Severe Malaria

Management Severe and
Non Severe Malaria in Adults
PKB XXXIII IPD PAPDI SURABAYA 2018

Introduction
• Malaria remains a global health problem.
• WHO 2017, estimates there were 214 million new cases .The African
Region accounted for most global cases of malaria (88%), followed by
the South-East Asia Region (10%) and the Eastern Mediterranean
Region (2%), there were an estimated 438 000 malaria deaths.
• Malaria in humans is caused by five species of parasites belonging to
the genus Plasmodium.
• Plasmodium falciparum is the major cause of severe malaria.
• Severe malaria causes high mortality that need rapid and appropriate
treatment.
PKB XXXIII IPD PAPDI SURABAYA 2018 2

Malaria-endemic Areas

Salivary gland
sporozoite
Midgut sporozoite
Mosquito
stageoocyst
ookinete
zygote
gametes
♀
♂ +
gametocytes
trophozoite
schizont
ring
merozoite
♀♂
Liver stage
Exoerythrocytic Cycle
Blood stage
Erythrocytic Cycle
• Sporozoites injected during
mosquito feeding
• Invade liver cells
• Exoerythrocytic schizogony
(merozoites)
• Merozoites invade RBCs
• Repeated erythrocytic
schizogony cycles
• Gametocytes infective for
mosquito
• Fusion of gametes in gut
• Sporogony on gut wall in
hemocoel
• Sporozoites invade salivary
glands
Pathogenesis Malaria
Sporogony
Schizogony

Malaria Transmission Cycle
Parasite undergoes
sexual reproduction in
the mosquito
Some merozoites
differentiate into male or
female gametocyctes
Erythrocytic Cycle:
Merozoites infect red
blood cells to form
schizonts
Dormant liver stages
(hypnozoites) of P.
vivax and P. ovale
Exo-erythrocytic (hepatic) Cycle:
Sporozoites infect liver cells and
develop into schizonts, which release
merozoites into the blood
MOSQUITO HUMAN
Sporozoires injected
into human host during
blood meal
Parasites
mature in
mosquito
midgut and
migrate to
salivary
glands

Clinical Presentation Malaria
• Early symptoms
• Headache
• Malaise
• Fatigue
• Nausea
• Muscular pains
• Slight diarrhea
• Slight fever, usually not intermittent
• Could mistake for influenza or gastrointestinal infection

• Acute febrile illness, may have periodic febrile paroxysms every 48 –
72 hours with
• Afebrile asymptomatic intervals
• Tendency to recrudesce or relapse over months to years
• Anemia, thrombocytopenia, jaundice, hepatosplenomegaly,
respiratory distress syndrome, renal dysfunction, hypoglycemia,
mental status changes, tropical splenomegaly syndrome

• Varies in severity and course
• Parasite factors
• Species and strain of parasite
• Geographic origin of parasite
• Size of inoculum of parasite
• Host factors
• Age
• Immune status
• General health condition and nutritional status
• Chemoprophylaxis or chemotherapy use

Clinical features Laboratory findings
• Impaired consciousness or unrousable coma.
• Prostration, i.e. generalized weakness so that the
patient is unable walk or sit up without assistance
• Failure to feed.
• multiple convulsions – more than two episodes in
24 h.
• Deep breathing, respiratory distress (acidotic
breathing).
• Circulatory collapse or shock, systolic blood
pressure < 70 mm Hg in adults.
• Clinical jaundice plus evidence of other vital organ
dysfunction
• Haemoglobinuria.
• Abnormal spontaneous bleeding.
• Pulmonary oedema (radiological).
• Hypoglycaemia (blood glucose < 2.2 mmol/l or < 40
mg/dl).
• Metabolic acidosis (plasma bicarbonate < 15
mmol/l).
• Severe normocytic anaemia (Hb < 5 g/dl, packed
cell volume < 15%).
• Hyperparasitaemia (> 2%/100 000/μl in low
intensity transmission areas or > 5% or 250 000/μl
in areas of high stable malaria transmission
intensity).
• Hyperlactataemia (lactate > 5 mmol/l).
• Renal impairment (serum creatinine > 265 μmol/l).
Tabel2.Definition of severe malaria by the working group of
WHO 2010

