MALARIA

PROTOZOAL INFECTIONS

Laveran

Malaria remains the world's most devastating human parasitic infection. Malaria affects over 40% of the world's population. WHO, estimates that there are 350 - 500 million cases of malaria worldwide.In India 2 million cases and 1000 deaths annually

The malaria life cycle is a complex system with both sexual and asexual aspects .cycle of all species that infect humans is basically the same. There is an exogenous sexual phase in the mosquito called sporogony during which the parasite multiplies. There is also an endogenous asexual phase that takes place in the vertebrate or human host that is called schizogeny

A complex Life cycle

Human Cycle 1 Pre erythrocytic

schizogony2 Erythrocytic

Schizogony3 Gametogony4 Exoerythrocytic

schizogony

Events in Humans start with Bite of Mosquito Man – Intermediate

host. Mosquito –

Definitive host – Sporozoites are

infective forms Present in the salivary

gland of female anopheles mosquito

After bite of infected mosquito sporozoites are introduced into blood circulation.

Pre erythrocytic cycle Sprozoites undergo

developmental phase in the liver cell

Multiple nuclear divisions develop to Schozonts

A Schizont contains 20,000 – 50,000 merozoites.

Period of Pre erythrocytic cycle

1 P.vivax 8 days 2 P.falciparum – 6 days 3 P.malariae - 13 – 16 days, 4 P.ovale 9 days On maturation Liver cells ruputure Liberate Merozoites into blood stream

Erythrocyte cycle

Merozoites released invade red cells P.vivax infects young erythrocytes P.malariae Infects old erythrocytes P.falciparum infects RBC of all ages The Merozoites are pear shaped 1-5

microns in length The receptors for Merozoites are on red

cells in the glycoprotein

Erythrocytic Schizogony

Liberated Merozoites penetrate RBC

Three stages occur 1 Trophozoites 2 Schizont 3 Merozoite

Exo-erythrocytic (tissue) phase

P. malariae or P. falciparum sporozoites do not form hypnotizes, develop directly into pre-erythrocytic schizonts in the liver

Schizonts rupture, releasing merozoites which invade red blood cells (RBC) in liver

Gametogony Merozoites differentiate into Male and

female gametocytes They develop in the red cells Found in the peripheral blood smears Microgametocyte of all species are similar

in size Macro gametocytes are larger in size.

Mosquito cycleSexual cycle

Sexual cycle will be initiated in the Humans by the formation of Gametocytes

Develop further in the female Anopheles Mosquito

Fertilization occurs when a Microgametocyte penetrate into Macrogametocyte

ZYGOTE is formed matures into OOKINETE OOKINETE to OOCYST OOCYST matures with large number of

Sporozoites ( A few hundred to thousands)

Mosquito cycleA definitive Host – Mosquito

Malaria the disease

9-14 day incubation period

Early symptoms The common first symptoms

– fever, headache, chills and vomiting – usually appear 10 to 15 days after a person is infected. If not treated promptly with effective medicines, malaria can cause severe illness and is often fatal.

How Malaria present Clinically

Stage 1(cold stage) Chills for 15 mt to 1 hour Caused due to rupture from the host red

cells escape into Blood Preset with nausea, vomitting,headache

Stage 2(hotstage) Fever may reach upto 400c may last for

several hours starts invading newer red cells.

Clinical Malaria

Stage 3(sweating stage) Patent starts sweating, concludes the

episode Cycles are frequently Asynchronous Paroxysms occur every 48 – 72 hours In P.malariae pyrexia may last for 8 hours

or more and temperature my exceed 410c

Malaria stages of the disease

More commonly, the patient presents with a combination of the following symptoms

Fever Chills Sweats Headaches Nausea and vomiting Body aches General malaise.

Periodicity can be clue in Diagnosis and species relation

Malaria tertiana: 48h between fevers (P. vivax and ovale)

Malaria quartana: 72h between fevers (P. malariae)

Malaria tropica: irregular high fever (P. falciparum)

SEVERE COMPLICATED MALARIA

Alteration in the level of consciousness (ranging from drowsiness to deep coma)

Cerebral malaria (unrousable coma not attributable to any other cause in a patient with falciparum malaria)

Respiratory distress (metabolic acidosis bicarb less than 15 meq/l) Multiple generalized convulsions (2 or more episodes within a 24 hour

period) Shock (circulatory collapse, septicaemia) Pulmonary oedema Abnormal bleeding (Disseminated Intravascular coagulopathy) Jaundice Haemoglobinuria (black water fever) Acute renal failure - presenting as oliguria or anuria Severe anaemia (Haemoglobin < 5g/dl or Haematocrit < 15%) High fever Hypoglycaemia (blood glucose level < 2.2.mmol/l)

