MALARIA Pathophysiology, Clinical features, Management & Epidemiology

Rumala Morel Department of Parasitology University of Peradeniya

Y3S2

Objectives
Name the parasites causing human malaria worldwide indicating those present in Sri Lanka. Describe the life cycle - recapitulation Describe the pathological and clinical consequences of the erythrocytic cycle including relapse & recrudescence Malaria diagnosis - recapitulation Name the anti malarial drugs in common use and describe the mode of action of each recapitulation Describe the current malaria situation in Sri Lanka Describe the preventive and control measures used by Anti Malaria Campaign in Sri Lanka

World map of current malaria incidence

2.4 Billion Population at risk 1 million children die every year

5 Plasmodium spp. causing HUMAN MALARIA

Found in SL Common Species worldwide Not in SL

1. P.falciparum
small rings

3. P.malariae
band form

5. P.knowlesi
Monkey parasite. Human disease South-East Asia

2. P.vivax
large rings & schizonts

4. P.ovale
red cell has oval shape

5th Human Malaria Parasite Rapidly multiply Plasmodium knowlesi Quotidian 24h Erythrocytic cycle
Early Trophozoites: small rings similar to P.falciparum

Late Trophozoites : band-forms like P.malariae

PREPATENT PERIOD:
Interval between infection and demonstration of parasites

11-12 days

2-3 days more (about 2 weeks) Interval between infection and clinical signs/symptoms INCUBATION PERIOD

PATHOPHYSIOLOGY Pathology is due to erythrocytic cycle

A). Destruction of RBCs haemolysis
anaemia releases endotoxins, malaria pigment

B). Host reaction:

1. IMMUNOPATHOLOGY Balance between pro-inflammatory & anti-inflammatory cytokines 2. hyperplasia of RES system splenomegaly & hepatomegaly

Red Blood Cells rupture

Release parasite endotoxins

Glycosyl Phosphatidyl Inositol (GPI)

Activate MACROPHAGE-MONOCYTE system

Pro inflammatory Cytokines: TNF, interleukin-(IL-1), interferon-, IL-6, IL-8, macrophage colony-stimulating factor , lymphotoxin, superoxide and nitric oxide(NO)

Symptoms: FEVER, malaise, headache, nausea and vomiting, diarrhea, anorexia, body aches, thrombocytopenia, immunosuppression, coagulopathy, CNS symptoms

Plasmodial DNA presented by hemozoin

Release of proinflammatory cytokines

Induce COX-2upregulating prostaglandins

FEVER

after the infection gets established for about a week

MALARIA FEBRILE PAROXYSMS

CLASSIC THREE STAGES : 1. Cold stage chills (15 min 1hour)

2. Hot stage High fever 106 F (2 - 6 hours) accompanied by head aches, vomiting, delirium, anxiety, restlessness

3. Sweating stage - profuse sweating and fever subsides (2-4 hours) .

FEVER with chills & rigors

Palpable SPLEEN

ANAEMIA Severe anaemia = leading cause of death in children with falciparum malaria.

CLINICAL FEATURES Depends on parasite species, parasitaemia, host immunity

72h cycle - Pm Quartan

1. FEVER - intermittent with chills & rigors

48h cycle- Pf, Pv, Po Tertian

day 1

2. SPLENOMEGALY 3. ANAEMIA

Fever patterns in malaria D1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 7 8

P falciparum

P vivax , P ovale

P malariae

Tertian
tertian periodicity uncommon in primary attack of Pf

Quartan

ANAEMIA

normocytic, normochromic
(1). Major mechanism = haemolysis of parasitized cells

(2). Phagocytosis of non parasitized cells Splenic clearance - rigidity of RBCs immune clearance

(3). Dyserythropoiesis in bone marrow

Haemoglobin utilization by parasite

Haem + parasite protein globin

Malaria pigment (haemozoin)

Haemozoin

induction of apoptosis in erythroid cells in the bone marrow

DYSERYTHROPOIETIC ANAEMIA

Dysconjugate (asymmetric) Severe falciparum gaze in comatose Gambian malaria child with cerebral malaria

Gambian 3yr old cerebral malaria & opisthotonos

P. falciparum Pathophysiology of Severe Malaria 1. Cytoadherence of parasitized RBCs = RBCs with

mature parasites stick to blood vessel walls in deep organs

SEQUESTRATION
Infected RBCs get sequestered in capillaries of vital organs eg. brain, liver, kidney

Mechanical obstruction of microcirculation = obstruction of small blood vessels eg. capillaries, post capillary venules

P. falciparum Pathophysiology of Severe Malaria

2. Rosetting = Parasitized RBCs stick to

uninfected RBCs

3. Rigid parasitized RBCs get stuck in narrowed

capillary lumen

Interfere with microcirculation 1. Tissue hypoxia 2. Nitric oxide [NO] release

P. falciparum - Mechanisms of Microcirculatory Obstruction

1. Cytoadherence (mainly)
2. Rosetting 3. Rigid parasitized RBCs

(1).Rosetting

(2). Endothelial Cytoadherence

VASCULAR OBSTRUCTION

HYPOXIA

Cytoadherence , Rosetting & Rigid RBCs

Block capillaries & post capillary venules
Ischaemia & Tissue hypoxia

NO = Nitric Oxide release

Oxidative damage to tissue

Severe Malaria

Pathogenesis
Cerebral

Clinical Features

Sluggish flow caused by sticky knobs on parasitized redcells leading to stagnant hypoxia and vascular damage.

