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Malaria in trauma.
Studies of post-traumatic malaria falciparum
in Cambodia
Contents
• Background
• Landmines
• Malaria: The public health problem in the world and in Cambodia, livecycle,
immunology, clinical features, postoperative and postinjury malaria
•
•
•
•
•
Aims
Material and methods
Discussion
Conclusions
Recommendations for further studies
Land mines
• Injuries by blast and
penetration of
fragments
• Many dies out in the
field if pre-hospital life
support is not
provided
Malaria
• Malaria caused by
Plasmodium falciparum is a
major public health threat,
over 500 million cases of
malaria annually among the
world’s poorest populations
• P. falciparum has proven
adept at acquiring and
rapidly spreading resistance
to antimalarial drugs
• Vector control is threatened
by the inevitability of the
emergence of insecticideresistant mosquitoes
boardingpasses.org.
Malaria and land mines:
the poor man’s burden
“… Living here you starve to death
or you have to take risks.”
Anti-malarial drug resistance
in cambodia
• Verdens mest drug
resistene parasitt
• 60-70:Chloroquin
• -80: Fansidar, quinine
• -90: Mefloquine
• 2003: Artemisin
Counterfeit drugs
• Associated with up to 20 %
of all malaria deaths
• Typically sold in small
village drugstores, where
owners may lack the
expertise to identify fakes.
• An estimated 70 percent of
malaria patients in
Cambodia seek treatment at
local village vendors
• Containes a variety of drugs
and chemicals
• Some containe small
amounts of genuine
artesunate, which can
cause spread of drugresistant paracites
Malaria livssyklus og kroppens
immunrespons
RBC rupture
• When the RBC
rupture the
malariatoxin is
released in to the
bloodstream where it
stimulates
inflammatory cells to
release proinflammatory
cytokines giving rise
to the
malariasymptoms.
Pathophysiology and clinical
features
• Sequestration: PfEMP1 (variant Ag) on RBC’s infected with paracites binds
to host receptors. Avoids destruction in the spleen.
Centre for Medical Parasitology
Cytoadhesion and parasite varantigens (PfEMP1)
Variant multigene encoded
proteins expressed on the
surface of infected red
blood cells – PfEMP1
+ Ab
blockage of microvasculature
and detrimental inflammation
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The wave
• Parasite attacs come
in waves,
corresponding to a
new family of
PfEMP1.
• 60 different types
• The human host
developes antibodies
to each new type
Centre for Medical Parasitology
Surface antigens and the development of immunity in
malaria endemic areas
……………
Each parasite (clone) has the capacity to express many antigenically distinct surface antigens and a
broad repertoire of Ab and immunity is developed after repeated infections
.......
+ Ab
+ Ab
+ Ab
- However, immunity to severe
malaria develops after a few
infections
Effective binding/growth
advantage >< Limited variation
Vaccination: Induce an immune
response resembling the naturally
acquired immunity
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23 October 2012
Natural aquired immunity and
malaria tolerance
• High endemic areas
• Low-grade parasitemia
without symptoms
• Control disease and
parasite denisty
• Antidisease:Repetive
stimulation of TLR by the
toxine leads to
downregulation of the
receptor→reduced
production av
cytokines→Reduced
symptoms (Rapidly
acquired)
• Antiparasite: Antibodies
(slowly acquired)
Postoperative malaria
• Malaria may follow surgery
• Relapse rates 6-15%
• Routine anti-malarial chemophylaxis
Study aims
1. Post-injury incidence and risk fators for
developing malariasympthoms after
trauma (Paper I).
2. Effects on post-traumatic mortality and
morbidity (Papers II and III).
3. The sources of knowledge (Paper III).
4. To examine if post-injury malaria can be
prevented by early anti-malarial treatment
of trauma patients (Paper IV).
Study-area
Study populations
• Study population 1: All land mine and war casualties consecutively
admitted for in-hospital trauma care at Emergency (1998 to
2000.)Study sample 1: 342 patients. Study sample 2: Subsample of
study population 1, 227 patients
• Study population 2: 18 experienced trauma care providers working in
rural hospitals in Battambang province in North-western Cambodia
• Study population 3: All patients in the provinces Battambang and
Pailin managed and referred for primary trauma surgery to rural
district hospitals by Trauma Care Foundation medics during the
period May 2002 to October 2005. 222 trauma patients were
examined. A subset of 108 patients from Pailin Hospital was used for
the main analysis.
Study design
• Study I and II were performed as
retrospective cohort trials
• The Information of study number III was
gathered by semi-structured interviews
and focus groups.
Study design
• Study IV was an
interventional study.
• Dipstick test after
medical stabilization
• All patients testing
positive received
antimalarial treatment
• Additional treatment,
bloodsmears and
mapping out malaria
symtoms at hospital
Definition of variables
• Post-injury malaria: Positive blood smear and
fever after trauma, within 10 days after the injury.
• Bacterial WI: Within 30 days, purulent disharge +
one of the three following signs - pain/tenderness,
localized swelling, or tenderness/heat.
• Malaria endemicity: High and low endemic areas
were defined based on public reports.
• Anatomical injury severity: Injury Severity Score
(ISS). Severe injuries: ISS above or equal to nine.
Antimalaria treatment
• The anti-malarial treatment was given
according to national standards, one
initial dose of artesunate 3.2 mg/kg
was to be given as a single injection
intravenously, further in-hospital
treatment of P. falciparum carriers
consisted of two doses of artesunate
1.6 mg/kg followed by one single per
oral dose of mefloquine 20 mg/kg.
