MALARIA – Pathophysiology, Clinical features, Management & Epidemiology

Rumala MorelDepartment of ParasitologyUniversity 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

3. P.malariae band form

1. P.falciparum small rings

2. P.vivax large rings & schizonts

4. P.ovale red cell has oval shape

Found in SL Not in SL

Common Species worldwide

5. P.knowlesiMonkey parasite.Human diseaseSouth-East Asia

5th Human Malaria ParasitePlasmodium knowlesi

Rapidly multiply –

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

INCUBATION PERIOD

Interval between infection and clinical signs/symptoms

11-12 days

2-3 days more (about 2 weeks)

PATHOPHYSIOLOGY

Pathology is due to erythrocytic cycle

A). Destruction of RBCs – haemolysis anaemiareleases 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 endotoxinsGlycosyl Phosphatidyl Inositol (GPI)

Activate MACROPHAGE-MONOCYTE system

Pro inflammatory Cytokines:TNF, interleukin-(IL-1), interferon-γ, 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-2-upregulating

prostaglandins

FEVER

after the infection gets established for about a week

MALARIA FEBRILE PAROXYSMSCLASSIC THREE STAGES :–

1. Cold stage – chills (15 min – 1hour)

2. Hot stage – High fever 106 ºF (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 causeof death in children with falciparum malaria.

CLINICAL FEATURES

Depends on parasite species, parasitaemia, host immunity

1. FEVER - intermittent with chills & rigors

48h cycle- Pf, Pv, Po Tertian

72h cycle - Pm Quartan

1 3day 1 4

2. SPLENOMEGALY3. ANAEMIA

D 1 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

Fever patterns in malaria

tertian periodicity uncommon in primary attack of Pf

Tertian Quartan

ANAEMIA normocytic, normochromic

(1). Major mechanism = haemolysis of parasitized cells

(2). Phagocytosis of non parasitized cellsSplenic clearance - rigidity of RBCs

immune clearance

(3). Dyserythropoiesis in bone marrow

Haemoglobinutilization byparasite

Haem + parasite protein

Malaria pigment(haemozoin)

globin

Haemozoin induction of apoptosis in erythroid cells in the bone marrow

DYSERYTHROPOIETIC ANAEMIA

Severe falciparum malaria

Gambian 3yr old cerebral malaria & opisthotonos

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

Infected RBCs get sequestered in capillaries ofvital 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

1. Cytoadherence of parasitized RBCs = RBCs with mature parasites stick to blood vessel walls in deep organs

SEQUESTRATION

Interfere with microcirculation

1. Tissue hypoxia2. Nitric oxide [NO] release

2. Rosetting = Parasitized RBCs stick to uninfected RBCs

P. falciparum – Pathophysiology of Severe Malaria

3. Rigid parasitized RBCs get stuck in narrowed capillary lumen

1. Cytoadherence (mainly) 2. Rosetting

3. Rigid parasitized RBCs

P. falciparum - Mechanisms of

Microcirculatory Obstruction

(1).Rosetting (2). Endothelial Cytoadherence

VASCULAR OBSTRUCTION HYPOXIA

Ischaemia &Tissue hypoxia

Cytoadherence , Rosetting & Rigid RBCs

Block capillaries & post capillary venules

NO = Nitric Oxide release

Oxidative damage to tissue

Severe Malaria

• Impaired level ofconsciousness, COMA

• Convulsions• Generalized and

localizedneurological signs

Cerebral

Pathogenesis Clinical Features

Renal

• Acute tubular necrosis -sluggish blood flow and hypotension. • Intravascular haemolysis

• Oliguria• Haemoglobinuria• Acute Renal Failure [ARF]

Sluggish flow caused bysticky knobs on parasitizedredcells leading to stagnant

hypoxia and vascular damage.

Severe Malaria: Common Clinical Manifestations 2 Pathogenesis Clinical Features

Increased pulmonarycapillary permeability

• Cough

• Pulmonary oedema [ARDS]

• Bronchopneumoni

a

• Elevated serum enzyme levels • Prolonged prothrombin time

Jaundice (mainly haemolytic) Bleeding

Respiratory

Hepatic

Severe Malaria: Common Clinical Manifestations 3

BLOOD Severe anaemia – Hb < 5g/dlHypoglycaemiaAcidaemia

Shock Disseminated Intravascular Circulation [DIC]

Multiple Organ Dysfunction [MODS]

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]

