What’s New In Malaria Treatment Guidelinesjknj.jknj.moh.gov.my/jsm/day1/What's New in Malaria Treatment Guideline... · Complicated Malaria •It is caused by presence of high density

What’s New In Malaria

Treatment Guidelines

Dr Chua Hock Hin

Infectious Disease Unit

SGH

2013 2015

Malaria Infection

• Epidemiology

• Clinical manifestations

• Diagnosis

• Treatment

• Prevention

Malaria

• Infection caused by protozoan parasites of

the genus Plasmodium.

• Human malaria ( 5 species ) : P falciparum,

vivax, ovale ( 2 species ) and malariae.

• Simian malaria : P knowlesi

• Transmitted by female anopheles mosquitoe.

Epidemiology Of Malaria In Malaysia

• Majority of cases occur in Sarawak and Sabah

• Malaysia is now in the pre-elimination phase of malaria

control. ( NSPEM 2011-2020 )12,705

4,725

0.55

0.16

Epidemiology Of Malaria In Malaysia - 2012

• Human malaria – 61.6 % , Zoonotic – 38.4%

• Human malaria :

– P. vivax ( 50.2 % ) , P. falciparum ( 30.7% ) , P malariae ( 16.7 % )

– Indigenous cases ( 70.4% ), Imported ( 29.6% )

– Indigenous cases : Sabah -70.4%, Sarawak – 15.9%, Peninsular

Malaysia – 10.1%

• Zoonotic malaria : P knowlesi

– Sarawak ( 56.9 % ) , Peninsular M’sia ( 23.3% ), Sabah ( 19.8% )

The Changing Landscape

• In Malaysia :

• Most human malaria cases are “imported”

• Most locally acquired malaria are zoonotic

malaria – mainly P knowlesi.

• Worldwide :

• Emergence of artemisinin resistant malaria

in Greater Mekong subregion (GMS):

– Cambodia, Laos, Myanmar, Thailand &

Vietnam.

Malaria Cases in Sarawak 2012-2013

2012 2013

Locally Acquired P

falciparum14 0

Locally Acquired P vivax 310 97

Locally Acquired P knowlesi 1007 725

Total Locally Acquired 1331 822

Total Imported Malaria 246 183

TOTAL 1577 1005

Data courtesy of Dr Ooi Choo Huck, JKNS

It is a “Notifiable” Disease

• Malaria is a notifiable disease under the

Communicable Diseases Control Act 1988

which mandates notification within 7 days.

• To ensure early investigation & institution

of control measures, all practitioners are to

notify malaria cases within 24 hours to the

nearest health office.

P falciparum , vivax,

ovale – 48 hours

P knowlesi – 24 hours

P malariae – 72 hours

Clinical Features

• Incubation period : 10-14 days ( average )

• Symptoms occur within:

– 6 weeks in >90% for P falciparum infections

– 1 year for P vivax infections

– 9-12 days for P knowlesi infections

Clinical Features

• Early symptoms are non-specific.

• Most common presentation is high fever; “cold

stage” “hot stage” “sweating stage”

• In high transmission area, majority usually are

asymptomatic and infections are acquired

repeatedly throughout life.

• Immunity is often gradually lost when people

move out of the endemic areas for long

durations. ( many years )

Clinical Features Of Malaria

• Fever

• Headache, dizziness

• Arthralgias, myalgias,

back ache

• Abdominal pain

• Nausea, vomiting

• Diarrhoea

• Cough,

breathlessness

• Abnormal bleeding

• Jaundice

• Pallor

• Hepatosplenomegaly

• Petechiae, brusing

• Tachypnoea, hypoxia

• Acute abdomen

Biochemical Features

• Anaemia

• Thrombocytopenia

• Hypoglycemia

• Hyperbilirubinemia

• ↑ ALT/AST (usually mild)

• Renal failure

• Metabolic acidosis

Diagnosis Of Malaria

• Malaria must be excluded in :

– All febrile patients living in, or returning from,

an endemic country, regardless of whether

they have been taking anti-malarial drugs.

– All immigrants from malaria endemic

countries with fever.

• Consideration of the possibility of malaria

is an important step in diagnosis especially

in patient from outside endemic areas.

• Must always ask for travel history.

Diagnosis

• In all settings, clinical suspicion of malaria

should be confirmed with a parasitological

diagnosis.

• However, in settings where parasitological

diagnosis is not possible, the decision to

provide anti-malarial treatment must be

based on the prior probability of the illness

being malaria.

