and should not be used as monotherapy. 250 mg is the recommended adult dosage (it should 63 .governmental control and the prescription-only basis on which it can be used contributes to the cost. Lumefantrine is a relative of halofantrine that is used in some combination antimalarial regimens. pregnant or lactating women and those with a known hepatic dysfunction. occasionally causing death are seen when high doses are administered. gastrointestinal disturbances and some increased levels of photosensitivity. When treating acute cases and given in combination with quinine. Severe ventricular dysrhythmias.
The techniques used to demonstrate this are: in vivo. Thus excluding all cases where anti-malarial prophylaxis has failed. falciparum infections and not as a prophylactic. However these can be alleviated by consuming large quantities of water and food when taking the drug. this condition may be fatal in a small number of cases. vomiting and abdominal pains and cramps. Clindamycin should be given in conjunction with quinine as a 300 mg dose (in adults) four times a day for 5 days." In most instances this refers to parasites that remaining following on from an observed treatment. The only side effects recorded in patients taking clindamycin are nausea. In order for a case to be defined as resistant. Resistance Antimalarial resistance is common. with a slow action against blood schizonticides. in vitro. gastrointestinal upset and interferences with the process of ossification and depression of bone growth are known to occur. 64 . 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. The majority of side effects associated with doxycycline are also experienced. Clindamycin Clindamycin is a derivative of lincomycin. the patient under question must have received a known and observed anti-malarial therapy whilst the blood drug and metabolite concentrations are monitored concurrently. it is used only in cases where the Tetracyclines are contraindicated (for example in children).not be used in children) for 5 or 7 days depending on the level of adherence and compliance expected. It is only used in combination with quinine in the treatment of acute cases of resistant P. 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. Pseudomembranous colitis (caused by Clostridium difficile) has also developed in some patients. Oesophageal ulceration. animal model testing and the most recently developed molecular techniques. Being more expensive and toxic than the other antibiotic alternatives.
This theory has been supported by evidence showing that resistance can be effectively reversed on the addition of substances which halt the efflux. halofantrine and quinine are thought to have occurred by similar mechanisms. the most commonly used being sulfadoxine and pyrimethamine. A multitude of factors can be involved in the processes including problems with non-compliance and adherence. Drug resistance may lead to treatment failure. However. but treatment failure is not necessarily caused by drug resistance despite assisting with its development. they are two potentially very different clinical scenarios. Plasmodium have developed resistance against antifolate combination drugs. It is generally accepted to be initiated primarily through a spontaneous mutation that provides some evolutionary benefit. interactions with other pharmaceuticals. thus giving an anti-malarial used a reduced level of sensitivity. existing for long periods of time. allowing synergistic blockages of two enzymes involved in 65 . The resistance of other quinolone anti-malarials such as amiodiaquine. poor drug quality. 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. Resistance can become firmly established within a parasite population. The first type of resistance to be acknowledged was to chloroquine in Thailand in 1957. This can be caused by a single point mutation or multiple mutations. 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). poor absorption.Drug resistant parasites are often used to explain malaria treatment failure. Two gene mutations are thought to be responsible. however some resistant parasites will survive. misdiagnosis and incorrect doses being given. In most instances a mutation will be fatal for the parasite or the drug pressure will remove parasites that remain susceptible. mefloquine. The generation of resistance can be complicated and varies between plasmodium species. The majority of these factors also contribute to the development of drug resistance.
4. allowing the rapid development of resistance to a new drug. These include aspects of economics. causing 'pocket-like' areas of resistance. 66 . human behaviour.folate synthesis. where a degree of phenotypic plasticity was exhibited. 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. two 4-aminoquinolones and mefloquine conferring resistance to quinine and halofantrine. but a number of plausible causes associated with an increase have been acknowledged. Spread of resistance There is no single factor that confers the greatest degree of influence on the spread of drug resistance. even if the drug has not been previously experienced. The most influential causes are examined below: 1. Resistance is thought to originate from a single-point mutation in the gene coding for cytochrome-b. for example crossresistance to chloroquine and amiodiaquine. Atovaquone is recommended to be used only in combination with another antimalarial compound as the selection of resistant parasites occurs very quickly when used in mono-therapy. therefore any factors that act to reduce the elimination of parasites could facilitate the development of resistance. 3. pregnant women and young children. The resistance to anti-malarials may be increased by a process found in some species of plasmodium. and the biology of vectors and parasites. pharmokinetics. In normal circumstances any parasites that persist after treatment are destroyed by the host's immune system. This phenomenon may reduce the usefulness of newly developed therapies prior to large-scale usage. The use of anti-malarials developed from similar basic chemical compounds can increase the rate of resistance development. 2. Regional variations of specific mutations give differing levels of resistance. This attempts to explain the poorer response associated with immunocompromised individuals. There has been evidence to suggest that certain parasite-vector combinations can alternatively enhance or inhibit the transmission of resistant parasites.
