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PBL SEMINAR
FEVER IN A RETURNED TRAVELLER
OUR PATIENT CASE
Our patient is Jenny Randall, a 23 y.o. female student
who presents to her local doctor with cough and fever
having recently returned from a 3 week holiday
IMPORTANT
1.
2.
What’s common is common
The diagnosis is
MALARIA MALARIA
MALARIA
until proven otherwise.
How to take a History from a
Returned Traveller
Fever
WWQQAAB
Travel History:
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Country of birth
Housing
Occupation
Contacts
Other drugs
Leisure time
Animals
Travel
Eating and Drinking
Sexual history
CHOCOLATES
 HOPC
 Travel
History:
CHOCOLATES
Travel History:
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Country of birth
Housing
Occupation
Contacts
Other drugs
Leisure time
Animals
Travel
Eating and Drinking
Sexual history
CHOCOLATES
Patient History
Ms Jenny Randall, a
previously well 23 year old
medical student, presents to
her local doctor with a cough
and fever.
Jenny recently returned from
a 3 week trip to Thailand,
Cambodia and Vietnam.
In the 3 days leading up to
her presentation at the clinic,
Jenny experienced the
following symptoms:
•fevers
•rigours (what makes them
rigours?)
•myalgia
•mild non-productive cough
•malaise
•mild headache
•No relevant past
medical history
•Family history of
CVD- father died of
AMI at 58
Medications
•OCP
•Paracetamol for fever
•NKDA
Social History
•Smokes 10-20
cigarettes/day,
•no ETOH,
•one regular and one
new sexual partner in
past 6 months, uses
condoms 100 % of the
time
TRAVEL SPECIFIC QUESTIONS
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Born in Australia
Travelled to Vietnam via Thailand and Cambodia for 3
weeks during the hot/rainy season
Returned for two weeks before becoming unwell
Stayed in budget, sometimes crowded accomodation
throughout recent travel
Exposure to water, mosquitos, flies
Recent contact has a 'cold'
Took prophylactic Doxycycline for one week before
discontinuing
Had pre-travel Typhoid and HepA immunisation and
previous HepB immunisation
Often prepared own food, no GI symptoms
!~RED FLAG~!
What symptom stands out as a red flag?
RIGORS!
What are rigors?
Episodes of uncontrollable shakes with or
without teeth chattering lasting 15 minutes or
more.
What causes them?
•Bacterial sepsis e.g. From biliary sepsis or
pyelonephritis, visceral abscesses, pneumonia
•Malaria
•Influenza
Why can we not ignore rigors?
Causes can be immediately life threatening and
are treatable!!
Pyrexia of Unknown Origin (PUO)
Definition: In adults: T>38.3 for>3 weeks with no known origin despite appropriate Ix.