Confusion, or drowsiness with extreme weakness (prostration).In addition, the following may develop:

defined as the detection of P. falciparum in the peripheral blood

Malaria the disease

Why Falciparum Infections are Dangerous

Can produce fatal complications, 1.Cerebral malaria 2.Malarial hyperpyrexia 3.Gastrointestinal disorders. 4.Algid malaria(SHOCK) 5 Black water fever can lead to

death

Pernicious Malaria

Is a life threatening complication in acute falciparum malaria

It is due to heavy parasitization Manifest with 1 Cerebral malaria – it presents with

hyperpyrexia, coma and paralysis. Brain is congested

2 Algid malaria – presents with clammy skin leading to peripheral circulatory failure.

Cerebral Malaria

Malignant malaria can affect the brain and the rest of the central nervous system. It is characterized by changes in the level of consciousness, convulsions and paralysis.

Cerebral Malaria

Present with Hyperpyrexia

Can lead to Coma Paralysis and other

complications. Brain appears

congested

Pathogenesis of Cerebral malaria

High cytokine levels could be toxic on their own High levels of cytokine also enhance the second process

thought to be responsible for cerebral malaria: sequestration of infected RBCs

Sequestration & cytoadherence

Rosetting (adhesion of infected RBCs to other RBCs) and clumping (adhesion between infected cells) was first observed in in vitro culture

Black Water Fever

In malignant malaria a large number of the red blood corpuscles are destroyed. Haemoglobin from the blood corpuscles is excreted in the urine, which therefore is dark and almost the colour of cola

How long Malaria infection can lost in Man

Without treatment P.falciparum will terminate in less than 1 year.

But in P.vivax and P.ovale persist as hypnozoites after the parasites have disppeared from blood.

Can prodce periodic relapses upto 5 years In P.malariae may last for 40 years ( Called as recrudescence X relapse ) Parasites survive in erythrocytes Liver ?

LABORATORY DIAGNOSIS OF MALARIA

Diagnostic Toolsfor Human Infections with Malaria

Blood film examination(Microscopy)

QBC system Rapid Diagnostic Tests" (RDTs) PCR

Thin and Thick smear

Microscopy

Malaria parasites can be identified by examining under the microscope a drop of the patient's blood, spread out as a "blood smear" on a microscope slide. Prior to examination, the specimen is stained (most often with the Giemsa stain) to give to the parasites a distinctive appearance. This technique remains the gold standard for laboratory confirmation of malaria.

QBC system has evolved as rapid and precise method in Diagnosis

The QBC Malaria method is the simplest and most sensitive method for diagnosing the following diseases. Malaria Babesiosis Trypanosomiasis (Chagas disease, Sleeping

Sickness) Filariasis (Elephantiasis, Loa-Loa) Relapsing Fever (Borreliosis)

Appearance of Malarial parasite in QBC system

Antigen Detection Methods are Rapid and Precise

Antigen Detection Various test kits are available to detect antigens

derived from malaria parasites and provide results in 2-15 minutes. These "Rapid Diagnostic Tests" (RDTs). Rapid diagnostic tests (RDTs) are immunochromatographic tests based on detection of specific parasite antigens. Tests which detect histidine-rich protein 2 (HRP2) are specific for P.falciparum while those that detect parasite lactate dehydrogenase (pLDH)-OptiMAL

or aldolase have the ability to differentiate between P.falciparum and non-P.falciparum malaria

Newer Diagnostic methods

Molecular Diagnosis

Parasite nucleic acids are detected using polymerase chain reaction (PCR). This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory (even though technical advances will likely result in field-operated PCR machines).

Sensitivity of Tools forDiagnosis of Malarial Infection

1. Most sensitive: Antibody detection2. PCR3. Blood film examination

Malaria Relapses

In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks ("relapses") after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites ("hypnozoites") that may reactivate.

THE PHARMACOLOGY OF ANTIMALARIALSClass Definition Examples

Class Definition Examples

Class Definition Examples

Blood schizonticidal drugs

Act on (erythrocytic) stage of the parasite thereby terminating clinical illness

Quinine, artemisinins, amodiaquine, chloroquine, lumefantrine, tetracyclinea , atovaquone, sulphadoxine, clindamycina , proguanila

Tissue schizonticidal drugs

Act on primary tissue forms of plasmodia which initiate the erythrocytic stage. They block furtherdevelopment of theinfection

Primaquine, pyrimethamine,proguanil, tetracycline

Gametocytocidal drugs

Destroy sexual forms of theparasite thereby preventing transmission of infection tomosquitoes

Primaquine, artemisinins,quinineb

a Slow acting, cannot be used alone to avert clinical symptomsb Weakly gametocytocidal

THE PHARMACOLOGY OF ANTIMALARIALS (cont.)