insofar as it is possible. One method proposed that aims to avoid the fundamental 67 . Ecologically there is a linkage between the level of transmission and the development of resistance. but longer-lasting drugs can increase the development of resistance due to prolonged periods of low drug concentration. 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 that the degree to which malaria can be controlled depends on the careful use of the current drugs to limit. as the rate at which new drugs are produced by no means matches the rate of the development of resistance. there is the possibility of resistance developing to any given therapy that is developed. any further development of resistance.5. The treatment regime prescribed can have a substantial influence on the 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. the decision of choosing a long-half life over a drug that is metabolised quickly is complex and still remains unclear. The pharmokinetics of the chosen anti-malarial are key. 6. however at present this still remains unclear. Drugs with shorter half-life's require more frequent administration to maintain the correct plasma concentrations. The pharmokinetics of anti-malarials is important when using combination therapy. In addition. 7. In accordance with this. It can be assumed that no therapy currently under development or to be developed in the foreseeable future will be totally protective against malaria. 8. therefore potentially presenting more problems if levels of adherence and compliance are unreliable. combination and interactions as well as the drug's pharmokinetic and dynamic properties. This is a serious concern. for example having an 'unprotected' period where one drug dominates can seriously increase the likelihood of selection for resistant parasites. PREVENTION The prevention of anti-malarial drug resistance is of enormous public health importance. This in itself is inadequate in large areas where malaria is endemic thus presenting an initial problem. This can involve the drug intake. Mismatched drug combinations.
environmental controls (such as swamp draining) and personal protective methods such as using mosquito repellent. COMBINATION TERAPHY The problem of the development of malaria resistance must be weighed against the essential goal of anti-malarial care. thereby reducing the chance of vaccine resistance developing. thus reducing the risk of resistance developing. There are two general approaches to preventing the spread of resistance: preventing malaria infections and. providing a costeffective and easily applicable approach to preventing not only the onset of malaria but the transmission of gametocytes. 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. The most successful attempts so far have been in the administration of combination therapy. Thus a balance must be reached that attempts to achieve both goals whilst not compromising either too much by doing so. There is much evidence to support the use of 68 . thus enabling drugs to be purchased on the open market from sources that are not officially related to the health care industry. This can be defined as.lack in certain countries health care infrastructure is the privatisation of some areas. Preventing malaria infections developing has a substantial effect on the potential rate of development of resistance. Although this is now gaining some support there are many problems related to limited access and improper drug use. A hope for future of anti-malarial therapy is the development of an effective malaria vaccine. which could potentially increase the rate of resistance development to an even greater extent. Antimalarial therapy could be also be diversified by combining a potentially effective vaccine with current chemotherapy. Chemoprophylaxis is also important in the transmission of malaria infection and resistance in defined populations (for example travellers). 'the simultaneous use of two or more blood schizonticidal drugs with independent modes of action and different biochemical targets in the parasite'. indoor residual spraying. preventing the transmission of resistant parasites. This could have enormous public health benefits. that is to reduce morbidity and mortality.
