Management of Malaria

Dr M Ridwanur Rahman

Professor (Medicine), ShSMC, Dhaka

Member, Malaria Research Group, Ctg

THE BURDEN OF MALARIA

>100 countries in the world are malarious >2 billion people are exposed to the risk of

malaria infection annually. Residents of non-endemic areas also have,

Travel malariaAirport malaria

High Risk Groups Young children (6 months - 5 years) -Pregnant women (primigravids) -Non-immune migrants (Military personnel,

expatriates, tourists, refugees).

High Risk Malaria Areas in Bangladesh

Case Load: Malaria in Bangladesh, 1963 – 1998

Clinical Malaria - Treatment

Non falciparum malaria- Uncomplicated

Uncomplicated Malaria (falciparum)

Severe (Complicated) Malaria

Malaria Case Fatality Rates

Severe malaria 10-40%

Moderately severe malaria 3%

Uncomplicated malaria <1%

Relationship between life cycle & clinical features

Cycle/feature Vivax/ovale Malariae Falciparum

Incubation 8-25 days 15-30 days 8-25 days

Asexual cycle 48 hrs, synchronus

72 hrs, synchronus

<48 hrs, asynchronus

Periodicity of fever

Tertian Quartan Aperiodic

Exo-erythrocytic

Persist as hypnozoites

None None

Delayed onset common rare Rare

Relapses Common upto 2 years

Recrudescence many years

Recrudescence upto 1 year

Clinical Features Fever- classically intermittent & periodic 3 stages described Asymptomatic apyrexial intervals Malaise, Headache, bodyache & vomiting Cough & mild diarrhoea- children Jaundice relatively common- falciparum No specific physical sign Liver & spleen- enlarge & tender Anaemia frequent in falciparum

D/D in uncomplicated disease

Flue like illness’ Enteric feversRTI’s UTI Dengue SSTI Others

Diagnosis

High index of suspicion- H/O chance of contact, absence of symptom/signs of other disease, characteristic C/F

Blood slide examination Dipstick Tests Other tests- to exclude other D/D,

e.g., urine R/M/E, CBC, CXR etc.

Classification of antimalarial drugs based on chemical structures

4-aminoquinolines e.g. chloroquine, hydroxychloroquine, amodiaquine

8-aminoquinolnes e.g. primaquine 2,4-diaminopyrimidine e.g. pyrimethamine Arylaminoalcohols e.g. quinine, mefloquine, lumefantrine Acridine derivatives e.g. quinacrine, mepacrine, pyronaridine Biguanides e.g. chloroguanide, chloroproguanil Suphonamides and sulphones e.g. sulphadoxine and dapsone

respectively Phenanthrene methanols e.g. halofanthrine Naphthoquinones e.g. atovaquone Artemisinins e.g. dihydroartemisinin, artesunate, artemether,

arteether, e.t.c.

FACTORS THAT GOVERN CHOICE OF DRUGS

Parasite species

Local Level of resistance to drugs

Patient’s general health and medical

history. Availability of medication in the country

of prescription.

Intended use (prophylactic or

therapeutic).

Drug resistant Malaria

Resistance is the ability of an organism to survive or multiply despite presence of the drug – exhibited by falciparum only

CQ, S/P resistance in Bangladesh May have reduced sensitivity to Q & M Bangladesh is a multi-drug resistant

falciparum area

Factors aiding Resistance in

malaria parasites. Indiscriminate drug useSub-optimal dosagesNon compliance with treatment

courseLow quality drugsFake and substandard drugs

WHO Treatment Guidelines

Artemisinin-based Combination Therapies (ACTs) should be first line treatment for falciparum malaria everywhere.

This should ideally be formulated in fixed dose combinations when possible.

Therapeutic options for ACT -Artesunate-SP -Artemether-lumefantrine -Artesunate-amodiaquine -Artesunate-mefloquine -Dihydroartemisinin-piperaquine

What are Artemisinins ?