Diagnosis

• Malaria should be suspected in the

presence of

– Thrombocytopenia

– Relative lymphopenia

– Atypical lymphocytes

– Elevated LDH.

BFMP

Blood may be sent in EDTA bottle but slide must

be made within 2 hours to minimize morphological

changes by anticoagulant in the tube.

When to do BFMP ?

• Do immediately.

• No need to wait for a peak of fever.

• If initial film is negative, repeat another 2

samples or more especially at peak of

fever.

BFMP

• Advantages :

– Detect malaria parasites at low densities.

( High Sensitivity )

– Can quantify the parasite load

– Able to distinguish different species and

stages of malaria parasite

• Disadvantages :

– Need training.

P knowlesi P falciparum

Rapid Diagnostic Tests - RDT

• Detection of circulating parasite antigens or

enzymes that are either genus or species specific.

• It cannot replace microscopy but can be

supplementary when malaria diagnosis is being

performed by relatively inexperienced staff (e.g.,

in low prevalence areas and outside normal

working hours).

• It has high sensitivity (>95%) and should be

highly stable in all situations.

RDT – HRP2

• Histidine-rich protein-2 is a water-soluble protein

produced by trophozoites and young ( but not

mature) gametocytes of P. falciparum. It detects

P. falciparum only.

• It should be used only for diagnosis of acute

malaria infections, and not for follow-up, as they

may remain positive for several weeks even after

successful treatment.

RDT – pLDH , aldolase based

• Plasmodium lactase dehydrogenase (pLDH) and

the pan-specific aldolase are produced by both

asexual and sexual stages (gametocytes) of

malaria parasites.

• The use of pLDH-based RDTs ( high sensitivity )

is recommended.

• No commercially available RDTs have been

sufficiently sensitive overall for P. knowlesi, thus a

negative pLDH or aldolase-based RDT does not

exclude the diagnosis of knowlesi malaria.

PCR

• Cases having microscopic appearance of

P malariae.

• Cases with clinical symptoms of malaria

but BFMP repeatedly negative.

• Mortality cases.

Definition Of Uncomplicated

• Symptomatic malaria without signs of

severity or evidence (clinical or

laboratory) of vital organ dysfunction.

Severe Malaria ( Clinical

Manifestation )

• Prostration

• Impaired consciousness

or unrousable coma

• Respiratory distress

( acidotic breathing )

• Convulsion (>2 in 24hr )

• Failure to feed

• Pulmonary oedema

( CXR )

• Abnormal spontaneous

bleeding

• Haemoglobinuria

• Jaundice + other organ

failure

• Shock / Circulatory

collapse

WHO Guidelines For Treatment

Of Severe Malaria 2010

Severe Malaria ( Laboratory )

• Severe anemia ( Hct < 24% or Hb < 8g/dL )

• Hypoglycaemia ( Blood sugar level < 3 mmol/L )

• Metabolic Acidosis ( HCO3 < 18 mmol/L )

• Renal impairment

• Hyperlactatemia

• Hyperparasetemia ( > 100,000 parasites/µl for

other plasmodium sp; for P knowlesi > 20,000

parasites/µl )

Treatment

Treatment

• Few factors :

–Malaria species

–Severity of illness

–G6PD status

–Special groups – pregnant mothers

Drugs Available• Chloroquine

• Quinine ( Oral & IV )

• Artemisinin derivative ( oral and IV )

• Primaquine

Treatment of Uncomplicated Plasmodium falciparum

Plasmodium falciparum infection should

be presumed to be chloroquine

resistance in most cases

Uncomplicated P falciparum

• Artemisinin-based combination

therapies (ACTs) are the recommended

treatments

– Riamet (artemether/lumefantrine) or

– AS/MQ (artesunate/mefloquine)

• Artemisinin and its derivatives should not

be used as monotherapy

Why Artemisinin?

• Short half life, auto-metabolism

• Rapid resolution of clinical symptoms

• Effective action against multi-drug

resistant P falciparum

• Few adverse effects

– Cough, body aches, nausea, vomiting,

anorexia, palpitation, dizziness, weakness,

skin rash and itchiness

Why Artemisinin?

