Curriculum Vitae

Name Place/Birth Education : : KURNIA FITRI JAMIL : Medan, 8 February 1965

- Medical Doctor Graduate : FK-UI (Jakarta, 1992) - Internist Graduate : FK-UNPAD (Bandung, 2003) - Health Magister Graduate : FK-UNPAD (Bandung, 2004) - Consultant of Tropical Infection: Colegium of Internal Medicine Indonesia (Kolegium Ilmu Penyakit Dalam di Jakarta, 2008) - Pasca Sarjana Ph.D Program : FK-UGM, Yogyakarta (start 2008-...) - Fellow of Indonesian Society of Internal Medicine (PB.PAPDI, 2009) - Course of Internal Medicine (Germany, 2004, Netherland, 2006) - International Workshop of Internal Medicine (France, 2007) - Course Tropical Diseases & Genetics (Australia, 2008) - Course of Biology Molecular of Tropical Medicine (Germany, 2009) - International of Tropical Medicine & Infectious Diseases (UGM, 2010)

Occupation: - Staff of Internal Medicine, Medical Faculty of Syiah Kuala University/RSUZA

- Head of Infectious Diseases and Tropical Medicine Division, Internal Medicine Dept- Zainoel Abidin General Hospital - Coordinator of Skills Medical Laboratory of Faculty of Medicine Unsyiah - Consultant of HIV/AIDS Group Zainoel Abidin General Hospital - Head of PETRI Aceh Branch

MANIFESTASI KLINIK MALARIA BERAT

KURNIA FITRI JAMIL
Divisi Penyakit Tropik & Infeksi Bagian/SMF. Ilmu Penyakit Dalam FK-UNSYIAH/RSUZA BANDA ACEH - 2011

MALARIA RINGAN

MALARIA DAPAT MENYEBABKAN KEMATIAN

400 Gigitan Nyamuk

200 Meng-infeksi Manusia

100 Malaria Klinis

26% Malaria Berat

2-- 6%

Plasmodium Falciparum, Vivax, Knowlesi dapat menyebabkan Malaria Berat

10 50 %

Kematian

MALARIA BERAT
Ditemukan Aseksual Plasmodium F/V/K, dengan salah satu :

MALARIA SEREBRAL ANEMIA BERAT HB < 5 gr% / Ht < 15% + parasit > 10000 GAGAL GINJAL AKUT < 400 ml/24 jam & Kreat > 3 mg% EDEMA PARU / ARDS HIPOGLIKEMI < 40 mg% SYOK SISTOLIK < 70 mmHg / Anak < 50 mmHg PERDARAHAN SPONTAN / DIC KEJANG BERULANG > 2 x/ 24 jam ASIDOSIS Ph <7.25 , Plasma Bicarb < 15 mmol/L HAEMOGLOBINURIA HIPERPARASITEMIA > 5 % MALARIA DGN BILIRUBIN > 3 MG% + gagal Organ lain HIPERTERMIA > 40 C (Oral)

SEVERE MALARIA
DEFINITION : Patient, Plasmosium Asexual parasitemia,with one or more CLINICAL or LABORATORY FEATURES :

PROSTRATION IMPAIRED CONSCIOUSNESS RESPIRATORY DISTRESS MULTIPLE CONVULSIONS CIRCULATORY COLLAPSE PULMONARY EDEMA ABNORMAL BLEEDING JAUNDICE HAEMOGLOBINURIA

SEVERE ANAEMIA HYPOGLYCAEMIA ACIDOSIS RENAL IMPAIRMENT HYPERLACTATAEMIA HYPERPARASITEMIA

WHO: Guidelines for the Treatment of Malaria 2010

BEDA MALARIA BERAT PADA DEWASA & ANAK

ANAK DEWASA

Batuk Kejang Ikterik Lama sakit Lama koma Hiperparasitemia Hipoglikemia Gagal ginjal Tek.I.K naik Edema paru Perdarahan Ggn brain stem Sequelae Neuro.

