fever in the returned traveller - rcplondon.ac.uk
TRANSCRIPT
Fever in the Returned Traveller
Anna Checkley, HTD
Royal College of Physicians
Acute Medicine Conference
23-24th May 2016
Manchester
Images and data courtesy of
Mike Brown
Vicky Johnston
Tom Doherty
Caoimhe Nic Fhogartaigh
Maggie Armstrong
& others
2
Background
Travel abroad is increasing¹
8-15% travellers are ill enough to seek medical care while
abroad or on return home²
Fever common symptom of illness in returning travellers³
Some diagnoses are life threatening, e.g. malaria
Potential public health consequences, e.g. viral
haemorrhagic fever
Wide differential diagnosis
3 1. Travel trends 2006; 2. Steffen R Int J Antimicrob Agents, Rack J Trav Med 2005,
Hill DR J Trav Med 2000; 3. Freedman DO NEJM 2006
0
200
400
600
800
1000
1200
1400
1600
1800
Year
No o
f vis
its (
thousands)
Indian sub-continent (ISC)
South and Central America
Caribbean
Sub-Saharan and Southern Africa
Other Asia (not ISC)
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2008 2009 2010 2011 2012
Indian sub-continent(ISC)
South and CentralAmerica
Carribean
Sub-Saharan Africa
Other Asia (not ISC)
Data from the International Passenger
Survey, Office for National Statistics
Number of visits abroad by UK residents to tropical
regions of the world: 1996-2005, 2008-2012
Asia
Africa
Latin
America
Caribbean
All visits
Background
Travel abroad is increasing¹
8-15% travellers are ill enough to seek medical care while
abroad or on return home²
Fever common symptom of illness in returning travellers³
Some diagnoses are life threatening, e.g. malaria
Potential public health consequences, e.g. viral
haemorrhagic fever
Wide differential diagnosis
5 1. Travel trends 2006; 2. Steffen R Int J Antimicrob Agents, Rack J Trav Med 2005,
Hill DR J Trav Med 2000; 3. Freedman DO NEJM 2006
Assessment
“Why does this PERSON, from this
PLACE develop these SYMPTOMS at
this TIME?”
Professor Eldryd Parry
Travel History:
What people do in the tropics as important as
where they went
8
Travellers,
expats
Visiting friends
and relatives
(VFR)
South America:
Undiagnosed (554)
Dengue (138)
MALARIA (133)
Mononucleosis (79)
Enteric fever (17)
Central America:
Undiagnosed (473*)
MALARIA (133)
Dengue (123)
Mononucleosis (69)
Enteric fever (25)
Sub-Saharan Africa:
Undiagnosed (282)
MALARIA (622)
Rickettsial (56)
Mononucleosis (10)
Enteric fever (7)
Dengue (7)
South Central Asia:
Undiagnosed (478)
Dengue (142)
Enteric fever (141)
MALARIA (139)
Mononucleosis (17)
Rickettsial (10)
Southeast Asia:
Undiagnosed (546)
Dengue (315)
MALARIA (130)
Mononucleosis (32)
Enteric fever (26)
Rickettsial (16)
Caribbean:
Undiagnosed (541)
Dengue (238)
Mononucleosis (70)
MALARIA (65)
Enteric fever (22)
Spectrum of disease in relation to place of exposure
amongst travellers with systemic febrile illness
9
Freedman et al. NEJM 2006
N=3907 travellers with fever; *per 1000 patients with systemic febrile illness
10 J infection 2009 59, 1-18
Risk factor Common Occasional Rare but important
GEOGRAPHICAL
Sub-
Saharan
Africa
Malaria, P. falciparum
Malaria, non-falciparum
Rickettsial infection
HIV-associated
Acute
Schistosomiasis
Dengue
Enteric fever
Meningococcus
Brucellosis
Viral haemorrhagic
fever
Trypanosomiasis
Other arbovirus e.g.