Class Definition Examples

Class Definition Examples

Class Definition Examples

Hypnozoitocidal drugs

These act on persistentliver stages of P.ovaleand P.vivax which causerecurrent illness

Primaquine, tafenoquine

Sporozontocidal drugs

These act by affectingfurther development ofgametocytes into oocyteswithin the mosquito thusabating transmission

Primaquine, proguanil,chlorguanil

1. Treatment of severe falciparum malaria

Preferred regime Alternative regime

IV Artesunate (60mg): 2.4mg/kg on admission, followed by 2.4mg/kg at 12h & 24h, then once daily for 7 days.

Once the patient can tolerate oral therapy, treatment should be switched to a complete dosage of Riamet (artemether/lumefantrine) for 3 day.

IV Quinine loading 7mg salt /kg over 1hr followed by infusion quinine 10mg salt/kg over 4 hrs, then 10mg salt/kg Q8H or IV Quinine 20mg/kg over 4 hrs, then 10mg/kg Q8H.PlusAdult & child >8yrs old: Doxycycline (3.5mg/kg once daily)or Pregnant women & child < 8yrs old: Clindamycin (10mg/kg twice daily). Both drug can be given for 7 days.

Reconstitute with 5% Sodium Bicarbonate & shake 2-3min until clear solution obtained. Then add 5ml of D5% or 0.9%NaCl to create total volume of 6ml.Slow IV injection with rate of 3-4ml/min or IM injection to the anterior thigh.The solution should be prepared freshly for each administration & should not be stored.

Dilute injection quinine in 250ml od D5% and infused over 4hrs.

Infusion rate should not exceed 5 mg salt/kg per hour.

2. Treatment of uncomplicated p.falciparum

Preferred regime Alternative regime

Artemether plus lumefantrine(Riamet)(1 tab: 20mg artemether/120mg lumefantrine)

Quinine sulphate (300mg/tab)

Weight Group

Day 1 Day 2 Day3 Day 1-7: Quinine 10mg salt/kg PO Q8H

Plus*Doxycycline (3.5mg/kg once a day) OR

*Clindamycin (10mg/kg twice a day)

*Any of these combinations should be given for 7 days.Doxycycline: Children>8yrClindamycin: Children<8yr

5-14kg 1 tab stat then 8hr later

1 tab Q12H

1 tab Q12H

15-24kg

2 tab stat then 8hr later

2 tab Q12H

2 tab Q12H

25-34kg

3 tab stat then 8hr later

3 tab Q12H

3 tab Q12H

>34kg 4 tab stat then 8hr later

4 tab Q12H

4 tab Q12H

Take immediately after a meal or drink containing at least 1.2g fat to enhance lumefantrine absorption.

Add primaquine 0.75mg base salt/kg single dose if gametocyte is present at any time during treatment.

Dosage and administration Plasmodium falciparum for young infant

Age Group Weight group Artesunate or *Quinine

0 - 4 months <5 kg

** IM first dose Artesunate 1.2 mg/kg or IM Arthemeter 1.6 mg/kg)

***Oral Artesunate 2mg/kg/day day 2 to day 7

Oral Quinine 10 mg/kgTDS for 4 days then 15-20 mg/kg TDS for 4 days

Source: Malaria in Children, Department of tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University.

** Preferably Artesunate/Artemether IM on day 1 if available *** When Artesunate/Artemether IM is unavailable, give oral Artesunate from day 1 to day 7* Treat the young infant with Quinine when oral Artesunate is not available

Children under 5 kg or below 4 months should not be given Riamet instead treat with the following regimen (see table).

3. Treatment of malaria caused by p.knowlesi & mixed infection (p. falciparum + p. vivax)

Treat as p. falciparum

4. Treatment of of malaria caused by p.vivax, p. ovale or p. malariae.

CHLOROQUINE(150 mg base/tab) 25 mg

base/kg divided over 3 days

PRIMAQUINE(7.5 mg base/tab)

Day 1 Day 2 Day 3 Start concurrently with CHLOROQUINE 0.5 mg base/kg Q24H for 2 weeksTake with foodCheck G6PD status before start primaquineIn mild-to-moderate G6PD deficiency, primaquine 0.75 mg base/kg body weight given once a week for 8 weeks. In severe G6PD deficiency, primaquine is contraindicated and should not be used.

10mg base/kg stat, then 5mg

base/kg

5mg base/kg Q24H

5mg base/kg Q24H

1 tab of chloroquine phosphate 250mg equivalent to 150mg base. Calculation of dose for chloroquine is based on BASE, not SALT form. 1 tab of primaquine phosphate contains 7.5mg base.

