Microbiology JC090: Fever After Travelling

Question 1

Causes of death among tourists

Answer 1

1. Cardiovascular (majority)
2. Injury (majority)
3. Infection (only small amount)

Question 2

Health risks during travel

Answer 2

1. Environmental risks
   - accidents
   - motion sickness
   - travel by air
   - altitude sickness
   - heat and humidity
   - UV radiation from sun
   - foodborne / waterborne health risks
   - exposure to cold
   - animals / insects
2. Infections
   - foodborne / waterborne diseases
   - vectorborne diseases
   - zoonoses
   - STD
   - bloodborne diseases
   - airborne diseases
   - diseases transmitted from soil and water

Question 3

Risks to travellers

Answer 3

Depends on:
1. **Destination
2. **Season of travel
3. Duration of visit
4. ***Purpose / Nature of visit
5. Standards of accommodation and food hygiene
6. Behaviour of the traveller
7. Pre-existing health of traveller
- children / infants
- elderly
- pregnant women
- disabled people
- chronic medical illness
8. Pre-travel preparations

Question 4

Travel health

Answer 4

1. Medical counselling before travel
   - assessment of health risks associated with travel
   - **vaccinations, **antimicrobial prophylaxis, ***usual medications
   - preferably 4-6 weeks before journey, particularly if vaccination may be required
   - usually vaccine take 2-3 weeks before effective
   - anti-malarials: 1-2 day/week
2. Remind patients of **Precautions / Risks during travel
   - foodborne, waterborne, vectorborne transmissions
   - **medical kit (esp. in patients with chronic disease)
   - ***certification letter from doctor to prove medication required by patients
3. Follow up after travel
   - indicated if:
   —> suffer from chronic disease / disease during the travel
   —> experience illness during the weeks following return
   —> consider that they have been exposed to a serious infectious disease while travelling
   —> spent >=3 months in a developing country

Question 5

Fever in the traveller

Answer 5

2-10% international travellers will experience a febrile illness either during travel / within 2 weeks of returning
- 39% fever abroad only
- 37% fever abroad + at home
- 24% fever at home only

Problems:
- Detailed travel history required
- Knowledge in exotic diseases

Question 6

***History taking in Travel medicine

Answer 6

1. Detailed history of present illness
   - Onset —> **Incubation period
   - Duration
   - **Symptomatology
   —> Local: abdominal pain, diarrhoea, CNS S/S
   —> Systemic signs: fever, relative bradycardia, rash, joint pain
   - Fever pattern (periodic fever in malaria)
2. ***Complete travel history
   - exact dates and places
   - intermediate stops, mode of travel
   - duration of stay (SpC Medicine)
   - type of accommodation
   - activities
3. ***Sexual exposure
4. ***Needle / Blood exposure
   - drug abuse, tattoo, body piercing, injection, medical procedures
5. ***Animal / Arthropod contacts
   - any type of animals, bites, scratches, licks, spelunking
   —> zoonotic infections
6. ***Exposure to water / soil (SpC Medicine)
   - swimming, walking, rafting
7. ***Food / Drink exposure
8. Prophylactic measures
   - antibiotics, insect repellents

Question 7

***Exposure history and related infections

Answer 7

1. Sex, blood, body fluids, surgical operations, IV drug use:
   - Hep B, Hep C, HIV, Syphilis
2. Tattoos, body piercing, other body modification procedures:
   - Hep B, Hep C, HIV, Syphilis, ***NTM infections
3. ***Hospitalisation
   - Antibiotic-resistant bacteria (colonisation / infection)
   - Other nosocomial pathogens
4. Ingestion of raw / undercooked food
   - various foodborne infections e.g. bacterial / viral GE, **salmonellosis, **traveller’s diarrhoea, **EHEC infection, **campylobacteriosis, protozoal, helminth infections, brucellosis, listeriosis, toxoplasmosis, Hep A, Hep E
5. Soil
   - histoplasmosis, coccidioidomycoses, other endemic mycoses, cutaneous larva migrans, strongyloidiasis
6. Freshwater
   - **schistosomiasis (Katayama fever), **leptospirosis
7. Arthropod bites
   - arthropod-borne infections: **dengue, chikungunya, **Zika, rickettsioses, relapsing fever, ***malaria, babesiosis, leishmaniasis, trypanosomiasis, dirofilariasis
8. Dog, bat, other animal bites
   - **rabies, bat rabies, herpes B virus infection, **bite wound infections
9. Animals, animal products
   - Rodents: hantavirus e.g. Lassa fever, Crimean-Congo haemorrhagic fever, plague, rat-bite fever, **leptospirosis
   - **avian influenza, MERS, ***Q fever, brucellosis, tularaemia, anthrax, psittacosis