Rift Valley fever
Histoplasmosis
Visceral
Leishmaniasis
South-East
Asia
Enteric fever
Dengue, Chikungunya
Malaria, non-falciparum
Malaria, P. falciparum
Leptospirosis Scrub typhus
Meliodosis
Penicilliosis
SPECIFIC RISK FACTORS
Game Parks Tick typhus Trypanosomiasis
Anthrax
HIV Tuberculosis
Non-typhoid salmonella
Amoebiasis
Visceral leishmaniasis
STI e.g. syphillis
Penicilliosis
Histoplasmosis
Coccidioidomycosis
Table 2, Johnston et al Journal of Infection 2009
Syndromic presentations
Many patients present with undifferentiated fever
However, some will present with a “syndrome”
e.g. Fever and..... rash
gastrointestinal symptoms
jaundice
hepatosplenomegaly
eosinophilia
respiratory symptoms
neurological symptoms
Chronic fever
12
Incubation
Period Infection
Short
(<10days)
Acute gastroenteritis
Respiratory Tract Infection
Meningitis
Arboviral infection e.g. Dengue
Rickettsial infection e.g. Tick
typhus
Relapsing fever (borrelia)
Medium
(10-21
days)
Protozoal
• Malaria (Plasmodium falciparum)
• Trypanosomiasis rhodesiensae
• Acute Chagas disease
Viral
• HIV, CMV, EBV, viral
haemorrhagic fever
Bacterial
• Enteric fever
• Brucellosis
• Q fever
• Leptospirosis
Long (>21
days)
Protozoal
• Malaria (including Plasmodium
falciparum)
• Amoebic liver abscess
• Visceral Leishmaniasis
Viral
• Viral hepatitis
• HIV
Table 3: Johnston et al. Journal of Infection 2009
Incubation periods
Case 1
28 years old student
48 hour history Fever
aching muscles
mild headache
loose bowels
Born in Nigeria
One month trip home to visit family
Returned 1 week ago
No malaria prophylaxis
Temperature: 38.6ºC
Pulse: 100 regular
BP: 110/60
RR: 20 breaths/min
Sats: 97% room air
? Mild jaundice
CVS, RS, GI, CNS:
unremarkable
?
Differential diagnosis
Malaria
Virus URTI / influenza
arbovirus: dengue,
hepatitis A /B /C /E
Acute EBV, CMV
HIV seroconversion
Bacteria enteric fever
gastroenteritis
other bacterial sepsis
typhus
Protozoa amoebic liver abscess
Nigerian M, 28
Blood film: P falciparum, 3% parasitaemia with schizonts
No evidence of organ dysfunction
What treatment would you provide?
A. Admit and give IV quinine
B. Admit and give IV artesunate
C. Admit and give oral Riamet
D. Discharge and give oral Riamet
E. Discharge and give oral quinine and doxycycline
Nigerian M, 28
Blood film: P falciparum, 3% parasitaemia with schizonts
No evidence of organ dysfunction
What treatment would you provide?
A. Admit and give IV quinine
B. Admit and give IV artesunate
C. Admit and give oral Riamet
D. Discharge and give oral Riamet
E. Discharge and give oral quinine and doxycycline
• 2867 patients with Hx fever on return from tropics:
11.8% malaria (90% Sub-Saharan Africa)
Proportion of all febrile travellers with malaria:
Sub-Saharan Africa 19.4% ISC/SEA 2.3%
Only 45% had fever at time of presentation
published in PHE malaria prevention guideline, c/o Malaria Atlas
Project http://www.map.ox.ac.uk/
Malaria
P. falciparum potentially fatal
Presents non-specifically
Fever/ myalgia/ headache/ confusion/ diarrhoea/ LRTI
>90% occur within 2 months of leaving endemic area
Diagnosis
Thick Film
Thin Film
Schizonts?