Tabel3.Definition of severe malaria by the working group of
WHO 2015
One / more of the following, occuring in the absence of an identified alternative cause and in the presence of
P. falciparum asexual.
• Impaired consciousness: GCS < 11 in adults.
• Prostration: Generalized weakness & unable to sit, stand, walk.
• Multiple convulsions: More than two episodes within 24hrs.
• Acidosis: A base deficit of > 8 mEq/L or bicarbonate level of < 15 mmol/L or plasma lactate >=5mmol/L.
respiratory distress
• Hypoglycaemia: RBS < 40mg/dL.
• Severe Malarial anaemia: HB < 5, haematocrit <1 5%.
• Renal impairment: creatinine>3mg/dl, blood urea > 20mmol/L.
• Jaundice: Sr bilirubin > 3mg/dL with a parasite count >1,00 000/µL.
• Pulmonary oedema: Radiologically confirmed oxygen saturation < 92% on room air, RR > 30/min,with chest
indrawing crepitations on auscultation.
• Significant bleeding: recurrent / prolonged bleeding from the nose, gums or venepuncture sites,
haematemesis or melaena.

Roseting
Receptor: Blood group antigens
CD36, CR1 and HS
Endothelial cytoadherence
Receptor: CD31, CD36, CSA
E-selectin, ICAM-1, TSP, and VCAM-1
Endothelial
activation
Rolling on
endothelium
Receptor: ICAM-1
In situ rosetting Vascular occlusion
Flow
IFN-
TNF-
Pathogenesis
Severe Malaria
11

Toxic mediators
Inflammatory
responses
Hemolysis
Adhere to
blood vessels
Hypoglycaemia
Chill, fever, sweat
Anemia
Obstruct
blood flow
Splenomegaly
Hepatomegaly
Phagocytosis Renal failure
Black water fever
Metabolic
disturbances
Tissue hypoxia
Impaired
microcirculation DIC
Cerebral malaria
Pulmonary edema
Pathogenesis Severe Malaria
12

Clinical Features Severe Malaria
• Impaired consciousness/coma.
• Prostration, i.e. generalized weakness
so that the patient is unable walk or
sit up without assistance.
• Failure to feed.
• Multiple convulsions – more than
two episodes in 24 h or activity of
subtle convulsion.
• Clinical jaundice.
• Deep breathing, respiratory distress /
acidotic breathing.
• Circulatory collapse/shock (SBP < 80
mmHg).
• Clinical jaundice.
• Anuria.
• Abnormal spontaneous bleeding.
• Hyperpyrexia (Temperature >106°F or
>42°C).
• Pulmonary oedema (radiological).

Laboratory Findings Severe Malaria
• Hypoglycaemia (blood glucose < 2.2 mmol/l or < 40 mg/dl).
• Metabolic acidosis ( pH < 7.25 or plasma bicarbonate < 15 mmol/l).
• Severe normocytic anaemia (Hb < 5 g/dl, packed cell volume < 15%).
• Hyperparasitaemia (> 2%/100 000/μl in low intensity transmission.
areas or > 5% or 250 000/μl in areas of high stable malaria
transmission intensity).
• Hyperlactataemia (lactate > 5 mmol/l).
• Renal impairment (serum creatinine > 3 mg/dL).

Laboratory Findings Cont…
• Decreased platelet count (< 50,000/L).
• Prolonged prothrombin time (> 3 s).
• Prolonged partial thromboplastin time.
• Decreased fibrinogen (< 200 mg/dL).

Diagnosis Malaria
Microscopy
• Thick and thin blood
• gold standard for confirmation of diagnosis of malaria.
• Advantages :
1. Sensitivity is high.
It is possible to detect malaria parasites at low densities.
2. To quantify the parasite load.
3. To distinguish different species of malaria parasites and their different
stages.