Question 8

Physical examination

Answer 8

1. General
   - Pallor
   - Jaundice
   - ***Skin lesions (rash, eschar, bite marks, needle marks)
   - Bleeding tendencies (ecchymosis, gum bleeding) —> usually serious due to thrombocytopenia, clotting impairment
2. Systemic
   - **Lymphadenopathy
   - **Organomegaly (e.g. Hepatosplenomegaly)
   - Localising sign (e.g. Meningism)

Question 9

Investigations

Answer 9

1. Haematological
   - cell counts and differentials
   - coagulation studies
2. Biochemistry
   - LRFT
   - creatinine kinase
3. Radiological imaging
   - X-ray
   - CT, MRI (as indicated)
4. Microbiological
   - Microscopy: **blood film (parasites in malaria), **stool (parasites)
   - Culture: blood, stool, urine, tissue, sputum
   - Serology
5. Tissue biopsy
   - Microbiology
   - Histopathology

Question 10

Presumptive (Differential) diagnoses

Answer 10

1. What diagnoses are possible based on ***geographical areas visited?
   - Eastern Africa: Malaria
2. What diagnoses are possible based on ***time of travel (incubation periods)?
3. What diagnoses are possible based on ***activities, exposures, host factors, clinical and laboratory findings?
   - Fever + Rash
   - Fever + Joint symptoms
   - Fever + CNS symptoms
4. Among possible diagnoses, what are **treatable, **transmissible?
   - Isolation requirement

Question 11

Common considerations of DDx

Answer 11

1. Systemic infections
   - vectorborne diseases e.g. **malaria, rickettsioses, **dengue (common in HK), chikungunya, Zika virus infection
   - foodborne / waterborne diseases e.g. **enteric fever
   - zoonoses e.g. **brucellosis, **Q fever
   - leptospirosis
   - **hep A, B, C, E
2. Respiratory tract infections
   - **influenza, viral infections, **pneumonia, legionellosis
3. Enteric infections (Mostly)
   - **traveller’s diarrhoea, **enteric fever including typhoid fever, dysentery (bacillary + amoebic dysentery), GE, cholera, giardiasis, amoebiasis, Norovirus / other enteric virus infections
4. STD, Bloodborne viruses
   - HIV, HBV, HCV, other STD

Question 12

Other recent considerations

Answer 12

1. Epidemic / Pandemic prone infections
   - SARS
   - pandemic influenza
   - **MERS-CoV (Middle East with contact history with camels)
   - **avian / animal influenza virus
   - viral haemorrhagic fevers
   - ***Zika virus infection
2. Potential for local transmission
   - **malaria
   - **dengue
   - chikungunya
   - viral haemorrhagic fevers
   - Zika virus infection
3. ***Antibiotic-resistant bacteria
   - ESBL
   - Carbapenemase-producing Enterobacteriaceae
   - MRSA
   - VRE
   - MDRAB
   - MDRPA
   - highest risks in Indian subcontinent, SE Asia, Africa
4. Multi-resistant Candida auris
5. Re-emerging infectious diseases e.g. measles in adults

Question 13

First principle of management: Recognise infectious disease emergencies

Answer 13

1. Haemorrhagic signs
   - **meningococcaemia (petechiae rash)
   - **gram -ve bacterial sepsis
   - ***viral haemorrhagic fever
2. ***Malaria
   - must exclude first

Question 14

Malaria

Answer 14

5 Plasmodium species
1. **P. vivax (commonest)
2. **P. falciparum (commonest, causes most fulminant form of disease)
- ***Medical emergency (can die within a day)
- accounts for most mortality due to malaria
- prompt initiation of treatment +/- ICU monitoring)
3. P. malariae
4. P. ovale
5. P. knowlesi (only some countries in SE Asia)