For urgent opinion: send to HTD Dept Clinical Parasitology
(24h service: call duty tropical SpR on 07908 250924)
Rapid diagnostic tests
• Similar sensitivity to a
single thick film
• Good for P. falciparum,
P. vivax
• May remain positive 2-4
weeks after treatment
• No indication of
parasitaemia (or
parasite stage)
• Follow up all positive
RDT’s with microscopy
Negative
Positive
Severe malaria
Parasitaemia >2%
OR schizonts
OR complications
renal failure
shock
DIC *
acidosis
jaundice
cerebral involvement
severe anaemia
ARDS +
bleeding *disseminated intravascular coagulation + adult respiratory distress syndrome
http://courses.washington.edu/med620/images/mv_c3fig1.jpg
SEAQUAMAT Trial Lancet 2005
Artesunate vs quinine for treatment of severe falciparum malaria in SE Asian adults
Mortality
Artesunate Quinine p
15% (107/730) 22% (64/731) 0.0002
23% vs 53% if parasitaemia > 10%
AQUAMAT Trial Lancet 2010
Artesunate vs quinine for treatment of severe falciparum malaria in African children
First line: IV artesunate
Second line: IV quinine
Then oral, eg 3 days riamet
Artesunate for severe malaria
HTD can arrange to
courier artesunate -
07908 250924
Haemolysis post-artesunate
1-3 weeks after artesunate
7-22% incidence
Haemolysis of previously infected rbc
2-4 week follow up recommended
Jaureguiberry, Blood 2014, Rolling, JID 2014
Treatment of uncomplicated malaria
Parasitaemia < 2%
Patient ambulant
No complications
1. Riamet 4 tabs at time 0, 8, 24, 36, 48, 60 hrs
2. Oral quinine 600mg 8 hourly, min. 9 doses
plus doxycycline 100mg od for 7 days
or clindamycin 450mg tds for 7 days
3. Malarone 4 tabs for 3 days
Clinical case
28 years old Nigerian student
48 hour history fever
aching muscles
mild headache
loose bowels
returned to UK one week ago
visiting family in Nigeria
no significant past medical or family history
………..
FURTHER HISTORY
stayed with family in Lagos
brief trip north to visit relatives in their village - burial
rites
sick contacts
contact with rats
A patient presents with 48 hr history of fever, having
returned 7 days previously from a 1 month stay in Lagos
and in northern Nigeria
Which viral haemorrhagic fever(s) is he at risk of?
A. Ebola
B. Lassa
C. Marburg
D. Ebola and Lassa
E. Lassa and Crimean-Congo Haemorrhagic Fever
(CCHF)
Lassa Fever
31
17 March 2014
Ebola: total cases (2014-15 outbreak)
32
VHF early management
Need to exclude malaria
Careful with further investigations
Isolation protocols
34
Severe acute respiratory illness
• With fever and cough AND
• Signs of consolidation or ARDS
AND
• Travel to endemic area within 14 days OR
• Contact with confirmed case within 14 days
MERS CoV
35
WHO, May 2016
Clinical case
Arrived from Bangladesh 10 days ago Unwell one week before leaving, then improved
on ‘some drugs from the local chemist’
Recurrence of symptoms over last 4 days
Complaining of: Fever and rigors
Night sweats
Headache
Neck stiffness
Cough
Examination:
39.5°C
Pulse 125, BP 90/50
RR 24, Sats 97% RA
No neck stiffness
Investigations:
Hb 15.3 g/dl
WCC 5.3 x 109/L
Platelets 98
CRP 74 mg/L
LFTs: mild transaminitis
Malaria film –ve
CXR: normal
Blood and urine culture pending
moderately
tender
spleen
PERSON: migrant
PLACE: Bangladesh
TIME: incubation period?
SYNDROME:
• Fever and splenomegaly
• Chronic fever
?
• OR
Chronic fever
Enteric fever (typhoid)
Tuberculosis
HIV + opportunistic
infection
Deep seated abscess
Amoebic liver abscess
Brucellosis or Q fever
Non-infectious
Differential diagnosis
What empirical treatment would you start?
1. IV artesunate
2. PO ciprofloxacin
3. IV ceftriaxone
4. PO rifampicin, isoniazid, pyrazinamide, ethambutol
5. Nothing
39
Chronic fever
Enteric fever (typhoid)
Tuberculosis
HIV + opportunistic
infection
Deep seated abscess
Amoebic liver abscess
Brucellosis or Q fever
Non-infectious
Differential diagnosis
You are called by
microbiology
“gram negative rods on his
blood culture”
http://www.ludekvincent.wz.cz/bacteriology_salmonelosis.htm
Typhoid
Salmonella enterica serotype typhi / paratyphi
Through-out tropics, especially Asia
Faecal-oral spread
IP: 7-18 days (3-60 days)
Non-specific symptoms: Fever
Headache
Myalgia and lethargy
Diarrhoea / constipation
Dry cough
Signs: Splenomegaly
Investigations: ↓ platelets
transaminitis (mild)
Typhoid: antibiotic resistance
42 www.who.int
Patel AJTMH 2010; Hume et al Eur J Clin Micro Inf Dis
2009; Cooke F et al Trav Med IF 2004
~90% of cases travelled to
Indian sub-continent
(2011)
If unstable:
Ceftriaxone
If clinically stable:
Azithromycin
Suspect bacterial infection in patient
returning from abroad?