• Rapid clearance of parasites

– reduce parasite density by a factor of 10,000 in each 48

hr asexual cycle ( 108 fold reduction within 3 days )

• Rapidly eliminated from blood in 1-3 hours, so

need combination with longer acting partner drug

– 3 day course of artemisinin derivative will clear ≥90% of

parasites, remaining 10% of parasites will be cleared

by partner drug

– Lumefantrine ( 4-5 days ) , mefloquine ( 2-3 weeks )

• Reduce gametocyte carriage

Artemether 20mg / Lumefantrine 120mg

First Line Treatment Of Uncomplicated P

falciparum

REGIME :

Artemisinin based combination therapy ( ACT )

Artemether ( 20mg ) and Lumefantrine ( 120mg )

( Wt > 35kg ) :

4 tablets stat followed by 4 tablets 8 hours later,

then 4 tablets twice daily for 2 days

TOTAL : 6 doses ( 24 tablets )

Practice points : Riamet

• For children

• 25 –34kg: 3 tabs ( Total 18 tablets )

• 15 –24kg: 2 tabs ( Total 12 tablets )

• 5 –14kg: 1 tab ( Total 6 tablets )

• If possible, must be given with fat to increase

absorption especially on 2nd and 3rd day of

treatment. ( To give after food or with milk )

Treatment Of Uncomplicated P falciparum

REGIME ( Alternatives ):

Other oral Artemisinin based combination therapy

( ACT )

Artesunate / mefloquine ( ASMQ )

T Quinine 10mg/kg TDS + doxycycline 100mg BD for

7 days

Artesunate-Mefloquine ( AS-MQ )

• Do not use in pregnancy ( 1st trimester )

• May cause seizure in children with

epilepsy

• Interact with quinine, chloroquine and

halofantrine and may cause arhythmia.

• Do not reuse within 60 days as increase

risk of neuropsychiatric side effects.

ASMQ Drug Interactions ↑Arrhymia

• Amiodarone

• Disopyramide

• TCA

• Phenothiazines

• Haloperidol

• Ketoconazole

• Moxifloxacin

• Metoclopramide

Artesunate-Mefloquine ( AS-MQ )

• Strength : Artesunate 100mg and

Mefloquine 220mg

• Dosage ( daily for 3 days ) :

– 5 – 8 kg: 1 tab ( 25mg AS / 55MQ )

– 9 –17kg: 2 tabs (25mg AS / 55MQ )

– 18 –29kg: 1 tab (100mg AS / 220MQ )

– ≥30kg: 2 tabs (100mg AS / 220MQ )

Treatment Of Uncomplicated P falciparum

REGIME :

Doxycyline and Tetracycline ~ AVOID in children

< 8 years old, pregnancy.

REGIME :

T Primaquine 0.25mg/kg single dose for anti-

gametocidal action at Day 1.

Avoid if patient is pregnant or breast feeding an infant < 6

months old or infant < 6 months old. Risk of severe

hemolysis with single dose in patient with G6PD deficient

is negligible.

Treatment Of Uncomplicated P falciparum :

Treatment Failure

REGIME :

Alternative oral Artemisinin based combination

therapy ( ACT )

1st time : Riamet, then use ASMQ

T Quinine 10mg/kg TDS + doxycycline 100mg BD for

7 days

Basically its about

• Safety – risk of teratogenicity in pregnancy

especially in 1st trimester

• Adequate dose vs overdose

• Drug interactions – patient co-infected with

HIV and TB

Treatment Of Uncomplicated P vivax / ovale

• Plasmodium vivax and ovale infection are

chloroquine sensitive except those who

acquired from overseas such as Papua

New Guinea, Oceania countries.

Treatment Of Uncomplicated P vivax / ovale

REGIME ( Chloroquine Sensitive ):

T.Chloroquine 10mg base/kg (max 600mg ) followed by 5mg/kg

( max 300mg ) 6hrs later and 5mg/kg/day for 2 days or 10mg/kg

Day 1 and 2 followed by 5mg/kg Day 3(Total 25mg/kg )

T Primaquine 0.5 mg/kg/day ( usual 30mg base ) for 14 days is

given to eradicate hypnozoite in G6PD normal patient.

T Primaquine 0.75 mg/kg weekly for 8 weeks in mild variant

G6PD deficiency patient.