• Blood protozoa
• transmission from person-to-person via bites of female ***Anopheles mosquitoes (瘧蚊) / occasionally blood transfusion
• **MUST be considered in all cases of **unexplained fever that start after ***7th day of stay in endemic area
• ***Medico-legal (SpC Medicine)

Classical symptoms:
1. **Periodic (Intermittent) fever with **48-72 hour cycle (not commonly seen in early stage)
2. Protean manifestations (mimic other diseases)

Question 15

Life cycle of Plasmodium (from IASM L48)

Answer 15

1. Infection: Sporozoites (from mosquito) enter hepatocytes
2. Pre-erythrocytic/exoerythrocytic cycle: Merozoites replicate within hepatocytes and rupture into blood)
3. Erythrocytic cycle: invasion into RBC
   - Schizogony: Merozoites in RBC
   - Gametogony: male/female Gametocytes (ingested by Anopheles mosquito)
4. Secondary schizogony: Hypnozoites in hepatocytes (P. vivax and P. ovale)
5. Within mosquito
   —> Zygote
   —> Ookinete (penetrate stomach wall of mosquito)
   —> Oocyst
   —> Sporogony: formation of Sporozoitesu

Question 16

Pathophysiology of Malaria (SpC Teaching Clinic + IASM L48)

Answer 16

1. ***Hypoglycemia
   - Derive energy by glycolysis of glucose to lactic acid
2. ***Haemolysis
   - Decreased deformability
   - Infection by parasites
   - Clearance in splenomegaly
   —> Jaundice, Iron depletion, Anaemia, Haemoglobinuria
3. ***Cytokine storm: TNF-A
4. Thrombocytopenia
5. ***Microvascular obstruction
   - Adhesion of infected RBC to vessel by P. falciparum —> may obstruct brain vessels: dangerous)
   - Multi-organ failure
6. ***Nephrotic syndrome
   - Immune complex deposition in chronic infection by P. malariae)
7. Genetic diversity

NB:
- Host genetics: Absence of Duffy antigen protective against P. vivax
- Sickle cell: lower parasite density

Question 17

Clinical features of Malaria (SpC Teaching Clinic)

Answer 17

1. Asymptomatic for 1 week after bitten
2. Incubation 2 weeks to 1 year
3. ***Fever, chills, headache, abdominal pain, diarrhoea and cough
4. ***Febrile paroxysms coordinated with rupture of RBC
   - 24 hours for PF, PV and PO
   - 3 days for PM
5. ***Hepatomegaly
6. ***Splenomegaly
   - Enlarge 3-4 days after onset
   - Greater likelihood to relapse if splenomegaly fails to regress
   - Hypersplenism: Pancytopenia
7. ***Jaundice
8. ***Thrombocytopenia

Question 18

When to suspect malaria?

Answer 18

1. After ***7 days of stay in an endemic area (shortest incubation period for malaria)
   - must be suspected if febrile patient who could have been exposed to malaria
2. Fever pattern
   - usually not helpful
3. Malaria symptoms are **non-specific!!!
   - **no pathognomonic S/S
4. Usually exclude malaria by investigations
5. Severe malaria
   - parasitaemia >5%
   - impaired consciousness
   - **acidosis
   - hypoglycaemia
   - **severe malarial anaemia
   - **renal impairment
   - **jaundice
   - pulmonary edema
   - **significant bleeding
   - **shock
   - hyperparasitaemia (P. falciparum >10%)

Question 19

Diagnosis of malaria

Answer 19

1. Demonstration of Plasmodium parasites
   - **Blood smear (peripheral blood / marrow blood) —> most useful one
   - thick and thin films
   - tissue samples / post-mortem examination
   - parasitaemia level
   - 1 set of negative blood film does NOT exclude malaria (esp. if patient received prophylaxis / partial treatment)
   - If first blood smear is negative and suspicion is still high:
   —> **repeat 3 smear over 48 hours / alternative tests (Antigen / PCR)
2. Antigen detection
   - not as sensitive as blood film
3. ***PCR
   - most sensitive