Rapid Diagnostic Test
• Based on the detection of circulating parasite antigens.
• Several types of RDTs are available.
• Some of them can only detect P.falciparum, while others can detect
other parasite species also.
• NVBDCP has recently rolled out bivalent RDTs for detecting P.
falciparum and P. vivax.
Diagnosis Malaria

P. falciparum P. vivax
P. ovaleP. malariae
P. knowlesi
Severe
Malaria
18

Differential Diagnosis
• Typhoid
• Respiratory and urinary tract
infections.
• Viral illnesses (such as
influenza, dengue fever etc)
Acute coma
•viral encephalitis (herpes simplex,
HIV, mumps, etc)
•bacterial meningoencephalitis
(pyogenic and rarely tuberculous)
•fungal and protozoal
meningoencephalitis (African
trypanosomiasis),
•cerebral typhoid,
•brain abscess
•heat stroke / CVA events
•hypertensive encephalopathy
•intoxications with drugs and
poisons
Renal failure
•Glomerulonephritis
•hypertension.
•herbal medicines
•Snakebite
Jaundice and hepatomegaly
•viral hepatitis
•alcohol
•drug-induced diseases
•biliary disease
•yellow fever
•leptospirosis

Treatment of Non-Severe Malaria
1. Malaria falciparum and Malaria vivax
Treatment of malaria falciparum and malaria vivax currently uses ACT
plus primaquine.
The ACT dose for malaria falciparum is the same as malaria vivax,
Primaquine for malaria falciparum is only given on the first day with a
dose of 0.25 mg / kgBB and malaria vivax for 14 days at a dose of 0.25
mg / kgBB.

Treatment of malaria falciparum according to body weight
with DHP and Primaquine
Treatment of malaria vivax according to body weight with
DHP and Primaquine

2. Relapse of Malaria vivax
Same regiment of ACT with increased dose of rPimaquine
0,5mg/kgBB/day
3. Malaria Ovale
Regiment of ACT, DHP + Primaquine 0,25mg/kgBB/day for 14 days
4. Malaria Malariae
DHP for 3 days without Primaquine

5. Mixed infection P. falciparum + P. vivax / P. Ovale
Treatment of mixed infections according to body weight with
DHP and Primaquine

Treatment Severe Malaria
Patients with severe malaria should be treated in ICU
• Parenteral antimalarials, antipyretics, antibiotics, anticonvulsants.
• Intravenous infusion facilities.
• Special nursing for coma patients.
• Blood transfusion.
• Laboratory facilities.
• Facility for Oxygen, dialysis, ventilator, etc.

Group at Risk of Severe Malaria
• These are people whose immunity to malaria is low
• People of all ages in areas of low malaria endemicity
• Pregnant women especially during the 1st and 2nd pregnancies
• Travelers from non-endemic ares
• People returning to endemic areas after a long(more than 6 months)
stay in non malaria areas
• People with HIV/AIDs
• Persons with Sickle cell anemia

Supportive Treatment Severe Malaria
• Supportive measures: oxygen, ventilatory support, cardiac
monitoring, pulse oximetry
• Unconscious pts require lumbar puncture to rule out concomitant
bacterial meningitis
• Repeat clinical assessment should be preformed every 2-4 hrs & lab
investigations every 6 hrs to detect & treat complications
• If coma score decreases, investigatons should focus on possibility of
seizures, hypoglycemia or worsening anemia
• Predictors for fatality include acidosis, impaired consciousness,
elevated blood urea nitrogen etc

Fluid Therapy in Severe Malaria
Fluid requirements should be assessed individually. Adults with severe
malaria are very vulnerable to fluid overload.
Giving fluids appropriately by:
• Maintenance 30 ml/kg, if there is dehydration can be added fluids as
dehydration, added 10% mild, 20% moderate and 30% severe.
• The temperature rise every 1oC plus 10% of the required maintenance
fluids.
• Insert of CVP (central venous pressure) to accurately monitor fluid.
• Used dextrose 5% to prevent hypoglycemia.
• When there hyponatremia (Na <120 mEq / L) can use NaCl.