Artemisinin derivatives

Methyl Ether

Hemisuccinate

Ethyl Ether

Arteether Artemether

Artesunate

Dihydroartemisin

Qinghaosu ("ching-how-soo")

40

60

80

100

Year

Cured (%)

Mefloquine15

Mefloquine25

Mefloquine +

artesunate

Treatment efficacy at Thai-Burmese border

First demonstration project in Thailand

Widespread use of 1st line Rx withArtemisinin-basedCombination Therapy

Improve clinical cure ratesDelay emergence of resistanceReduce transmission

Cost effective

Artemisinin-based combination therapy in uncomplicated malaria

Treatment of Uncomplicated MalariaNon-Falciparum-

- Chloroquine 25 mg/kg over 3 days, (Tab 4-4-2, adults)

- & primaquine 15 mg/d, 14 days Falciparum- ACT

Co-artem - 6 doses

2nd line- Alternative ACT, Q7T7 or Q7D7

What to give in pregnancy ?

In 1st trimester Quinine + Clindamycin 7 days

In 2nd and 3rd trimesters Any ACT combination as per rec. or Artesunate + Clindamycin 7 days or Quinine + Clindamycin 7 days

Lactating women same ACT

CLASSIFICATION OF THERAPEUTIC RESPONSE (WHO 2004)

3 Categories Early treatment failure (ETF)

Late treatment failure (LTF)  Late clinical failure Late parasitological failure

Adequate clinical and parasitological response (ACPR)

Severe & Complicated Malaria (SCM)

Falciparum malaria Children, pregnant & short term

travel/resident – endemic zones Severe symptoms Life threatening in the absence

of early effective treatment Medical emergency

Table-1 Types of Severe Manifestations (n=829)

Type SCM (Major) Full Recovery

DeathN (%, CFR)

Others 2 TotalN (%)

CNS Manifestations 304 39 (31) 19 362 (44)

Unrousable Coma 86 36 (27) 10 132 (16)

Impaired Consciousness 185 2 (1) 8 195 (24)

Convulsion 33 1 (3) 1 35 (4)

Severe Prostation 193 0 4 197 (24)

Hyper-parasitaemia 172 0 6 178 (22)

Severe Anamia 51 0 16 67 (8)

Hyperpyrexia 14 1 (7) 0 15 (2)

Others 7 0 3 10

Total n (row%) 741 (89) 40 (4.8) 48 (6) 829

SCM – Other Manifestations

Acute renal failure Pulmonary Oedema Haemoglobinuria Hypoglycaemia DIC Jaundice Multi-organ involvement/failure

May occur singly, often in combination

Management (SCM)

• Medical Emergency • Appropriate anti-parasitic

Treatment • Crucial General Management • Identification & management

of complications

Treatment of severe falciparum malaria

Any of the following antimalarial medicines are recommended

–Artesunate i.v. or i.m –artemether i.m. –quinine (i.v. infusion or i.m. injection).

Full course of ACT or quinine + clindamycin or doxycycline when patient can tolerate oral treatment

Artemisinins parenteral

αβ Arteether – 150 mg (2ml) i.m od x 3 days or 3 mg/kg od i.m. x 3 days

Artesunate 2.4 mg/kg i.v. or i.m. given on admission (time = 0), then at 12 h and 24 h, then once a day

Artemether 3.2 mg/kg i.m. given on admission then 1.6 mg/kg per day is an acceptable alternative to quinine i.v infusions

Rectal artemisinins are not as effective

Quinine parenteral

A loading dose of quinine of 20 mg salt/kg bw. 10 mg/kg 8th hrly i.v infusion

Rate-controlled i.v. infusion is the preferred route of quinine admin.

If this cannot be given safely, then i.m. injection is a satisfactory alternative.