Sering Sangat sering Jarang Pendek (1-2 hr) Pendek (1-2 hr) Sering Sering sebelum Rx Jarang Sering/naik Jarang Jarang Lebih sering > 10 %

Jarang Sering Sering Panjang (5-7 hr) Panjang (2-4 hr) Jarang Sering sesudah Rx/Hml Sering Jarang/ normal Sering ---10 % Jarang <5%

Syndromes of severe malaria: 1. Children

1. Severe anemia 2. Metabolic acidosis 3. Cerebral malaria Exacerbated by: hypovolemia hypoglycemia salicylate toxicity
Renal failure rare Lung injury/ARDS rare

Syndromes of severe malaria: 2. non-immune adults

Multiorgan failure: Hyperparasitemia Acute renal failure Jaundice Metabolic acidosis Hypoglycemia Acute respiratory distress syndrome Anemia/thrombocytopenia Cerebral malaria

Prognostic value & frequency of SM in adults / children

Children Adults

Clinical manifestations or Laboratory finding

Prostration Impaired counciousness

Children

Adults

+ +++ +++ + +++ +++ +++ ++ + +

? ++ +++ ++ +++ +++ ++ + + +

+++ +++ +++ +++ + +/+/+ +/+++

+++ ++ + + + + + +++ + +

Respiratory distress ( acidotic breathing )

Multiple convulsions Circulatory collapse Pulmonary Edema (radiological) Abnormal bleeding Jaundice Haemoglobinuria Severe Anemia

Classifications Severe Malaria in Children

Group 1: (require parenteral Rx & Support.Tx ) 1. Prostration ( inability to sit upright), 3 subsgroup : Prostrate but fully concious Prostrate with impaired conciousness not coma Coma 2. Respiratory distress ( acidotic breathing Mild nasal flaring &/ or mild intercostal indrawing Severe mark intercoctal indrawing or deep acidotic Group 2 (able to take oral Rx, require supervised) : 1. Haemoglobin < 5 gr% or haematocrit < 15% 2. > = 2 convulsions in 24 hours Group 3 : require parenteral Tx because of persistent vomiting, not in group 1 or 2.

DIAGNOSIS OF 114 CASES SEVERE MALARIA RSUD. Dr. Zainoel Abidin Banda Aceh

Severe Malaria 48 (42%) Clinical Malaria 35 (31%) Stroke 7 (6%) Hepatitis 5 (4%) Typhoid fever 4 (3.5%) Gastritis 3 (2.6%) Liver absces 2 (2%) Pneumonia 2 (2%) Dehydration 1% Pharyngitis 1% Chronic Renal Failure 1% Urinary Tract Infection 1%

Malaria cerebral 25 (52%) Malaria + jaundice 22 (46%) Malaria + ARF 1 (2%) Malaria + jaundice 16 (46^) Malaria + ARF 9 (26%) Malaria cerebral 6 (17%) Hyperparasitemia 3 (11%)

Sepsis 1 %

Nephrolithiasis 1%
Syncope 1% Epilepsy 1%

RELATIONSHIP BETWEEN ORGAN INVOLVEMENT AND MORTALITY in Severe Malaria

100 80 60 47,6 40 20 0 0 0 1 2 3 4 10,5 Mortality 100 88,9

Severe Malaria in Indonesia

Not ONLY in Endemic Malaria Area (East

Indonesia ) Spreading to Jawa & Bali ( Denpasar, Malang, Surabaya, Yogya, Semarang, Bandung & Jakarta ) Also reported in Sumatra (Padang, Riau, Batam, Lampung, Palembang, Aceh)

PATOGENESIS MALARIA CEREBRAL

MEKANISME OBSTRUKSI KAPILER :
Rosetting ( penggerombolan eritrosit )
Sitoadherensi ( perlekatan eritrosit ke endothel )

MEKANISME IMUNOLOGIK : pembentukan

sitokin, nitrit oxide MEKANISME PENINGKATAN TEKANAN INTRACRANIAL : hanya kasus anak MEKANISME ENDOTOKSIN

MEKANISME PATOGENESIS: ROSSETTING

PRBC

MEKANISME SITOADHEREN
EP

PRBC

Knob

ENDOTEL

MEKANISME PATOGENESIS
PRBC

Pf-EMP-1

ICAM-1

ELAM VCAM

CD-36

TSP ENDOTEL

Pathophysiology 1. Red cell destruction/impaired production

Pathophysiology 2: cytoadherence

Cytoadherence: cerebral malaria: brain histology

Pathophysiology 3: dysregulated cytokine response

GPI
, LT

Is NO protective in malaria?
NO: antiparasitic effects:
inhibits parasite growth in vitro