Impaired level of consciousness, COMA Convulsions Generalized and localized neurological signs

Renal
Acute tubular necrosis sluggish blood flow and hypotension.

Intravascular haemolysis

Oliguria Haemoglobinuria Acute Renal Failure [ARF]

Severe Malaria: Common Clinical Manifestations 2

Pathogenesis
Respiratory

Clinical Features
Cough Pulmonary oedema [ARDS] Bronchopneumonia

Increased pulmonary capillary permeability

Hepatic

Elevated serum enzyme levels Prolonged prothrombin time

Jaundice (mainly haemolytic) Bleeding

Severe Malaria: Common Clinical Manifestations 3

BLOOD

Severe anaemia Hb < 5g/dl Hypoglycaemia Acidaemia

Shock Disseminated Intravascular Circulation [DIC] Multiple Organ Dysfunction [MODS]

SEVERE MALARIA 2000 WHO

1. Impairment of consciousness
Glasgow Coma Scale [adults] & Blantyre Scale [children]

2. Prostration inability to sit unassisted in a child.

In infant not old enough to sit, inability to feed [on examination - not just told in history]

3. Hyperparasitaemia >4% in non-immune [SL]

BUT
Treat any patient as SEVERE MALARIA if physician is worried about Signs & Symptoms

Severe Malaria

Cerebral malaria -P falciparum

Africa - cerebral malaria common in children (6m to 3 yrs)

high mortality - survivors, 10% have neurological sequelae

Brain in cerebral malaria-autopsy specimen

perivascular haemorrhage
Parasitized RBCs filling venules/capillaries

ANAEMIA in recurrent malaria hypersplenism

severe dyserythropoeisis - ineffective erythropoeisis in bone marrow

Liver in chronic malaria: dark colour is due to malarial pigment in macrophages

HAEMOGLOBINURIA (blackwater fever)

Intravascular haemolysis
often due to G6PD deficiency & oxidant drugs eg. Primaquine

quinine therapy - immune lysis

Post-malaria neurological syndromes

Following cerebral malaria <than in other encephalopathies 3% in adults & 10-20% in children Hemiparesis, cortical blindness, tremor, cranial N palsy ?subtle persistent cognitive/behavioural effects

Cerebellar Ataxia in Sri Lanka

2-3 wks after P vivax uncomplicated malaria. Self limiting few wks

Hyperreactive malarial splenomegaly syndrome (Tropical splenomegaly syndrome)

massive spleens seen in endemic areas Overproduction of polyclonal IgM immune response

Malaria in Children

Severe Pf rapid progression <1d fever P/C Coma Convulsions Acidosis Hypoglycaemia Severe anaemia
High risk of dying - if Respiratory distress (acidotic breathing) Deep coma

Malaria in Pregnancy
Areas with UNSTABLE Malaria (SL)

MOTHER
oSevere anaemia oAcute pulmonary oedema oHypoglycaemia

Higher maternal mortality & fetal loss

BABY
oPremature births oLow Birth Weight Higher Neonatal Mortality

RELAPSE OR RECRUDESCENCE? Reappearance of clinical symptoms following a period of being well

Recrudescence: 2- 4 weeks specially in Pf

Due to presence of asexual blood stages that are not cleared - Inadequate treatment or drug resistance Relapse: 3- 6 weeks - Pv, Po

Due to hypnozoite activation

merozoites

>% hypnozoites - relapses over longer term

Recrudescence

Relapse 3-6 wks later

Clinical symptoms

Fever threshold

1st attack
parasitiaemia

Microscopic threshold
subpatent

Liver schizogony-hypnozoites

Recrudescence & Relapse

MALARIA ENDEMICITY
STABLE OR UNSTABLE TRANSMISSION
STABLE MALARIA [AFRICA] Hyper/holo endemic High anopheline biting frequency Severe malaria in 6 months -3 yrs age Older asymptomatic parasitaemic [PREMUNITION] Pregnancy severe malaria Spleen rate .50% in children 2-9yrs UNSTABLE MALARIA [Sri Lanka,Thailand, Cambodia]

Meso / hypoendemic Severe malaria in all ages Cerebral malaria > common Spleen rate in children <50%

Laboratory diagnosis
Diagnosis confirmed by finding parasites/products in blood using microscopy/ Antigen detection RDTs

1. Microscopy - thin /thick blood film x3 (if ve repeat 12-24h)

THICK FILM (3-5l) Very Sensitive Limit of detection 10-20 p/l =0.002% parasitaemia THIN FILM (1l) - accurate species identification 2. Antigen detection - parasite derived products - proteins enzymes 3. PCR identify DNA (for research only)