is cheap and effective in a single dose. SP plus chloroquine components means this combination is effective in few locations and it is no longer recommended by WHO guidelines. however several problems prevent the wide use in the areas where its use is most advisable. 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. High levels of resistance to one or both 25 mg/kg of sulfadoxine and 1. the expense of combined therapy (it is over 10 times more expensive than traditional mono-therapy).combination therapies. SP plus mefloquine (Fansimef) This single dose pill offered obvious advantages of convenience over more complex 69 . causes few adverse effects. but is clearly inferior to artemisinin-based combinations (ACTs) for the treatment of malaria.  This combination has been shown to produce a faster rate of clinical recovery than SP SP plus amodiaquine and chloroquine. thus Dose Sulfadoxinepyrimethamine(SP) (Fansidar) decreasing problems associated with adherence and compliance. Fansidar should no longer be used alone for treatment of falciparum malaria. In technical terms Fansidar is not generally considered a true combination therapy since the components do not possess independent curative activity. The combinations of drugs currently prescribed can be divided into two categories: non-artemesinin-based combinations and artemesinin based combinations. Non-artemisinin based combinations Components Description This fixed-dose combination has been used for many years. 10 mg/kg of Amodiaquine per day for 3 days with a single standard dose of SP. These include: problems identifying the most suitable drug for different epidemiological situations. Chloroquine 25 mg/kg over 3 days with a single dose of SP as described above. how soon the programmes should be introduced and problems linked with policy implementation and issues of compliance.25 mg/kg of pyrimethamine. some of which has been discussed previously.
Components Artesunate and amodiaquine (Coarsucam and ASAQ) Description This combination has been tested and proved to be efficacious in many areas where amodiaquine retains some efficacy. Quinine 10 mg/kg doses every 8 hours and tetracycline in 4 mg/kg doses every 6 hours for 7 days. Problems with this regime include the relatively complicated drug regimen. quinine-based treatment is less popular than previously. this makes is particularly useful in the treatment of resistant infections. This combination retains a high cure rate in many areas. Quinine plus tetracycline/doxycycline Additionally. however this data is limited.regimes but it has not been recommended for use for many years owing to widespread resistance to the components. artemisinin-based combination therapies should be used in preference to amodiaquine plus sulfadoxine-pyrimethamine for the treatment of uncomplicated P. According to WHO guidelines 2010. 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. A Dose Dosage is as a fixed-dose combination (ASAQ) recommended 70 . With the advent of artemisinin-combination therapies. Artemisinin-based combination therapies (ACTs) Artemesinin has a very different mode of action than conventional anti-malarials (see information above). there are significant side effects with quinine ('cinchonism') and tetracyclines are contraindicated in children and pregnant women (these groups should use clindamycin instead). falciparum malaria. however in order to prevent the development of resistance to this drug it is only recommended in combination with another non-artemesinin based therapy. where quinine must be taken every 8 hours for 7 days. At present there is no known resistance to Artemesinin (though some resistant strains may be emerging) and very few reported side-effects to drug usage.
which potentially could exert a high selection pressure on parasites. Artemether and lumefantrine (Coartem Riamet. interestingly these Artesunate and mefloquine (Artequin and ASMQ) adverse reactions seem to be reduced when the drug is combined with artesunate. proving effective in children under 5 and has been shown to be better tolerated than artesunate plus mefloquine combinations. Artesunate and sulfadoxine/pyrimethamine This is a well tolerated combination but the overall level of efficacy still depends It is recommended in doses 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.  as 4 mg/kg of Artesunate and 10 mg/kg of Amodiaquine per day for 3 days. It's recommended by the WHO for uncomplicated falciparum malaria. This is the most viable option for widespread use and is available in fixed-dose formulas thus increasing compliance and adherence. This is not considered a viable option to be introduced in Africa due to the long half-life of mefloquine. It's recommended by the WHO for uncomplicated falciparum malaria. It's recommended by the WHO for uncomplicated falciparum malaria. it is suggested that this is due to a delayed onset of action of mefloquine. 71 . Mefloquine is known to cause vomiting in children and induces some neuropsychiatric and cardiotoxic effects.potential disadvantage is a suggested link with neutropenia. This has been used as an efficacious first-line treatment regimen in areas of Thailand for many years. This combination has been extensively tested in 16 clinical trials. Amatem and Lonart) 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.