Approach: - identify cause
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Detailed history and regular examination
Confirm temperature objectively, ?admission, ?physiological with
circadian pattern
Guide investigation based on initial test results
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◦
◦
FBE, ESR, U+E, CRP, LFT, ANA, Rh Fx, TFT
Regular cultures (any fluid – blood, sputum, urine, stool, CSF)
CXR, CTA, echo
CT, IVP, MRI, PET
Treatment – ideally symptomatic prior to Dx
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Infection
•Pyogenic Abscess
•TB
•IE
•Toxoplasmosis
•EBV
•CMV
•HIV
•Brucellosis
•Lyme Disease
Malignancy
•Lymphoma
•Leukaemia
•RCC
•HCC
CTD
•Adult Still’s disease
•RA
•SLE
•Wegener’s granulomatosis
•Giant cell arteritis
Misc
•Drug Fevers
•Thyrotoxicosis
•IBD
•Sarcoidosis
•Granulomatous hepatitis
•Factitious fever
•Familial Mediterranean fever
Blind investigation may be necessary
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Causes
Empirical A/B therapy may mask infectious Dx
Empirical steroid therapy may mask inflammatory response w/o treating cause
Undiagnosable PUO – Sx usually spontaneously resolve, good prognosis
Excluded from case differential
Infection
Connective Tissue Disease
Tumours
Drug Fever
Miscellaneous
Idiopathic
Idiopathic
Examination of a Returned Traveller
Special points for an ID Ex
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Gen Inspection
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Patient
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Sputum cup
O2
IV – anything running
Drain tube
Catheter – check urine
Temp chart
Distress (RR, diaphoretic, conscious state)
Rash – blanching/nonTrack marks IVDU
Any lines – sepsis?
Weight loss – chronic illness
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Janeway
Splinters
Osler’s nodes
Erythema
Track marks
Bruising, petechiae
Phlebitis
Arthropathy, raynauds - CTD
Tenderness? – localised?
Organomegaly
rashes
Genitourinary
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New murmur
Abdomen
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Crepitations, consolidation
Praecordium
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Eyes – Roth spots (fundoscopy), pallor, jaundice
(BW fever)
Mouth – hygeine, ginigivitis, abscess
Neck – lymphadenopathy
Chest
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Hands
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Face
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Room
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Stool sample
Urinalysis
Discharge
orchitis
Legs
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Rash
ulcers
Signs in a returned Traveller
On examination:
Chest clear. Full CVS, respiratory and abdominal
examinations NAD
• No rashes, joints appeared normal.
 Vitals
• HR 72
• BP 120/60
• RR 16
• T 36.2
With these history and examination findings, Jenny was
sent home with a suspected viral URTI.
The next day, Jenny re-presents with continuing fevers,
having taken her own temperature measuring 36.9 that
morning.
•
The Pattern of Fever

Timeline of Jenny’s ‘fever’
Day 1 – onset of disease – T?
Day 4 – visit doctor – 36.2
Day 5 – 10am – 36.9
Day 5 – afternoon – 36.9
Day 5 – night – 38.5
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*NO FEVER RECORDED until day 5*
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◦ Doesn't always follow typical pattern in all
patients
 Typically – may be afebrile for days
 Atypically (common) – may be febrile or afebrile
the entire length of the disease
◦ Accurate recording procedure
◦ Hx of fever given by reliable witness should
not be ignored even if it is recorded as
afebrile.
Typical malarial fever patterns
- not necessarily useful diagnostically
DDx??
DDx!!
Malaria (parasite)
 Typhoid (bacteria)
 Dengue fever (virus)
 Hepatitis A

 We want to rule these out before progressing to investigate
for other conditions common in returned travellers.
Other Infections To Be Considered
in Returned Travellers
Developing Countries

Bacterial sepsis other than typhoid (such as meningococcal sepsis, sepsis from abdominal
organ perforation, pneumonia, urosepsis)

TB

Dysentry

Schistosomiasis

Amoebic liver abscess
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Tick typhus

Viral haemorrhagic fevers other
than Dengue
World Wide

Influenza

Atypical pneumonia

URTI/viral infection

STI including acute HIV infection
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UTI