Treatment Of Uncomplicated P vivax / ovale

REGIME ( Suspected chloroquine resistant /

treatment failure ):

T. Arthemether – Lumefantrine ( Riamet )

AND

T Primaquine 30mg once daily for 14 days

Toxicity of primaquine

• Abdominal discomfort, nausea, vomiting

– Usually resolved if taken with food

– Can given in divided doses

• Haemolytic Anaemia

– Occurs in people with G6PD deficiency

– Begins 24 –72 hours after commencing primaquine

– Severity depends on degree of enzyme deficiency

– Haemolysis less severe or absent using primaquine

45mg or 60mg weekly for 8 weeks

Preventing relapses in pregnant and

breastfeeding women

• Chloroquine 300mg prophylaxis weekly

until delivery or breastfeeding completed

• If failed chloroquine, mefloquine can be

used

• Primaquine ( full course ) to be given post-

delivery

First Line Treatment Of Uncomplicated P

knowlesi

REGIME :

Artemisinin based combination therapy ( ACT )

Artemether ( 20mg ) and Lumefantrine ( 120mg )

( Wt > 35kg ) :

4 tablets stat followed by 4 tablets 8 hours later,

then 4 tablets twice daily for 2 days

TOTAL : 6 doses ( 24 tablets )

Treatment Of Uncomplicated P knowlesi

REGIME ( Alternatives ):

Artesunate / mefloquine ( ASMQ ) for 3 days

T.Chloroquine 10mg base/kg (max 600mg ) followed

by 5mg/kg ( max 300mg ) 6hrs later and 5mg/kg/day

for 2 days

Management of Severe And

Complicated Malaria• It is caused by presence of high density of

asexual forms of plasmodium in patient’s body.

• P falciparum and knowlesi infection, occasionally

P vivax infection.

• It has high mortality ( approaching 100% ) if

untreated particularly cerebral malaria.

• With prompt, effective antimalarial treatment and

supportive care, the rate falls to 10–20% overall.

Therapeutic Objectives

• The main objective is to prevent death.

• Secondary objectives are prevention of disabilities

and prevention of recrudescent infection.

• Management of severe malaria :

– Clinical assessment

– Specific anti-malarial treatment

– Additional treatment

– Supportive care

General Management

• Take a complete history and physical

examination• Prostration

• Impaired consciousness

or unarousable coma

• Respiratory distress

( acidotic breathing )

• Multiple convulsion ( >2

within 24 hours )

• Failure to feed

• Pulmonary oedema

( CXR )

• Abnormal spontaneous

bleeding

• Haemoglobinuria

• Jaundice + other organ

failure

• Shock / Circulatory

collapse

General Management

• Blood investigations :

– Blood C&S

– FBC, BUSE, Creatinine, LFT, Blood sugar,

PT/PTT

– CXR

– ABG

– Serum lactate ( if available )

• CSF investigations ( LP )

Malaria Treatment

• All patients should be admitted.

• Only in exceptional case where admission is not

possible, patient is to be managed as outpatient

with close monitoring.

• Admission is mandatory for :

– Severe/ complicated malaria

– Patient unable to tolerate orally

– Patient with G6PD deficiency

– Pregnant mothers

– Severe malnutrition

– Children

When to refer to hospital with

specialist ?• All severe / complicated malaria cases

• Pregnant mothers.

• Patient with significant co-morbidities eg

hepatic or renal dysfunction.

General Management

• Admit patient to ICU or HDU

• Patient should be referred to physician or

intensivist

• IV artesunate ( 2.4mg/kg ) stat and at least

for 3 doses ( 24 hours ) before switching to

oral antimalarial if patient improves and

can tolerate orally.

• Close monitoring.

Severe Malaria ?

Yes

IV Artesunate

No Vomiting?

Yes

No

Treat as uncomplicated

using oral medications

General Approach

Treatment Of Severe/ Complicated P

falciparum/ knowlesi

Artesunate ( IV )

Loading dose 2.4mg/kg ( IV/IM ) given stat, 12 hours, 24

hours then once a day.

Change to riamet / AS-MQ when able to tolerate oral

medications or at least after 3 doses of IV artesunate

Treatment Of Severe/ Complicated P

falciparum

QUININE IV

Loading dose usually 20mg/kg but should be used with

“CARE” followed by 10mg/kg 3 times ( 8 hours later )

daily for 7 days. Earlier adjustment of dose by reducing 30

to 50% should be done after loading dose in liver

impairment and renal failure.

Change to oral quinine once stabilize and tolerate orally

Be careful in patient with prolong QTc on ECG, electrolyte

imbalance particularly hypokalemia and hypoglycaemia.

PLUS

T Doxycycline 100mg 12 hourly for 7 days

The danger of “Quinine”

• It should not be given as bolus IV – lethal

hypotension.