NO: antitoxic effects:

inhibits TNF production downregulates expression of endothelial

adhesion molecules (ICAM-1 etc..) inhibits host cell apoptosis in tissues

NO: rodent models:

either no effect or disease-protective

Indonesian subjects
Severe malaria (SM)
- cerebral malaria - non-cerebral malaria

Uncomplicated malaria

(UM)
Healthy controls (HC)
Rural (RHC) Urban (UHC)

Nitric oxide synthesis from arginine

L-arginine

NO synthase

L-citrulline +

NO

INVASI ERITROSIT MEROZOIT RING SIZON PECAH GPI EFEK FISIK PADA ERI MANUSIA KNOB, SITOADER DEFORM HILANG ANEMIA

TROPOZOIT

OBSTRUKSI MIKROVAS.

TNF

EFEK METABOLIK PARASIT

PEMAKAIAN GLU HIPOGLIKEMI LAKTIK ASIDOSIS

HIPOXIA HIPOGLIKEMI

DEMAM HIPOGLIKEMI

SEREBRAL, RENAL, PARU LAIN KOMPLIKASI

CEREBRAL MALARIA

10 % of falciparum malaria 80 % fatal cases 30.5 % mortality in

Indonesia (Adults) 30-50% children in Africa

DEFINITION
PRACTICAL : IMPAIRMENT OF CONSCIOUSNESS OR CONVULSION IN PATIENT EXPOSED TO MALARIA RESEARCH AN UNROUSABLE COMA MORE THAN 30 MINUTES, POSITIVE MALARIA SMEAR, WITHOUT OTHER CAUSES ENCEPHALOPATHY GCS : < 11 /15 or 9 / 11

14%

12%

Cerebral Cer+ 1or 29% 45% Cer+ 2or Cer+ 3or

Clinical Manifestations

Glasgow Coma Scale

Respon mata

: spontan dgn suara dgn nyeri tak ada reaksi : normal respon bingung berkata kacau suara merintih tak ada suara 5

4 3 2 1 4 3 2 1 6 4 2 1

Respon Bicara

Respon motorik

: gerakan normal dapat melokalisir nyeri 5 fleksi thdp nyeri extensi 3 decerebrate rigidity tak ada reaksi

TOTAL 3 -- 15

Extensi pada malaria cerebral

CLINICAL MANIFESTATION
NEUROLOGICAL SYNDROME : DIFFUSE, POTENTIALLY RAPIDLY REVERSIBLE ENCEPHALOPATHY ASSOCIATED WITH LOSS OF CONSCIOUSNESS AND FITTING

mild meningism, no neck rigidity dysconjugate gaze vertical nystagmus N.VI palsy dolls eye, oculovestibular reflex normal response symetri UMN, increased tone & jerk, clonus, extensor plantar response + , brisk Jaw jerk pout reflex + , abdominal reflex -, cremasteric reflex + . cerebellar sign present

Malaria Retinopathy
A. Gambaran retina pada penderita malaria serebral GCS 14, dengan anemia Hb 8.2 gr%. Tampak gambaran perdarahan dan papiledema.

B. Gambaran retina pada penderita malaria serebral GCS 8, edemaparu dan demam kencing hitam. Tampak gambaran pemutihan retina.
( Maude RJ, Beare NAR, et all, Trans. R. Soc. Trop.Med & Hyg, 2009, 103:665671)

DIFFERENTIAL DIAGNOSIS CM

INFECTION : MENINGITIS, ENCEPHALITIS, TYPHOID FEVER, SEPTIC SHOCK STROKE & HEAD INJURY METABOLIC COMA ECCLAMPSIA ALCOHOLISM , INTOXICATION

8 hours after admission

24 hours after admission

Ikterik & Cerebral

Malaria cerebral , jaundice, in Dr.Zainoel Abidin Hospital

GANGGUAN FAAL HATI PADA MALARIA BERAT

IKTERIK SERING DIJUMPAI ( RINGAN - BERAT )

IKTERIK TERGANTUNG JUMLAH PARASIT

IKTERIK ( HEMOLISIS / DISFUNGSI HATI ) BILIOUS REMITENT FEVER

( IKTERIK, HIPERPARASITEMIA, SEREBRAL & GAGAL GINJAL Algid Malaria ) AKIBAT: - Hipoalbuminemia - Gangguan koagulasi - Penurunan klirens

Malaria hepatitis ( Deller 1967 )