Pyelonephritis
DIFFERENTIALS
Malaria
Dengue
Fever
Typhoid
Fever
Hepatitis A
Definition
Protozoa injected by
Anopheles mosquitoes
multiply in RBCs causing
haemolysis, sequestration
and cytokine release.
RNA flavivirus (4 types)
causing sudden fever,
extreme myalgias and
arthralgias.
Bacterial infection with
salmonella typhi (Gbacillus), causing severe
diarrhoea
Hepatits A virus (HAV),
that is not chronic or
progressive and has no
permanent effect on liver,
acutely causes liver damage
using body’s own immune
response rather than viral
cytotoxicity.
Mode of Transmission
Mosquito vector,
transfusion, vertical,
needlestick
‘Aedes’ mosquitoes
Faecal-oral route,
complicated by
asymptomatic typhoid
(unknowing carriers)
Faecal-oral route,
Symptoms and signs
Malaria
non-specific flu-like
symptoms:
headache
malaise
myalgia
anorexia
fevers (periodic)
chills
faints
rigors initially
jaundice
hepatomegaly
splenomegaly
Dengue
Typhoid
Hepatitis A
Symptoms and signs
Malaria
Dengue
non-specific flu-like
symptoms:
headache
malaise
myalgia
anorexia
fevers (periodic)
chills
faints
rigors initially
fever
headache
myalgia
abdominal pain
nausea
vomiting
diarrhoea
rash
jaundice
hepatomegaly
splenomegaly
Typhoid
Hepatitis A
Symptoms and signs
Malaria
Dengue
Typhoid
non-specific flu-like
symptoms:
headache
malaise
myalgia
anorexia
fevers (periodic)
chills
faints
rigors initially
fever
headache
myalgia
abdominal pain
nausea
vomiting
diarrhoea
rash
fever (progresses
slowly)
malaise
headache
abdominal pains
dry cough
constipation or
diarrhoea
rose spots on
trunk
jaundice
hepatomegaly
splenomegaly
bradycardia
lymphadenopathy
splenomegaly
Hepatitis A
Symptoms and signs
Malaria
Dengue
Typhoid
Hepatitis A
non-specific flu-like
symptoms:
headache
malaise
myalgia
anorexia
fevers (periodic)
chills
faints
rigors initially
fever
headache
myalgia
abdominal pain
nausea
vomiting
diarrhoea
rash
fever (progresses
slowly)
malaise
headache
abdominal pains
dry cough
constipation or
diarrhoea
rose spots on
trunk
fever
malaise
anorexia
nausea
arthralgia
abdominal pain
diarrhoea
itching
bradycardia
lymphadenopathy
splenomegaly
jaundice
hepatomegaly
splenomegaly
jaundice
hepatomegaly
splenomegaly
Symptoms and signs
Malaria
Dengue
Typhoid
Hepatitis A
non-specific flu-like
symptoms:
headache
malaise
myalgia
anorexia
fevers
chills
faints
rigors
fever
headache
myalgia
abdominal pain
nausea
vomiting
diarrhoea
rash
fever
malaise
headache
abdominal pains
dry cough
constipation or
diarrhoea
rose spots on
trunk
fevers
malaise
anorexia
nausea
arthralgia
abdominal pain
diarrhoea
itching
bradycardia
lymphadenopathy
splenomegaly
jaundice
hepatomegaly
splenomegaly
jaundice
hepatomegaly
splenomegaly
Fever in the tropical traveller
<14 days
14 days – 6 weeks
> 6 weeks
Malaria
Typhoid
Leptospirosis
Dengue fever
Rickettsiae
Acute HIV infection
fever with CNS signs
Malaria
Typhoid
Leptospirosis
Hepatitis A or E
Acute schistosomiasis
Acute HIV infection
Malaria
Hepatitis B or E
Kala-azar
Lymphatic filariasis
Schistosomiasis
Amoebic liver abscess
Viral/bacterial meningitis +
encephalitis
East African Trypanosomiasis
Poliomyelitis
fever with chest signs
East African Trypanosomiasis
Rabies
Rabies
Influenza
Legionellosis
Q fever
Acute histoplasmosis
SARS
Tuberculosis
Q fever
Tuberculosis
undifferentiated fever
Incubation Periods
incubation period: time elapsed between
exposure to a pathogenic organism and
the onset of symptoms
 Jenny returned home 2 weeks prior to
feeling unwell (14 day incubation)
 no actual fever recorded until 5 days later
however atypical presentation is common