Treatment in specific population & situationsSpecific populations

Preferred regime Alternative regime

Pregnancy Quinine plus clindamycin to be given for 7 day

Artesunate plus Clindamycin for 7 days is indicated if first line treatment fails

Lactating women

Should receive standard antimalarial treatment (including ACTs) except for dapsone, primaquine and tetracyclines, which should be withheld during lactation

Hepatic impairment

Chloroquine: 30-50% is modified by liver, appropriate dosage adjustment is needed, monitor closely.Quinine : Mild to moderate hepatic impairment-no dosage adjustment, monitor closely. Artemisinins : No dosage adjustment

Renal Impairment

Chloroquine : ClCr<10ml/min-50% of normal dose.Hemodialysis, peritoneal dialysis: 50% of normal dose.Continuous Renal Replacement Therapy(CRRT) :100% of normal dose.Quinine : .ClCr 10-50ml/min : Administer Q8-12H, CLCr<10ml/min : administer Q24H,Severe chronic renal failure not on dialysis : initial dose: 600mg followed by 300mg Q12H, Hemo- or peritoneal dialysis: administer Q24H ,Continuous arteriovenous or hemodialysis: Administer Q8-12H.Artemisinin : no dosage adjustment.

Treatment of complications of malaria

Severe & complicated falciparum or knowlesi malaria is a medical emergency that requires intervention and intensive care as rapidly as possible.

Fluid, electolyte glucose & acid-base balance must be monitored.Intake & output should be carefully recorded.

Immediate clinical management of severe manifestations and complications of P. falciparum malaria

Definitive clinical features

Immediate management/treatment

Come (Cerebral malaria)

Monitor & record level of consciousness using Glaslow coma scale, temperature, respiratory, and depth, BP and vital signs.

Hyperpyrexia (rectal body temperature >40°C)

Treated by sponging, fanning &with an antipyretic drug.Rectal paracetamol is preferred over more nephrotoxic drugs (e.g. NSAIDs)

Convulsions A slow IV injection of diazepam(0.15mg/kg, maximum 20mg for adults).

Hypoglycaemia (glucose conc. <2.8mmol/L)

Correct with 50% dextrose (as infusion fluids). Check blood glucose Q4-6H in the first 48hrs.

Severe anaemia (hb < 7g/dl)

Transfuse with packed cells. Monitor carefully to avoid fluid overload. Give small IV dose of frusemide, 20mg, as necessary during blood transfusion to avoid circulatory overload.

Acute pulmonary oedema

Prop patient upright (45°), give oxygen, give IV diuretic (but most patient response poorly to diuretics), stop intravenous fluids. Early mechanical ventilation should be considered.

Immediate clinical management of severe manifestations and complications of P. falciparum malaria (cont.)

Definitive clinical features

Immediate management/treatment

Acute renal failure (urine output <400ml in 24hrs in adults or 0.5ml/kg/hr, failing to improve after rehydration & a serum creatinine of >265μmol/L)

Exclude pre-renal causes by assessing hydration status. Rule out urinary tract obstruction by abdominal examination or ultrasound.Give intravenous normal salineIf in established renal failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis.

Disseminated intravascularCoagulopathy (DIVC)

Transfuse with packed cell, clotting factors or platelet.Usual regime: Cryoprecipitate 10units,platelets 4-8units, fresh frozen plasma(10-15ml/kg).For prolonged PT, give vitamin K, 10mg by slow IV injection.

metabolic acidosis Infuse sodium bicarbonate 8.4% 1mg/kg over 30min and repeat if needed.if severe, add haemodialysis.

Shock (hypotension with systolic blood pressure <70mmHg)

Suspect septicaemia, take blood for cultures; give parenteral broad-spectrum antimicrobials, correct haemodynamic disturbances.

Monitoring & follow-up

Blood smear should be repeated daily (twice daily in severe infection). Within 48-72 hr after start of treatment, patients usually become afebrile and improve clinically except in complicated cases.

All patients should be investigated with repeated blood film of malarial parasite one month upon recovery of malarial infection, to ensure no recrudescence.

Prevention

Avoid mosquito bites:Wearing long sleeves, trousers.Insecticide Treated BednetsRepellent creams or sprays.

Chemoprophylaxis Indicated for travellers travel to

endemic areas. Mefloquinine 250mg weekly (up to 1

year) or doxycycline 100mg daily (up to 3 month), to start 1 week before and continue till 4 weeks after leaving the area.

Dosing schedule for mefloquine

Weight Age No of tablets per

week< 5 kg < 3 months Not

recommended

5 - 12 kg 3 - 23 months 1/413 - 24 kg 2 - 7 yrs 1/225 - 35 kg 8 - 10 yrs 3/4

36 and above 11 yrs and above

1

Dosing schedule for doxycycline

Weight in kg

Age in years

No of tablets

< 25 < 8 Contraindicated25 - 35 8 - 10 ½36 - 50 11 - 13 ¾50+ 14+ 1