Gagal hati jarang Hepatomegali sering, nyeri ringan,

splenomegali Hiperbilirubinemia ( direk & indirek ) Transaminase meningkat ringan sedang, jarang > 200 i.u Waktu protrombin memanjang

HIPOGLIKEMIA
Bila gula darah < 40 mg% Sering dijumpai pada ibu hamil ( primi-

gravida) Pada anak-anak sering sebelum pengobatan Pada orang dewasa sering terjadi sesudah pengobatan kina ( 3 jam post terapi kina )

Patogenesa Hipoglikemia
Parasit memerlukan karbo-hidrat untuk metabolismenya Pada malaria dengan hiperbilirubin aemia,

terjadi kegagalan glukoneogenesis Kina menstimuli produksi insulin ( hiperinsulinemia ) Peningkatan Tumor Necrosis factor ( TNF-alfa )

ACUTE KIDNEY INJURY (AKI)

Malaria related Acute Kidney Injury (MAKI) Penurunan fungsi ginjal dalam 48 jam :
Peningkatan serum kreatinin 0.3 mg/dL, atau Peningkatan serum kreatinn 50% dan nilai dasar, atau Penurunan urin output 0.5 ml/kg/jam untuk 6 jam

WHO : serum kreatinin > 3 mg/dL

Sering pada malaria dewasa dan jarang pada anak

 Faktor untuk mempermudah MAKI :

Kehamilan Parasitemia tinggi Ikterik yang tinggi Dehydrasi NSAID

Faktor yang penting prognosa MAKI

Hipovolemia/ hipervolemia Hiperparasitemia Hemoconcentrasi Hiperbilirubinemia

Hiperpireksia

Pulmonary Oedema in sev.malaria

2 Types of Pulm.Oedema :

* Overload pulm.oedema * ARDS

ARDS
A syndrome of severe respiratory failure due to any causes resulting in very low Pa O2 (<70 torr) during intermittent positive pressure breathing (IPPB) with FiO2 50%.

PULMONARY MANIFESTATION IN MALARIA

Historically :
Bronchitic Pneumonic Bronchopneumonic

Acute Lung Injury (ALI) Acute Respiratory Distress Syndrome

(ARDS)

A.R.D.S
Occurs in P. Falciparum, P. Vivax, P. Ovale & ? P. Knowlesi Common in adult than children, pregnancy and non-

immune Mechanism : Increased alveolar cappilary permeability intravascular fluid loss into the lungs Presentation : initial presentation or after initiation treatment Clinical : acute onset dyspnea respiratory failure

CLINICAL FINDING
Manifest abrupt onset dyspnoea, cough, tightness in the chest

that progresses rapidly over a few hours

Disorientation and agitation is frequently present. Physical examination : signs of respiratory distress ( air hunger,

use of accessory muscles of respiration, suprasternal and intercostal indrawing ), central and peripheral cyanosis (arterial hypoxaemia), basal crepitations and expiratory wheezing.
In these patients, high parasitaemia,acute renal failure,

hypoglycemia, metabolic acidosis, disseminated intravascular coagulation (DIC), and bacterial sepsis usually co-exist.

Chest radiography :
Bilateral frontal opacities (alveolar pattern), increased interstitial markings
The cardiac size is usually normal

Rarely, thickening of lung fissures, interlobular septal lines

Pleural effusion

In assisted ventilator :
complications pneumothorax, pneumomediastinum ,

pneumonia may occur

Malaria dengan edema paru:

Komplikasi berat, sering fatal.
Sering pada dewasa. Timbul cepat ( 1-2 hari Tx) Ada 2 tipe :

1.Kelebihan cairan: tekanan vena sentral , PAWP ,balance cairan +. 2. ARDS : tekanan vena sentral N/ , balance cairan N/+.