Incubation Periods
Malaria
Dengue
Typhoid
Hepatitis A
P. falciparum 6-21d
(typically 7-10d)
P. vivax 10-17d
P. ovale 10-17d
P. malariae 18-40d
3-14 days
3-21 days
2-6 weeks
most patients with
malaria present
within 2 months
If fevers start >2wks typically 8-14 days
after leaving a
dengue area
or lasts >2wks
dengue can be ‘ruled
out’
typically 28 days
DIFFERENTIALS
Malaria
Dengue Fever
Typhoid Fever
Hepatitis A
Definition
Protozoa parasite.
RNA flavivirus
Bacterial infection
Hepatits A virus (HAV)
Mode of Transmission
Mosquito vector, transfusion,
vertical, needlestick
‘Aedes’ mosquitoes
Faecal-oral route,
complicated by
asymptomatic typhoid
(unknowing carriers)
Faecal-oral route,
Incubation period (link to
case)
P. falciparum 6-21d
(typically 7-10d)
P. vivax 10-17d
P. ovale 10-17d
P. malariae 18-40d
3-14 days
3-21 days
2-6 weeks
most patients with malaria
present within 2 months
If fevers start >2wks after
leaving a dengue area
or lasts >2wks dengue can
be ‘ruled out’
typically 8-14 days
typically 28 days
STRAINS OF MALARIA
1) Falciparum – Causes almost
all severe disease (~85%).
Characterised by systemic
complications such as
cerebral malaria and
anaemia.
2) Vivax – Uncommonly causes
severe disease, but overall
infection rates are as common as
Falciparum. Can cause “chronic”
relapsing malarial disease.
3) Ovale – Uncommon cause of
disease, and even then clinical picture
is not as severe. Can cause relapsing
disease as well.
4) Malariae – Similar to Ovale.
THE MALARIAL CYCLE
1) MOSQUITO
VECTOR
2) EXTRAERYTHROCYTIC
3) ERYTHROCYTIC
PHASE
Malarial Immunology

Immunological evasion by Malaria –
◦ Malaria avoids WBCs by invading the body’s
own cells and using these “self” antigens as a
mask for infection. The body only has a
chance of reacting during a lysis cycle when
the parasites are free in the blood, though
time is limited.
◦ Splenic removal is the only effective method
of removal. Protozoal aggregation in small
capillaries counters this – causes
complications
◦
Investigations of a Returned Traveller
DIFFERENTIALS
Malaria
Dengue Fever
Typhoid Fever
Hepatitis A
Definition
Protozoa parasite.
RNA flavivirus
Bacterial infection
Hepatits A virus (HAV)
Mode of Transmission
Mosquito vector, transfusion, vertical, ‘Aedes’ mosquitoes
needlestick
Faecal-oral route, complicated Faecal-oral route,
by asymptomatic typhoid
(unknowing carriers)
Incubation period (link to case) Millsy
Signs and symptoms
Millsy
Ix and Common Thick and Thin Blood Serology (e.g.
Findings
films
arbovirus
serology) and PCR
Basic principles:
studies
Parasite =
microscopy
Bacteria =
culture
Virus = serology
Cultures - bone Serology for
marrow, blood, anti HepA IgM
stool, urine bone marrow
culture has
highest yield
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FBE
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HB 110, WCC 7.0, Plt 110
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HB 100, WCC 7.3, Plt 90
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HB 90, WCC 7.2, Plt 96
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HB 95, WCC 7.2, Plt 115
UECs
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Jenny’s Ix Findings
Na 140, K 4.0, Ur 7.0, Cr 110
LFTs
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Mildly elevated ALT and bilirubin, otherwise normal
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Atypical pneumonia - Legionella, Chlamydia species, Mycoplasma pneumoniae, Pneumocystis jiroveci serology pending
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CXR - clear
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Malarial Thick and Thin Film
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Negative
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Positive for plasmodium falciparum, parasite count 0.2%
◦
parasite count 0.1%
◦
parasite count 0%
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Hep A serology - Total Ab positive, IgM negative
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Hep B serology - Surface Antibody positive, surface negative
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Arbovirus (dengue) serology - negative
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HIV serology - negative
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Pregnancy Test - negative
Malarial Thick and Thin Blood
Films
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3 thick and thin smears 12-24hrs apart
should be obtained
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Highest yield of peripheral parasites occurs
during or soon after a fever spike; however
smears should not be delayed to await a
fever spike.
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Thin Films - qualitative (speciation)
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Thick Films - quantitative (parasite count)
Determining types of malaria
Histological Differences
Findings
P falciparum
P vivax
P ovale
P malariae
Only early
Yes
forms present in
peripheral blood
No
No
No
Multiply-infected Often
RBCs
Occasionally
Rare
Rare
Age of infected
RBCs
RBCs of all ages Young RBCs
Young RBCs
Old RBCs
Schüffner dots
No
Yes
Yes
No
Other features
Cells have thin
cytoplasm, 1 or
2 chromatin
dots, and
applique forms.
Late
trophozoites
develop
pleomorphic
cytoplasm.
Infected RBCs
become oval
with tufted
edges.
Bandlike
trophozoites are
distinctive.
Slides