Question 20

Problematic areas for malaria

Answer 20

1. Hyperendemicity
   - ***Subsaharan Africa
2. Multidrug-resistant falciparum malaria
   - SE Asia around ***Thailand

Question 21

Treatment and Prevention of malaria

Answer 21

Treatment:
1. Severe / Falciparum malaria
- Artemisinin-based therapy (e.g. **IV Artesunate)
—> Artesunate 2.4 mg/kg IV BD on first day, then 2.4 mg/kg IV OD till oral therapy (total 9.6mg/kg in 3 days)
+
—> Doxycycline 100mg BD for 1 week
- **Quinine

2. Other options
   - Atovaquone-proguanil (Malarone)
   - **Quinine + Doxycycline
   - (*Mefloquine)

Prevention
1. Exposure
- long-sleeve shirts
- insect repellents (DEET, IR3535, Picaridin, BioUD, PMD)
- bednets
- avoidance of exposure

2. Chemoprophylaxis
   - choice of drugs depend on destination
   - Doxycycline, Atovaquone-proguanil (Malarone), (***Mefloquine)
   - start 1 day - 3 weeks before —> continue throughout —> 7 days - 4 weeks after travel

Question 22

Case 1: Undifferentiated fever workup
- 44yo M
- HT, gout, OSA
- Diamond trader
- Africa 3 years, South Africa —> Central African Republic twice in recent years
- Visited Bangui and diamond mines
- 21/7 - 12/8
- Yellow fever, typhoid, cholera vaccine in May
- No anti-malarial prophylaxis
- 12/8: Fever, chills —> seen by GP, given Cefuroxime + Doxycycline
- 14/8: Admitted with 40.7 oC

Answer 22

1. Must exclude malaria if travel to endemic areas
2. Exclude other causes of undifferentiated fever

Question 23

Case 2: Fever + Rash workup

Answer 23

• Countless mosquito bites —> malaria likely
• Rash
  —> Not common in malaria (might be something else)
  —> Rash of meningococcaemia (haemorrhagic, petechiae in nature)?
  —> Serology +/- RT-PCR —> Dengue IgM positive
  —> RT-PCR —> Dengue type 2

Question 24

Dengue

Answer 24

• Asymptomatic / Subclinical infection
• Incubation period: ***4-7 days
• ***Rash: Generalised erythema rash

Vectors:
- ***Aedes aegypti (白紋伊蚊) / other Aedes species e.g. Aedes albopictus

Clinical course (**記住: Biphasic):
Phase 1:
- **sudden high fever (>=39oC), chilliness, prostration
- **frontal / retroorbital headache, backache, muscle, joint pain (“breakbone fever”)
- **facial flushing, eyelid puffiness, conjunctival congestion, **pain on moving eye balls
- transient **generalised macular rash in first 24 hour
- from day 2-4 of fever: cutaneous hyperasthesia / hyperalgesia, lymphadenopathy, anorexia, vomiting

Phase 2:
- fever subside within 3-4 days —> **generalised morbilliform rash **sparing palms / soles lasting for 1-5 days, associated with some scaling
- fever often reappears 1-2 days after lysis of temperature leading to ***biphasic temperature curve

Laboratory diagnosis:
1. Virus detection (first 5 days)
- Serum for **RT-PCR
- Serum for virus isolation (not performed)
2. **Ab detection (IgM)
3. **Ag detection (NS1 (nonstructural protein 1)) in blood
4. Common laboratory finding: **Lymphopenia, **Thrombocytopenia, **Deranged liver functions

Complications:
- Severe dengue (previously **dengue haemorrhagic fever + **dengue shock syndrome)
—> mainly in those who develop 2nd / 3rd episode of dengue infection due to different serotypes of virus
—> **epitaxis, **petechiae, oozing at IV drip sites, purpura, GI bleeding, ***internal bleeding in any organ / shock (usually in Phase 2)

Management:
- ***Supportive: symptomatic, transfusion if necessary
- Prevention: avoidance of mosquito bites, dengue vaccine available

Don’t forget other arboviruses: **chikungunya virus, **Zika virus (similar clinical features, distinguish by geographical location)

Question 25

Case 3: Undifferentiated fever + rash + diarrhoea + rose spot

Answer 25

***Rose spot: Typhoid / Paratyphoid (pathognomonic)

Investigation:
- Blood + Stool culture
- Serology with paired sera

Question 26

Enteric fever and Typhoid fever

Answer 26

Typhoid / Paratyphoid fever:
- commonest cause of enteric fever
- caused by systemic invasion of Salmonella enterica serotype Typhi / Paratyphi