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.  of 4 mg/kg of Artesunate per day for 3 days and a single dose of 25 mg/kg of SP.(Ariplus and Amalar plus) on the level of resistance to sulfadoxine and pyrimethamine thus limiting is usage. falciparum resistance to Pyronaridine). Manufactured by Shin Poong Pharmaceutical. Vietnam and other countries in SEAsia.3 Venous plasma HCO3 <15 mmol/L Serum creatinine >265 µmol/L 72 . Other combinations Several other anti-malarial combinations have been used or are in development. Has been tested and demonstrated a clinical response rate of Pyronaridine and artesunate (Pyramax) 100% in one trial in Hainan (an area with high levels of P. It is recommended by the WHO for uncomplicated falciparum malaria.5% response rate.2 mmol/L >5 mmol/L Arterial pH <7. The Dihydroartemisininpiperaquine (Duo-Cotecxin. PROGNOSTIC FACTORS The prognostic factors listed in the table below Biochemistry Hypoglicaemia Hyperlactatemia Acidosis <2. Has been studied mainly in China. A multi-centre phase III trial conducted in Africa found a 99. Artekin) drug has been shown to be highly efficacious (greater than 90%). For example. It's recommended by the WHO for uncomplicated falciparum malaria.
several factors usually co-exist.Total bilirubin Liver enzymes >50 µmol/L SGOT (AST) >3 upper limit of normal SGPT (ALT) >3 upper limit of normal 5-Nucleatidase ↑ CPK ↑ Myoglobin ↑ Muscle enzymes Urate Haematology Leucocytosis >600 µmol/L >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 >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. but shallow tachipneu can result from high fever alone (the tidal volume is lower). or pneumonia). 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 73 . Hyperventilation (respiratory distress) is usually a bad sign (indicating metabolic acidosis. pulmonary oedema. They are not absolute and in fatal case. the co-existing parasitemia and metabolic abnormalities and the stage of the infection. The prognostic implocations of severe anemia depend on the rate whoch haematocrit falls. Some of the apparently poor prognostic factors can have a benign explanation. Upper gastrointestinal bleeding in cerebral malaria may also occur spontaneously.
poorer prognosis). 74 . Patients particularly children.curve. with acute malaria often have very low blood pressures but they are warm and well perfused.Although a deep jaundice is often a bad sign. For any parasitemia the prognosis is worse if >20 % of parasites contain visible pigment and better if >50 % of parasites are at the tiny ring stage. as evidenced by cool peripheries and poor capillary refill. Persistent acidosis with low plasma bicarbonate and elevated plasma lactate 4 hours after admission indicates a poor prognosis. the admission venous bicarbonate concentration has the best sensitivity and specifity. Parasitemia has traditionally been used as a measure of severity. and it is available widely. Hypotension is a poorprognostic sign only when associated with poor perfusion. 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 % . some adults patients develop a profound cholestatic jaundice without other evidence of vital organ dysfunction. The concentration of lactate in venous or arterial blood or CSF is linearly proportional to the severity of disease. the increase in cardiac index and the fall in systemic vascular resistence. In terms of predictive prognostic values. The sensivity and specificity of parasitemia alone is limited. 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.
BUKU AJAR ILMU PENYAKIT DALAMjilid III. A. Aru W. Manson. 22th edition. 19321948. Braunwald. 2006. 2008.et all. Hauser. Kasper. Ed.. 2010 Sudoyo.. edisi IV. Pathophysiology of Disease: An Introduction to Clinical Medicine. Longo.L.BIBLIOGRAPHY Fauci. E. J Stephen. Harrison’s Principal of Internal Medicine...C. New York Chicago San Fransisco Lisbon London Madrid Mexico City New Delhi San Juan Seoul Singapore Sydney Toronto: Mc-Graw Hill Company Inc. Sixth Edition. Agustus 2003. Hammer D Garry. S.2009. J.L.L. Jameson. Acute Viral Hepatitis. Konsensus Penanganan Malaria 2003. et al. In: Powers . D. D. Perhimpunan Dokter Spesialis Penyakit Dalam Indonesia (PAPDI).. Jakarta : Pusat penerbitan Departemen ilmu penyakit dalam Fakultas kedokteran Universitas Indonesia...Mcphee.L..et all : Renal disease .. 75 . Tropical disease.S. Philadelphia : Elsevier Incorporation.. A. 17th ed.
41101125 Reported to : Kol (P).SpPD NRP 29886 INTERNAL MEDICINE DEPARTEMENT DUSTIRA HOSPITAL / MEDICAL FACULTY OF GENERAL ACHMAD YANI UNIVERSITY CIMAHI 2011 76 .CASE RESPONSE TROPICAL MALARIAE Oleh: Arief Fakhrizal NIM. Eddy Harjadi S. dr.