Plasmodium falciparum
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P vivax

P ovale

P malariae

Normal
Epidemiology and Risk Factors of
Malaria
Incidence

3 billion people (1/2 world’s population)
living in areas at risk

1-2 million deaths per year

5th most common cause of death from
infection worldwide
 2nd
most common cause of death from
infection in Africa
Where malaria occurs
Most countries in the tropics
107 countries
Transmission patterns
Unstable transmission
Lower levels of infection
Temperature a bit cooler
Climate varies with season
Immunity
Epidemic
Stable transmission
Year round infection
Warmer conditions
Less seasonal variation
Closer to the equator
Children affected the most
Mostly asymptomatic in
adults
High
Unlikely
Efficiency of mosquito
Efficient vector
Inefficient vector
Main parasite
P. falciparum
P. vivax
Fluctuation
Climate
Clinical manifestation
Social and Economic Toll
•Cost to individuals
•Cost to government
Symptomatic disease occurs
at all ages
Low
Likely
Risk factors for travellers
Destination
 Season
 Accommodation
 Activities
 Failure to carry out protective measures
 Taking counterfeit or substandard anti-malarials

Who is the most vulnerable?
 Young children
 Pregnant women
 Immunocompromised individuals
 Immigrants from endemic areas living in non-endemic areas
Treatment of Malaria
Treatment
There are many different types of
antimalarial drugs
 The decision of which to use is
dependent on the setting of treatment:

 ?Remote region - no infusion or injections available
 The resistances of the parasite
 Life-cycle of the parasite
Antimalarials
Acute Treatment
Prophylaxis
Chloroquine
Chloroquine
Quinine
Proguanil
Artemesinin and derivatives
(Artemether/Artesunate)
Atovaquone
Doxycycline/Clindamycin + Quinine salt
Doxycycline
Mefloquine
Mefloquine (overseas)
Sulphadoxine + Pyrimethamine
(Fansidar®)
Traditional thinking
Traditionally it has been taught that if the parasite
is sensitive to chloroquine, then this will be used
 And if the parasite is resistant to chloroquine, a
quinine salt is administered
 However these therapies are largely outdated, and
nearly all P. falciparum are resistant to chloroquine.
 It is useful to know this however, as treatment of
malaria is very dependant on the medical
resources available, and as the newer, more
effective drugs are also more expensive, in some
areas of the world old therapies must still be
relied upon.

Current therapy in Australia
- Uncomplicated Malaria

For uncomplicated Malarial infection, an
artemesinin derivative, typically artemether,
combined with lumefantrine (sold as Riamet®)
 Administer 4 tablets/12 hours for 6 doses.






Uncomplicated malarial infection can progress to
a more severe form, defined by:
•Altered conscious state
•Jaundice
•Oliguria
•Parasite count>2% of RBCs
•Acidotic
Current Therapy (2) - Severe
Malaria
Treatment alters slightly in severe malaria, and the primary
treatment is a different artemesinin derivative
 IV Artesunate, 2.4mg/kg on admission and given every 12
hours until oral therapy is possible
 Use artemether+lumefantrine when infection is less severe
 It is also essential to carefully monitor and correct if
necessary the patient’s:
 fluid levels,
 blood glucose
 urine output

•Daily parasite counts, platelets, U&E's and LFT's should also
be taken
Prophylaxis