In falciparum malaria- peripheral parasitaemia could underestimate the total parasite burden
The parasites causing the clinical symptoms are SEQUESTERED in the capillaries of deep organs ie. microvascular circulation In synchronous cycles, peripheral parasitaemia could even be negative

Repeat blood films daily 3 consecutive days

Microscopy identify parasite Thin & Thick film Consecutive days GOLD STANDARD THICK FILM (3-5 l) Very Sensitive Limit of detection 10-20 p/l Can quantify against WBCs THIN FILM (1l) Accurate species identification
42

x3

Microscopy
Advantages 1. Less costly 2. High sensitivity 3. Can quantify

Disadvantages 1. Need trained experienced personnel 2. Cant do in field

43

ANTIGEN DETECTION RAPID DIAGNOSTIC TESTS [RDTs] Dipstick/card methods 1. Most useful commercial tests detecting BOTH Pf + Pv
Detects parasite Lactate dehydrogenase ( pLDH) depends on LIVE parasites CAN USE TO TEST DRUG RESISTANCE

44

ANTIGEN DETECTION RAPID DIAGNOSTIC TESTS [RDTs] Disadvantages

1. High cost
2. RDTs sensitivity is low (wont detect below 100 200 parasites/l)
WHO malaria RDT performance evaluation - Round 2

Advantages
1. Easy to do in field 2. Dont need trained persons
45

Anti - malarials

The leaves of Artemisia annua, (China) are the source of artemisinin

Cinchona (Peru) Quinine

Malaria Treatment in Sri Lanka

Vivax malaria 1. Chloroquine blood schizonticide 2. Primaquine Kills hypnozoites & gametocytes Falciparum Malaria Combination therapy to limit Development of drug resisitance CO-ARTEMETHER [Artemether & Lumefantrine] & Primaquine

Severe Pf Quinine

Coartem is contraindicated for:Pregnant women in 1st trimester Exclusively breastfeeding Children weighing < 5 kg

Treatment = Quinine

ANTIMALARIAL RESISTANCE
DEFINITION Ability of a parasite strain to survive or multiply in spite of administration of a drug at usual or higher than usual dose. ( where drug failure due to defective intake /absorption / metabolism has been excluded)
RESISTANCE 3 grades : R1 (low grade) R ll (high) R lll (no response)

P falciparum
Multi Drug Resistance (MDR) combination therapy

P vivax - resistance to
chloroquine in a few areas

P.falciparum map of chloroquine resistance

Assessment of Therapeutic Response to Anti-malarials

(1) Parasite Clearance Time (PCT) Time between beginning the anti-malarial treatment and the first ve blood film
(2) Fever Clearance Time (FCT) Time from beginning anti- malarial treatment until the patient is apyrexial [no fever]

Prevention & Control of Malaria

Interrupt transmission @ different stages

1. MAN
2. VECTOR

3. PARASITE

Prevention & Control of Malaria

A. Prevent Man-Vector Contact / Reduce Vector Population most useful strategies Insecticide impregnated bed nets Residual insecticide spraying of houses

B. Reduce Parasite Population Treatment of patients Gametocytocides (Primaquine) also to prevent transmission

Vaccines
Still experimental Multistage, multi component anti sporozoite, liver stages, merozoite, ring infected erythrocytes Transmission blocking anti gametocyte Anti disease not anti parasitic So as not to prevent infection & reduce natural immunity = Premunition DNA vaccines

Prevention & Control of Malaria in SL

Ministry of Health Anti Malaria Campaign

ELIMINATION of Malaria transmission in SL by 2015

Dramatic reduction of microscopically confirmed case load

200,000 cases in 2000

23 in 2012 (99.99% reduction) 2012 lowest number of malaria cases since 1963
http://www.malariacampaign.gov.lk
56

Prevention & Control of Malaria in SL

Ministry of Health Anti Malaria Campaign

Goal - ELIMINATION of Malaria transmission in SL by 2015

Dramatic reduction of microscopically confirmed case load

200,000 cases in 2000 23 in 2012 (99.99% reduction) 2012 lowest number of malaria cases since 1963.

Most detected by 1. Activated Passive Case Detection (APCD) hospitals in endemic area also 1. Active Case Detection (ACD) and Mobile malaria clinics home visits
57 http://www.malariacampaign.gov.lk

MALARIA DAY WALK

Global fund - grant to eliminate malaria in SL given to TEDHA = Tropical and Environmental Diseases and Health Associates

Clinical features of severe falciparum malaria include A. Severe anaemia B. Acute pulmonary oedema C. Hypoglycaemia D. Coma E. Convulsions
T=ABCDE

References
Look at these websites

World health Organization: WHO - www.who.int/

Centers for Disease Control and Prevention (cdc) website : www.cdc.gov/ Books 1. Mansons Tropical Diseases 21st Ed 2. Worms & Human Disease Ralph Muller & Derek Wakelin