Rectal admin. is not effective Quinidine can substitute quinine

Quinine vs Artemesinin’s

• Artemesinins are more effective than Quinine in terms of survival (MRG, contributed)

• No significant difference in coma resolution time & fever clearance time

• Parasite clearance time faster with A’s • Hypoglycaemia & cardiotoxicity less A’s • ? Uterine contractions more with Q’s • ? Neurologic sequelae more with A’s

(animals)

Cerebral Malaria – D/D

Meningitis Encephalitis Sepsis Fever in CNS Disease Fever in Organ failure Typhoid encephalopathy Metabolic/Toxic encephalopathy

Severe Anaemia

• More in children & pregnant population

• Transfuse if Hb <6.0 g/dl • Fresh whole blood or packed cells • Include the transfusion volume in

I/O calculation • Use frusemide if volume over load

Acute Renal Failure• Continuous Catheter • Correct dehydration • Use bolus frusemide 20-40 mg IV • Monitor hourly urine output, if <17 ml/hr

established ARF • Control fluid input if established ARF • Referral to renal replacement facility • Pt. Unlikely to die if dialysis facility

available

Hypoglycaemia

• Frequent in young children, pregnant women & during quinine Rx

• Intervened on suspicion- most important being deterioration of consciousness & convulsion

• Bolus 25% glucose 50 cc • Follow with IV infusion of 5%/10%

glucose • Continue monitoring for recurrence

Metabolic Acidosis

• Look for dehydration & hypovolaemia • Isotonic IV infusion, avoid fluid overload • Monitor BP, urine volume & JVP • Improve oxygenation by

- clearing airway

- oxygen inhalation

- support ventilation, if necessary

Pulmonary Oedema• Very serious, mortality >50% • Frequent in ARF, pregnancy, severe

anaemia, & at extremes of ages • Prop up position & oxygen inhalation • Stop IV fluid & give IV frusemide (40-200

mg) • Sequential torniquette application• Haemofiltration • Mechanical ventilation • Withdraw blood by venesection

Circulatory Collapse

• Often associated with gm –ve septicaemia • Common sites- lung, urinary tract,

meningitis, IV lines & injection sites • Take blood culture, start broad-spectrum

antibiotics (Amoxy + Genta) • Maintain adequate hydration & output • Dopamine may be given

Spontaneous bleeding & DIC

• Spontaneous bleeding from DIC is uncommon but serious complication

• Thrombocytopenia is common but rarely causes bleeding

• Transfuse fresh blood, clotting factors or platelets as required

• If PT or PTT prolonged, Inj. Vit. K 10 mg may be given

Haemoglobinuria• G6PD deficiency or malaria itself- not

quinine• Continue appropriate antimalarial if

parasitaemia present • Transfuse fresh whole blood to Hct >20% • Monitor JVP/CVP to avoid fluid overload

& hypovolaemia • Give frusemide 20 mg IV • Monitor renal function & consider dialysis

if required

Nursing Care• As important as anti-parasitic Rx • Meticulous nursing care to

- maintain clear airway

- prevent aspiration pneumonia

- prevent pressure sores • Careful intake-output chart • Rate of infusion checked frequently • Temperature >1020F reduced by tepid sponging &

fanning • Change in level of consciousness, behaviour &

occurrence of convulsion reported

SCM Management – Common errors Misjudgement of severity Delay in starting treatment Failure to provide nursing care Inappropriate rate of infusion Delay in correcting hypoglycaemia Failure to control convulsions Unnecessary continuation of treatment Failure to evaluate con-comitant

conditions

Prevention of Malaria death

Pre-hospital treatment

- IM Quinine

- Artesunate Suppository (MRG received BMJ group award for Best Research Paper of the Year 2010)

Chemoprophylaxis / IPT

Malaria Vaccine

DRUGS FOR CHEMOPROPHYLAXIS

Pyrimethamine – Limited efficacy Proguanil – 200mg daily- Limited efficacy

Doxycycline – Travelers 200mg daily. Not in children or pregnant women

Malarone (Atovaquone/proguanil) – very effective, good safety margin but expensive ($32 – 35

USD/dose)

Mefloquine – 250mg weekly (T1/2 too long, neuro-psychiatric AE)

Chloroquine/Amodiaquine Not recommended as it is used in Rx Resistance emerged Bone marrow suppression with amodiaquine

Conclusion

Malaria has no characteristic clinical feature

High index of suspicion is the key Early diagnosis & Prompt &

appropriate treatment (EDPT) – 1st contact

Death is avoidable with early effective treatment & meticulous followup