Prophylactic therapy is typically chosen based on
the area the individual may be travelling to.
•In general terms, due to the high levels of
chloroquine resistance, Atovaquone+proguanil
(Adult: 250+100mg PO) is used, 1-2 days before
travel, and 7 days after.
•Doxycycline (100mg daily) is also used; 2 days
before travel, contuining until 4 weeks after.
–SE: Oesophagitis, photosensitivity, vaginal thrush
•Mefloquine (250mg weekly) is not used in
Australia, yet is used widely around the world.
Complications of Malaria
Complications of Malaria
CNS: cerebral malaria
Renal: blackwater fever: haemoglobinuria + haemolysis +
renal failure, uraemia (acute tubular necrosis)
Blood: severe anaemia (haemolysis, dyserythropoiesis,
splenomegaly with sequestration and folate depletion)
Respiratory: acute respiratory distress syndrome
(ARDS)
Metabolic: hyperglycaemia, metabolic acidosis
GI: diarrhoea, jaundice, splenic rupture  haemorrhage
Other: shock/hypotension (especially with secondary
bacterial infection), hyperpyrexia
Complications of Malaria
CNS: cerebral malaria
 Renal: blackwater fever: haemoglobinuria + haemolysis +
renal failure, uraemia (acute tubular necrosis)
 Blood: severe anaemia (haemolysis, dyserythropoiesis,
splenomegaly with sequestration and folate depletion)
 Respiratory: non-cardiogenic pulmonary
oedema/ acute respiratory distress syndrome
(ARDS)
 Metabolic: hyperglycaemia, metabolic acidosis
 GI: diarrhoea, jaundice, splenic rupture  haemorrhage
 Other: shock/hypotension (especially with secondary
bacterial infection), hyperpyrexia

Cerebral Malaria
- recognised by a decreased conscious state not a
headache
- causes 80% of deaths from Malaria and will kill 15-20%
of the people who have it even with treatment
Non-cardiogenic Pulmonary Oedema
- caused by overhydration, increased permeability of
pulmonary vessels in response to the infection or by
the clogging of pulmonary microcirculation by
infected red cells
- 50% mortality
Renal Failure
- caused by dehydration, increased blood viscosity and
the products of haemolysis
- adequate rehydration needed
Prognosis
Criteria for a poor prognosis:

< 3 years old

Pregnancy

Fits

Comas

No corneal reflex

Papilloedema

Pulmonary oedema/ARDS

HCO3- <15mmol/L

Plasma or CSF lactate >5mmol/L

Hyperparasitaemia (>5%RBCs or 250,000/mL)
Hb <5g/L


Creatinine >265mmol/L
Malaria pigment >5% neutrophils

Complicating infection

DIC

>20% of parasites are mature trophozoites or shizonts

The main criteria for poor prognosis:
The species of Malaria:
P. Falciparum
The number of parasites:
>5% of RBCs
Pre-Travel Advice
Traveller’s Advice
Risk assessment
 Administer vaccinations
 Malaria prevention
 Essential preventive behaviours

• Risk assessment:
–
–
–
–
–
–
–
–
–
–
–
–
–
Itinerary (country / regions / dates of travel)
Urban / rural
Age
Past vaccination Hx
Comorbidities
Current Medications
Pregnancy status
Allergies
Purpose of trip
Risk exposures (blood, body fluids, extreme sports, outdoors)
Types of accomodation
Travel insurance
Level of aversion to risk
•
Administer
Immunisations
– Routine vaccinations
– Travel vaccinations

Malaria Prevention
• Essential preventive behaviours
– Food and water safety
– Protection against STDs (always use condom)
– Motor vehicle safety
– Personal safety (appropriate dress, crime,
recreational activities, local customs, etc.)
– Altitude / motion sickness / jet-lag
OBJECTIVES
RED FLAGS
◦ Rigors = hospital admission
HOW TO TAKE A HISTORY IN A RETURNED
TRAVELLER
◦ How to take/interpret a fever
MALARIA
◦ Diagnosis
◦ Pathophysiology
◦ Management
COUNSELLING A PROSPECTIVE TRAVELLER