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Malaria clinical
1. MALARIA – Pathophysiology,
Clinical features, Management &
Epidemiology
Rumala Morel
Department of Parasitology
University of Peradeniya
Y3S2
2. 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
3. World map of current malaria incidence
2.4 Billion Population at risk
1 million children die every year
4.
5. 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.knowlesi
Monkey parasite.
Human disease
South-East Asia
6. 5th Human Malaria Parasite
Plasmodium knowlesi
Rapidly multiply –
Quotidian 24h
Erythrocytic cycle
Early Trophozoites:
small rings similar to
P.falciparum
Late Trophozoites :
band-forms like
P.malariae
7.
8. 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)
9. 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
10. Red Blood Cells
rupture
Release parasite endotoxins
Glycosyl 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, C
NS symptoms
11. Plasmodial DNA
presented by hemozoin
Release of
proinflammatory
cytokines
Induce COX-2-
upregulating
prostaglandins
FEVER
12. 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 ºF (2 - 6 hours)
accompanied by
head aches, vomiting, delirium,
anxiety, restlessness
3. Sweating stage - profuse sweating and fever subsides
(2-4 hours)
.
13. FEVER with chills & rigors
Palpable
SPLEEN
ANAEMIA
Severe anaemia = leading cause
of death in children with
falciparum malaria.
14. 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. SPLENOMEGALY
3. ANAEMIA
15. 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
16. 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
17. Haemoglobin
utilization by
parasite
Haem + parasite protein
Malaria pigment
(haemozoin)
globin
Haemozoin induction of apoptosis in
erythroid cells in the bone marrow
DYSERYTHROPOIETIC ANAEMIA
18. Severe falciparum
malaria
Gambian 3yr old
cerebral malaria
& opisthotonos
Dysconjugate (asymmetric)
gaze in comatose Gambian
child with cerebral malaria
19. 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
1. Cytoadherence of parasitized RBCs = RBCs with
mature parasites stick to blood vessel walls in deep organs
SEQUESTRATION
20. Interfere with microcirculation
1. Tissue hypoxia
2. 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
21. 1. Cytoadherence (mainly)
2. Rosetting
3. Rigid parasitized RBCs
P. falciparum - Mechanisms
of
Microcirculatory Obstruction
23. Ischaemia &
Tissue hypoxia
Cytoadherence , Rosetting & Rigid RBCs
Block capillaries & post capillary venules
NO = Nitric Oxide release
Oxidative damage to tissue
24. Severe Malaria
• Impaired level of
consciousness, COMA
• Convulsions
• Generalized and
localized
neurological 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 by
sticky knobs on parasitized
redcells leading to stagnant
hypoxia and vascular damage.
25. Severe Malaria: Common Clinical Manifestations 2
Pathogenesis Clinical Features
Increased pulmonary
capillary permeability
• Cough
• Pulmonary oedema
[ARDS]
•Bronchopneumonia
•Elevated serum enzyme levels
•Prolonged prothrombin time
Jaundice
(mainly haemolytic)
Bleeding
Respiratory
Hepatic
26. Severe Malaria: Common Clinical Manifestations 3
BLOOD Severe anaemia – Hb < 5g/dl
Hypoglycaemia
Acidaemia
Shock
Disseminated Intravascular Circulation [DIC]
Multiple Organ Dysfunction [MODS]
27. 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
29. Cerebral malaria -P falciparum
Africa - cerebral malaria common in children (6m to 3 yrs)
high mortality - survivors, 10% have neurological sequelae
31. 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
33. 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
2-3 wks after P vivax uncomplicated malaria.
Self limiting – few wks
Cerebellar Ataxia in Sri Lanka
35. 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
36. Malaria in Pregnancy
Areas with UNSTABLE Malaria (SL)
Higher maternal mortality
&
fetal loss
MOTHER
oSevere anaemia
oAcute pulmonary
oedema
oHypoglycaemia
BABY
oPremature births
oLow Birth Weight
Higher Neonatal Mortality
37. 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
39. MALARIA ENDEMICITY
STABLE 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]
40. 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)
41. 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
42. 42
Microscopy – identify parasite
Thin & Thick film x3 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
43. 43
Disadvantages
1. Need trained experienced personnel
2. Can’t do in field
Microscopy
Advantages
1. Less costly
2. High sensitivity
3. Can quantify
44. 44
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
45. 2. RDTs – sensitivity is low
(won’t detect below 100 – 200 parasites/μl)
45
ANTIGEN DETECTION
RAPID DIAGNOSTIC TESTS [RDTs]
WHO malaria RDT performance evaluation - Round 2
1. High cost
Disadvantages
Advantages
1. Easy to do in field
2. Don’t need trained persons
46.
47. The leaves of Artemisia annua,
(China) are the source of artemisinin
Cinchona (Peru) –
Quinine
Anti - malarials
48. 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
49. Pregnant women in 1st trimester
Exclusively breastfeeding
Children weighing < 5 kg
„Coartem‟ is contraindicated for:-
Treatment = Quinine
50. 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)
52. 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]
53. Prevention & Control of Malaria
Interrupt transmission @ different stages
1. MAN
3. PARASITE
2. VECTOR
54. A. Prevent Man-Vector Contact / Reduce Vector
Population
most useful strategies
Insecticide impregnated bed nets
Residual insecticide spraying of
houses
Prevention & Control of Malaria
B. Reduce Parasite Population
Treatment of patients –
Gametocytocides (Primaquine) also to prevent
transmission
55. 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
56. 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
57. 57
Prevention & Control of Malaria in SL
http://www.malariacampaign.gov.lk
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
58. MALARIA DAY WALK
Global fund - grant to eliminate
malaria in SL given to
TEDHA
= Tropical and Environmental
Diseases and Health Associates
59.
60. Clinical features of severe falciparum malaria
include
A. Severe anaemia
B. Acute pulmonary oedema
C. Hypoglycaemia
D. Coma
E. Convulsions
T=ABCDE
61. 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 – 22nd Ed
2. Worms & Human Disease – Ralph Muller & Derek
Wakelin