Think antibiotic resistance!
(particularly if patient has been in hospital.....)
Day
7 12 4
Amoxycillin 500mg TDS
S. paratyphi
A
No growth
Clinical progress:
Ciprofloxacin 750 mg BD
IV/oral
S. paratyphi A
Ciprofloxacin sensitive
Enteric fever has a long fever clearance time (regardless of antibiotic choice)
Ciprofloxacin < 4 days (average) Ceftrixone 7 days Azithromycin 5-7 days
Clinical case
History
4 days
Severe retro-orbital headache
Myalgia and arthralgia (wrists, ankles, lower back)
Fevers (measured 38.8) – settled 2 days
2 days
Rash, all over body, itchy
Travel
Rio de Janeiro, Brazil: 1 week, returning 5 days ago
Bitten by ‘stripy white mosquitoes’
Social
Landscape gardener, trying to conceive
45
By FRED - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=30734915
Which tests would you send?
Currently symptomatic………
PCR blood and urine for Zika virus
Serology: chikungunya, dengue
HIV serology
Results
Zika PCR blood negative
urine positive
Chikungunya IgM positive
Dengue serology negative
HIV serology negative
46
http://travelclinic.vch.ca/news/zika/
What would you advise him?
Likely Zika infection
PHE guidance
‘Use barrier contraception for 6 months’
(Asymptomatic men returning from Zika-endemic
countries are advised to use barrier contraception for
6 months)
47
48
Flavivirus, closely related to dengue,
yellow fever, Japanese encephalitis,
West Nile viruses
Transmitted by Aedes mosquitoes
peri-urban,
day biting
Few reports of sexual transmission
Zika virus
Clinical features
80% asymptomatic
20% mild, self-limiting illness:
macular/ papular rash (itch), fever, arthritis/ arthralgia,
non-purulent conjunctivitis
(headache, retro-orbital pain)
Guillain-Barre syndrome (GBS)
Risk lower than campylobacter-associated GBS
Congenital Zika Syndrome (including microcephaly)
~30% confirmed Zika infections in 1st trimester show fetal
abnormalities on ultrasound
49 Duffy MR et al. N Engl J Med 2009;360:2536-2543.
Diagnosis
Current symptoms
Blood PCR
Urine PCR
Serology (> day 21)
Past symptoms
Pregnant women urine PCR (<10 days), serology
All others serum save
Asymptomatic individuals
Pregnant women serum save
All others nil
Differential diagnosis
Don’t forget malaria! Dengue, chikungunya
50
9%
9%
3%
16%
63%
276 Patients seen at UCLH in FMU and HTD between 01/01/16-30/04/2016
Female not trying toconceive
Female trying toconceive
Female unknownpregnancy status
Male
Pregnant
Thanks to Kate Gaskell
52 Thanks to Kate Gaskell
Summary
Assessment
person
place
syndrome
incubation period
Malaria
Antimicrobial resistance
Outbreaks – www.promedmail.com
53
Sources of information
Recommendations for investigation and management of
fever in returned travellers, Johnston et al, J Infection 2009
British Infection Association/HTD guideline
Hospitals for Tropical Diseases (London, Liverpool) for
telephone advice
HTD SpR/consultant mobile 07908250924
PHE Imported Fever Service 0844 778 8990
Microcephaly and Zika virus infection
What we know
Maternal infection can
result in Congenital Zika
Syndrome, including
microcephaly
Associated with Guillain-
Barre Syndrome
What we don’t know
Risk of sexual transmission
Risk of Congenital Zika
Syndrome in infants
infected in utero
Impact of severity of
maternal infection
Impact of timing of infection
during pregnancy
Full spectrum of
phenotypes
56 CDC COCA call Jan 2016