WHO 2015 Recommendation
• Treat adults with severe malaria (including pregnant women in all
trimesters and lactating women) with IV or IM artesunate for at least
24 h and until they can tolerate oral medication.
• Once a patient has received at least 24 h of parenteral therapy and
can tolerate oral therapy, complete treatment with 3 days of an ACT
(add single dose primaquine in areas low transmission).
• If parenteral artesunate is not available, use IM artemether in
preference to quinine for treating children and adults with severe
malaria.

Anti malarial Therapy
• Artesunate: 2.4 mg/kg i.v. or i.m. on admission 0 hour then at 12 &
24 hours, then once a day (dilute artesunate in 5% Sodium
bicarbonate until they can tolerate oral medication, complete
treatment with 3 days of an ACT .
• Artemether: 3.2 mg/kg i.m. given on admission then 1.6 mg/kg per
day, until they can tolerate oral medication, complete treatment with
3 days of an ACT.
• Quinine: 20 mg/kg on admission (i.v. infusion in 5% dextrose over 4
hours), maintenance dose :- 10 mg/kg 8 hourly, beyond 48 hours:- 7
mg/kg 8 hourly. Never give bolus injection !!

Management of Complications
Manifestation or complication Immediate management
Coma(Cerebral malaria) Maintain airway, exclude other treatable causes of coma(e.g.
hypoglycaemia, bacterial meningitis); avoid harmful ancillary
treatments, intubate if necessary.
Hyperpyexia Administer tepid sponging, fanning a cooling blanket and
paracetamol
Convulsions Maintain airways; treat promptly with intravenous or rectal
diazepam, lorazepam, midazolam or intramuscular paraldehyde.
Check blood glucose.
Hypoglycaemia Check blood glucose, correct hypoglycemia and maintain with
glucose-containing infusion. Although hypoglycaemia is defined
as glucose <2.2mmol/L or <40 mg/dL, the threshold for
intervention is <3mmol/L for children <5 years and <2.2
mmol/L for older children and adults

Management of Complications (Cont…)
Severe anaemia Transfuse with screened fresh whole blood if available, PRC,
give furosemide 20mg during blood tranfuion
Acute Pulmonary edema Prop patient up at an angle of 45◦, give oxygen, give a diuretic,
stop intravenous fluids, intubate and add positive end-
expiratory pressure or continuous positive airway pressure in
life-threatening hypoxaemia.
Acute kidney injury Exclude pre-renal causes, check fluid balance and urinary
sodium, if in established renal failure, add haemofiltration or
haemodialysis, or if not available, peritoneal dialysis.
Spontaneous bleeding and
coagulopathy
Transfuse with screened fresh whole blood (cryoprecipitate,
fresh frozen plasma and platelets, if available); give vitamin K
injection, art gastric protection with a parenteral H2 -receptor
blocker (e.g. ranitidine) or a PPI (e.g. omeprazole)

Management of Complications (Cont…)
Metabolic acidosis Exclude or treat hypoglycaemia, hypovalaemia and septicaemia. If
severe, add haemofiltration or haemodialsis. Give isotonic fluid
(0,9%saline) by slow iv infusion, monitor BP every hour and JVP
Shock Suspect septicaemia, take blood for cultures; give parenteral
broad-spectrum antimicrobials, correct haemodynamic
disturbances.

Acidosis in Severe Malaria

Not Recommended Treatments
The following treatments for cerebral malaria are considered either useless
or dangerous and should not be given
• Heparin
• High dose-corticosteroid
• Prostacyclin
• Desferroxamine
• Pentoxifylline
• Anti-TNF antibody
• N-acetylcysteine
• Mannitol

Summary
• Severe malaria is potentially life-treatening.
• Blood film microscopy is the gold standart for diagnosis malaria.
• ACT and Primaquine is treatment for non-severe malaria.
• Parentral treatment is required in severe malaria.
• The recommended treatment is intravenous artesunate.
• General care, suppotrive and complication treatmens are essential to
survival.

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Severe Malaria

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