SEVERE MALARIA – 2000 WHO

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

BUT

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

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

ANAEMIA in recurrent malaria

• hypersplenism• severe dyserythropoeisis - ineffective

erythropoeisis in bone marrow

HAEMOGLOBINURIA (blackwater fever)

often due to G6PD deficiency & oxidant drugs eg. Primaquine

quinine therapy - immune lysis

Intravascular haemolysis

Post-malaria neurological syndromes

Following cerebral malaria <than in other encephalopathies – 3% in

adults & 10-20% in childrenHemiparesis, cortical blindness, tremor,

cranial N palsy?subtle persistent cognitive/behavioural

effects

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

Cerebellar Ataxia in Sri Lanka

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 feverP/CComaConvulsionsAcidosisHypoglycaemiaSevere anaemia

High risk of dying - ifRespiratory distress (acidotic breathing)Deep coma

Malaria in Pregnancy

Areas with UNSTABLE Malaria (SL)Higher maternal mortality

& fetal lossMOTHER

oSevere anaemiaoAcute pulmonary

oedemaoHypoglycaemia

BABYoPremature 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

Clinical symptoms

parasitiaemia

subpatent

Liver schizogony-hypnozoites

Recrudescence & Relapse

Fever threshold

Microscopic threshold

Recrudescence Relapse 3-6 wks later

1st attack

MALARIA ENDEMICITYSTABLE OR UNSTABLE TRANSMISSION

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%

STABLE MALARIA [AFRICA]

Laboratory diagnosis

Diagnosis confirmed by finding parasites/productsin 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 - proteinsenzymes

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 organsie. microvascular circulation

In synchronous cycles, peripheral parasitaemia could even be negative

Repeat blood films daily – 3 consecutive days

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Microscopy – identify parasite

Thin & Thick film x3 Consecutive daysGOLD STANDARD

THICK FILM(3-5 l)

Very SensitiveLimit of detection 10-20 p/l

Can quantify against WBCs

THIN FILM(1l) Accurate species identification

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Disadvantages1. Need trained experienced personnel2. Can’t do in field

Microscopy

Advantages1. Less costly2. High sensitivity3. Can quantify

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ANTIGEN DETECTIONRAPID DIAGNOSTIC TESTS [RDTs] Dipstick/card methods

1. Most useful commercial tests detectingBOTH Pf + Pv

Detects parasite Lactate dehydrogenase ( pLDH)depends on LIVE parasitesCAN USE TO TEST DRUG RESISTANCE

2. RDTs – sensitivity is low(won’t detect below 100 – 200 parasites/μl)

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ANTIGEN DETECTIONRAPID DIAGNOSTIC TESTS [RDTs]

WHO malaria RDT performance evaluation - Round 2

1. High cost

Disadvantages

Advantages1. Easy to do in field2. Don’t need trained persons

The leaves of Artemisia annua,

(China) are the source of artemisinin

Cinchona (Peru) – Quinine

Anti - malarials

Malaria Treatment in Sri Lanka

Vivax malaria

1. Chloroquine – blood schizonticide

2. Primaquine – Kills

hypnozoites &

gametocytes

Falciparum MalariaCombination therapy to limit Development of drug resisitanceCO-ARTEMETHER[Artemether & Lumefantrine]& Primaquine

Severe Pf – Quinine

Pregnant women in 1st trimester

Exclusively breastfeeding

Children weighing < 5 kg

‘Coartem’ is contraindicated for:-

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)”

P falciparum –Multi Drug Resistance (MDR) – combination therapy

P vivax - resistance to chloroquine in a few areas

RESISTANCE 3 grades :R1 (low grade) R ll (high) R lll (no response)

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

3. PARASITE

2. VECTOR

A

C

B

A. Prevent Man-Vector Contact / Reduce Vector Population

most useful strategies Insecticide impregnated bed nets Residual insecticide spraying ofhouses

Prevention & Control of Malaria

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

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

Vaccines

Prevention & Control of Malaria in SL

Ministry of Health – Anti Malaria Campaign ELIMINATION of Malaria transmission in SL by 2015

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200,000 cases in 2000

23 in 2012 (99.99% reduction)

2012 lowest number of malaria cases since

1963

Dramatic reduction of microscopically confirmed case load

http://www.malariacampaign.gov.lk

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Ministry of Health – Anti Malaria CampaignGoal - ELIMINATION of Malaria transmission in SL

by 2015

Prevention & Control of Malaria in SL

200,000 cases in 2000

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

Dramatic reduction of microscopically confirmed case load

http://www.malariacampaign.gov.lk

Most detected by1. Activated Passive Case

Detection (APCD) – hospitals in endemic area

also2. Active Case Detection

(ACD) and Mobile malaria clinics – home visits

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. Manson’s Tropical Diseases – 21st Ed

2. Worms & Human Disease – Ralph Muller & Derek Wakelin

• White NJ. Plasmodium knowlesi: the fifth human malaria parasite.Clinical Infectious Diseases 2008 Jan 15;46(2):172-3.

• Polrat Wilairatana et al Management of Plasmodium knowlesi malaria without PCR confirmation. http://www.tm.mahidol.ac.th/