Chest X-ray 18 hours After admission

Cerebral Malaria with infiltrate both lung

MM1-3

Definisi ARDS : Gagal respirasi berat Pa O2(<70torr) IPPB F1O2 50%

Faktor Predisposisi : Hiperparasitisme Gagal ginjal Kehamilan / post partum Hipoglikemi Asidosis metabolik Malaria serebral Kelebihan cairan

CM-ARDS, RSUP 2000

Pulmonary Oedema in sev.malaria

Dehydration
Low jugular venous pressure Skin tenting Postural dizziness Postural blood pressure drop of 15 mmHg Tachycardia Muscle cramps

Overhydration
Jugular venous naik distention Pitting oedema Hypertension Rales Cardiomegaly Third heart sound Progressive dyspnea Orthopnea Nocturnal cough

Edema paru:
Fisik ronki basah ke2 lap paru Radiologi infiltrat intrathorakal/ alveolus difus bilateral. Hipoksemia

Hiperkapnia kesadaran kejang renjatan DD : Pnemonia aspirasi Asidosis Metabolik

ANEMIA BERAT
Hb. < 5 gr% atau Ht < 15 % Parasit > 10.000 par/ uL Bukan thallasemia, iron deffeciency

atau keadaan lain yang dapat menyebabkan anemia.

Malaria dengan perdarahan:

Gejala: perdaraha gusi,petikie,

hematom, epiktaksi, perdarahan sub conjungtiva. Tanda: anemia, trombositosis, koagulopati, KID >10%. Berhubungan dengan : edema paru, ikterik, hiperparasitemia

MM4-1

A child, 5 months, malaria falciparum ++++, Hb. 1.6 gr% In RSMM-Timika Hospital, Papua

Perdarahan pada malaria berat : Hematom di pipi

Purpura ( perdarahan dibawah kulit, pada malaria dengan trombosit 2000/ mm3

Asidosis metabolik:
Nafas Kussmaull, Auskultasi paru normal
Kadar asam laktat pH serum < 7,2 Bikarbonat rendah (<15 ml/l) Berkaitan dengan : edema paru,

hiperparasitemia, syok, gagal ginjal, hipoglikemia.

HYPOTENSION (algid malaria)

Causes: gram - ve bacteriaemia, MOF Management :

1. CVP : 0 -- 5 cm H2O with crystalloid/ colloid infusion 2. I.V. Dopamine +/ dobutamine 3. Blood culture 4.Antibiotic ( Cephalosporin III)

Malaria Algid :
Malaria +renjatan : TD sistole < 80 mmHg. Tanda-Tanda sirkulasi perifer:

(kulit dingin, lembab, nadi cepat, nyeri epigastrium, mual, muntah, diare mirip kolera, ikterik, parasitemia berat schizon dalam darah, dll). Dapat disebabkan P. knowlesi ( simian Malaria) Berkaitan dengan :edema paru, asidosis, sepsis bakteri gram -, perdarahan saluran cerna. DD : -Dehidrasi berat renjatan septik. Setiap pasien malaria algid perlu kultur darah.

Infeksi sekunder bakteri:

Pnemonia aspirasi ( sering)

I.S.K ok kateter
Ulkus dikubitus terinfeksi Infeksi pada tempat infus

Sepsis : Gram >> Sering : pseudomonas, E.Coli, salmonela, streptokokus dll. Curiga : fibris bekepanjangan parasit-, syok menetap, leukositosis/neutropenia.

Diagnosis Banding:
Malaria Cerebral: encepalitis/ meninggitis (bakteri, virus, jamur), ggn metabolik, stroke, intoksikasi alkohol/obat, trauma kepala. Malaria dengan ikterus :leptospirosis, hepatitis tifosa, kolelitiasis dll. Malaria algid : Sepsis bakterial berat, IMA, dehidrasi berat , perdarahan tersembunyi dll. Edema paru :pnemonia aspirasi, kelebihan cairan, intoksikasi obat, dll.

Prognosis :
Jumlah & beratnya disfungsi organ Kecepatan diagnosis & mulai pengobatan yang adekuat. Indikator klinis: - Derajat kesadaran prog jelek - GGA +edema prog jelek - asidosis berat prog jelek

- gagal nafas prog jelek - perdarahan mortalitas >> - Imun (splenektomi, steroid, dll)prog jelek

Indikasi laboratorium:

Hiperparasitemia +Shizont perifer Lekositosis Kadar asam laktat CSS>, serum >6 mmoll/l Kadar gula CSS<< Kadar anti trombin III << Kreatinin>3 mg/dl, BUN >60 mg/dl Hb < 7,1 g/dl. GDS < 40 gr% Bikarbonat serum Transaminase > 3X N.

KEY SUCCEED FOR MANAGING SEVERE MALARIA

Accuracy diagnosis ( microscopic biochemical )

Malaria drug ( to combat resistency )

Ability to treat organ failure ( ICU & Medical equipment )

Good man power( nurses --- doctor ) Good referral system