Rapid Diagnostic Test
• Detect presence of
parasite spesific
antigens
• Para check dipstic
detect P.falciparum
• Highly sensitive at
high parasitaemia
density
Aim 1: Post-injury malaria
incidence and risk factors
• 33.3 % (114/342) developed post-injury
malaria.
• More than 40 times increased incidence
rate
Riscfactors
• Malaria endemicity
• ISS (22% vs 40%)
• Duration of surgery
(20.4% vs 51.2%)
• Pre-hospital evacuation
time (barely statistically
significant)
Recurrence or re-infection?
• 54% occured wthin
two days after injury,
only 12 % occured
after 10 days
• The incidence of
malaria outbreaks did
not follow the
seasons
Aim 2: Post-injury malaria morbidity
and mortality (Papers II and III)
•
•
•
•
•
•
•
•
Quantitative data
Rate of WI: 36.1 % vs 10.0%
Duration of hospital stay: 31 days vs 19 days
Qualitative data
A well known complication
Develops within 1-5 days
Increased risk of wound infection
Protracted recovery has a severe impact also on families‘ income.
(”The single most important cause of losing land is indebtedness
caused by illness and medical treatment costs” (Williams,1999)
• Early treatment important
• Some recommended blood screening and start of anti-malarial
treatment in all parasite carriers immediately after the injury.
Aim 3: The source of knowledge
of post-injury malaria (Paper III)
• “This knowledge doesn‘t come from the
books, but from experience.
• In the university they teach about trauma
and malaria separately.”
Aim 4: Early anti-malarial treatment of
parasite carriers (Paper IV)
• 222 patients, 30 dipstick-positive (parasite carriers).
• Subsample (Pailin): 108 patients, 28 dipstick- positive.
• Microscopi positive in 23 dipstick-positive and 0 dipstic
negative patients.
• 21 developed post-injury malaria.
• Prevalence of fever was higher: 21% vs 89%
• Mean duration of fever: 3 d
• Higher morbidity
Comparing Microscopy with
RDT
•The agreement of rapid test results (RDT) to
blood smear examination was very good,
kappa of 0.93 (95% CI 0.85 to 1.00).
Summary of findings
• 1/3 of trauma patients developed post-injury malaria.
• Risck factors: ISS, duration of surgery and malaria
endemicity in the patients‘ area of origin
• Increasing the risk of bacterial wound infections and
delaying recovery
• Prophylactic treatment did not prevent development of
post injury malaria
Why does symptomatic
falciparum infection develop
after trauma?
•
Because of Immunosuppression?
Why did Mefloquine artesunate and
early diagnosis not work?
”Failure of artesunate-mefloquine
combination therapy for uncomplicated
Plasmodium falciparum malaria in
southern Cambodia?”
Rogers WO et al,Malar J. 2009 Jan 12;8:10
BMJ 2011; 342:d211
WHO unveils plan to stop artemisinin resistance
Conclusions
1. A considerable number of trauma victims from P.
falciparum endemic areas may develop post-injury
malaria. The risk of the complication increases with the
severity of the injury and the duration of trauma surgery.
2. Post-injury malaria does not seem to not affect mortality,
but adds to the burden of trauma by increasing the risk of
bacterial wound infections and delaying recovery.
3. Early antimalarial treatment of injured P. falciparum
carriers did not seem to prevent post-injury malaria.
Recommendation for further studies:
• Identify levels of resistance to
antimalarials in South East
Asia among trauma-patients.
• Is PfEMP1 variants expressed
in an increased level in trauma
patients? (Study of variant
antigens in post-injury malaria
versus non-trauma malaria and
their potential similarity or
difference from those in
pregnancy related malaria.)
•Dag 0: Traume- RDT+ blodutstryk+ bloddråpe på filterpapir:
reistensmarkører
•(Umiddelbar oppstart behandling (1.linje) på alle med pos RDT,
kontinuere behandling på alle med positivt blodutstryk)
•Dag 1. Blodutstryk, klinisk respons, bloddråpe på filter papir: PCR
(mRNA) VAR gener og ELISA antigen og Ab-nivå mot VAR2CSA (o.a
PfEMP1 VAR-Ag)
•Dag 2-6: Blodutstryk, klinisk respons (inntil symptomfri og parasittere er
cleared fra blod)
•Dag 7: resistensmarkører, mengde medikament i blod
•Dag 28: resistensmarkører, mengde medikament i blod, PCR (mRNA)
VAR gener og ELISA antigen og Ab-nivå mot VAR2CSA (o.a PfEMP1
VAR-Ag)
•Endre behandling dersom manglende respons (2.linje)
Centre for Medical Parasitology
To identify the PfEMP1 variants expressed in
trauma patients
Indirect identification of PfEMP1 protein expressed in
trauma patients:
• Serum/Plasma samples collected at admission and 3
weeks after malaria disease (2ml full blood in CPDAtubes -20˚C, or filter paper)
• ELISA or Luminex to determine if these individuals
have acquired Abs to VAR2CSA or other PfEMP1 types
(20-30 individuals)
•
- trauma patients will develop Abs (IgG) to the
PfEMP1 variants expressed by the parasites during
malaria disease
• Large panel of recombinant PfEMP1 proteins from 3
P.f. genomes
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