Causes of enteric fever
1. **Salmonella Typhi (Typhoid)
2. **Salmonella Paratyphi A, B, C (Paratyphoid)
3. ***Yersinia enterocolitica
4. Brucella
5. Campylobacter fetus

Transmission:
- Faecal-oral route via contaminated water / food

Clinical presentation:
- Persistent fever
- **Relative bradycardia
- **Rose spots (Typhoid / Paratyphoid (pathognomonic))
- Normal peripheral leukocyte count

Complications (generally preventable by early + appropriate treatment):
- **Intestinal perforation
- **Intestinal haemorrhage
- Coma
- ***DIC

Diagnosis:
- Blood culture
- Stool culture (lower yield)
- **Serology (*Widal’s test) —> not specific for Salmonella Typhi / Paratyphi, not always useful in acute stage of disease
- Paired sera (showing rising Ab titre)

Treatment:
- ***Antibiotic (increasing resistance towards Fluoroquinolone)

Prevention:
- ***Vaccination
- Food + Water hygiene

Question 27

Case 4: Fever + Diarrhoea

Answer 27

• Workup for enteric infections
• Exclude other causes as appropriate (rmb malaria / other infections can present with diarrhoea)

Diagnosis:
- Traveller’s diarrhoea

Question 28

Traveller’s diarrhoea

Answer 28

• 30-50% travellers from industrialised to developing countries
• 90% in first 2 weeks, esp. first 3-4 days
• mean duration: ***3-4 days

Etiology:
- mostly bacteria in nature (esp. E. coli **ETEC), some **Campylobacter
- ***Norovirus (cruise ships)

Risk:
1. Destination
2. Country of origin
3. Travel behaviour
- accommodation, food, standard of hygiene, food habits
4. At risk populations
- hypo / achlorhydria
- extremes of age
- immunosuppressed (HIV/AIDS, steroids, transplant recipients etc.)

Preventive measures:
1. Pre-travel counselling and education
2. Behavioural modification / precaution
3. **Vaccination
- oral whole-cell / recombinant B-subunit cholera vaccine —> some protection against ETEC
4. **Pharmacological (antimicrobial) prophylaxis (not given routinely)
- Bismuth subsalicylate
- Rifaximin
- Fluoroquinolone

Management:
1. Fluid + Electrolyte replacement
- ***Oral rehydration solution

2. Symptomatic treatment
   - ***Loperamide (only for watery diarrhoea, NOT for inflammatory / invasive diseases)
3. Empirical antimicrobial therapy
   - **Ciprofloxacin
   - **Azithromycin
   - Rifaximin
   - Bismuth subsalicylate
   - Growing problem of antibiotic resistance esp. towards Fluoroquinolones

Question 29

Case 5: Fever + Recurrent diarrhoea with abnormal liver function

Answer 29

Approach:
- Look for enteric pathogens in stool, including parasite
- Serology if necessary
- Organ imaging of liver +/- aspiration

CT abdomen:
- Liver abscess

Question 30

Amoebiasis

Answer 30

Clinical presentation:
- Asymptomatic infection
- Symptomatic non-invasive infection: diarrhoea, abdominal pain
- ***Amoebic colitis with dysentery: abdominal pain, diarrhoea with blood + mucus, fever

Extra-intestinal disease:
- ***Liver abscess (commonest)
- rare: pleuropulmonary abscess, pericardial abscess, brain abscess

Amoebic liver abscess:
- 20% history of dysentery
- 10% diarrhoea / dysentery at time of diagnosis
- <50% positive stool microscopy
- ***right lobe of liver (79-95%)

Complications:
- **Colon perforation
- **Toxic megacolon
- Amoeboma (annular colonic granulation, a large local lesion of the bowel)
- Perianal ulceration

Diagnosis:
- Amoebic colitis caused by Entamoeba histolytica (parasite)

Treatment:
- Metronidazole + Luminal agent (Diloxanide furoate, not absorbed by GI tract, destroy trophozoites + prevent amoebic cyst formation)