• Each dose of parenteral quinine must be

administered as a slow, rate-controlled

infusion (usually diluted in 5% dextrose

and infused over 4 h). The infusion rate

should not exceed 5 mg salt/kg bw per

hour.

• Overdose – blindness and deafness ( rare)

What about if no IV access prior

to hospitalization ? • Children < 6 years old :

• IM artesunate : rectal artesunate : IM

artemether : IM quinine.

• Older children or adults :

• IM artesunate : IM artemether : IM quinine.

Pulmonary Oedema

• High mortality ( over 80% in falciparum malaria);

the prognosis is better in vivax malaria.

• It may develop several days after starting

treatment, at a time when the patient’s general condition is improving and the ↓ parasitemia.

• Management :

• a. Close input output monitoring ( Give adequate

fluids to maintain the circulation and correct

dehydration ).

Pulmonary Oedema

• b. Children : Half normal saline (0.45%) with 5%

dextrose with maintenance fluids (3-4ml/kg/hour),

Adults : normal saline at 1-2ml/kg/hour, until the

patient is able to take and retain oral fluids.

• c. Rapid fluid boluses are contraindicated in

severe malaria resuscitation.

• Dehydration should be managed cautiously and

ideally guided by urine output. ( aim > 1ml/kg/ hr),

unless the patient has anuric renal failure or

pulmonary oedema.

General Management

• If GCS is reduced, consider lumbar puncture ( if

not contra-indicated ) to rule our meningitis.

• If secondary infection is suspected, a septic

workout is to be done and institute broad

spectrum antibiotic such as ceftriazone 2g OD.

• Monitor – clinical and parasitological response.

• High fever – paracetamol and tepid sponging.

Role of adjunct therapy ?

• This is in reference to any additional

therapy that modifies physiologic

processes caused by malaria.

Exchange blood transfusion

• No RCT or consensus on indications, benefit

and risk.

• Requires expertise and intense monitoring.

• Rationale

– Reduce parasite burden ( can be achieved with

artemisinin )

– Rapidly reduced both Ag load and parasite toxins,

host metabolic and toxic mediators

– Alleviate microcirculatory obstruction replace with

more deformable cells

Severe Malaria In Pregnancy

• Women in the second and third trimesters of

pregnancy are more likely to have severe

malaria.

• In low-transmission settings, this is often

complicated by pulmonary oedema and

hypoglycaemia.

• Maternal mortality is approximately 50%, which

is higher than in non-pregnant adults.

• Fetal death and premature labour are common.

Severe Malaria In Pregnancy

• Parenteral artesunate is the treatment of choice

in all trimesters.

• Obstetric advice should be sought at an early

stage, a paediatrician alerted.

• Blood glucose should be checked frequently -

hypoglycaemia should be expected, and it is

often recurrent if the patient is receiving quinine.

• Severe malaria may also present immediately

post delivery.

• Post partum bacterial infection is a common

complications.

Congenital Malaria

• Uncommon ( Incidence : 0.3- 33% )

• Transmission during pregnancy or labour.

• Symptoms occur between 10- 30 days of age

( 14 hour to several months )

• May mimic neonatal sepsis.

• Treatment :

– P vivax ( chloroquine – total 25mg base/ kg )

– P falciparum ( quinine 10mg/kg TDS for 1 week )

• No need primaquine as no tissue / exo-

erythrocytic phase.

Discharge

• In high transmission settings, it is important

to keep the patients warded until they are

cleared of gametocytes which play a crucial

role in the spread of malaria and thus of

public health concern.

• Otherwise, the patients can be discharged

once they are clinically well with two

negative BFMP slides within 48 hours.

Follow-up After Discharge

• Current recommendation :

• Follow-up 28 days for all anti-malarial

medication to assess cure rate and drug

efficacy on weekly basis.

Malaria Prevention

• Mosquitoe avoidance measures

– Insect repellant ( DEET 20-50% )

– Wear long sleeves and pants

– Insecticide treated mosquitoe net

• Chemoprophylaxis

– Countries patient is travelling to

– Trips – length, specific areas

– Drug availability and drug-drug interaction

– Drug allergies.

Chemoprophylaxis

• Patient with severe splenic dysfunction or

pregnant women should avoid traveling to

endemic areas.

• 2 types :

– Suppressive : Chloroquine, mefloquine, doxycycline,

proguanil ( effective against erythrocytic stage ) ,

need to take up to 4 weeks after returning from risk

area.

– Causal : Atovaquone/ proguanil ( Malarone ) and

primaquine. ; take till 7 days after returning from risk

area.