Post on 07-Nov-2014
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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
44
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)
45
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
56
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/