The Tropics

Question 1

General rules re fevers in the returning traveller and country/region of travel, incubation period, activities and most common causes of fever in the returning traveller

Answer 1

Region

• Malaria → Sub-Saharan Africa
• Dengue → SEA, Latin America
• Enteric fever → South Central Asia

Incubation period

• <10 days → dengue, influenza, zika
• 10-21 days → malaria, viral haemorrhagic fever, typhoid
• >21 days → malaria, hepatitis, TB

Activities

• Fresh water/white water rafting → schistosomiasis, leptospirosis
• Caves → histoplasmosis
• Contact with birds/animals → avian influenza, q fever, rabies

Question 2

Physical findings as clues in fever in the returning traveller

Answer 2

• Eschar → rickettsia (e.g African tick bite fever), plague, trpanosomiasis
• Jaundice → hepatitis, malaria, yellow fever, leptospirosis, typhoid, fascioliasis, ALA
• Lymphadenopathy → dengue, rickettsia, brucellosis, HIV, syphilis, visceral leishmaniiasis, TB, trypanosomiasis, filariasis, monkey pox. Malaria not associated with lymphadenopathy
• Conjunctivitis → zika, measles
• Conjunctival suffision and subconjunctival haemorrhage → leptospirosis

Question 3

Fever in the returning traveller with rash → potential differentials

Answer 3

Question 4

Investigations for fever in the returning traveller

Answer 4

Question 5

How many thick and thin films required to rule out malaria

Answer 5

• 3
• If initial smear negative and malaria suspected - additional smears should be testing every 12-24 hours for a total of three sets before ruling out malaria

Question 6

Notes on amoebiasis

Answer 6

Amoeibic liver abscess

• 10x more common in men than women
• Diarrhoea only present at time of innoculation - stool microscopy for E. histolytica not sensitive
• Radiological features can persist for up to 2 years following erradication therapy

Question 7

Malaria basic facts and epidemiology

Answer 7

• Parasitic amoeba that infeects erythrocytes
  
  • Plasmodium falciparum, P vivax, P malariae, P knowlesi
• Incidence falling
• Most cases in sub-Saharan Africa but transmission intensity also very high in some Pacific countries

Question 8

Life cycle of the Malaria parasite

Answer 8

• Female Anopheles mosquito injects malaria parasites into the bloodstream by biting human → at this stage the parasite is called a sporazoite
• Sporazoites move to the liver → invade liver cells → replicate into mature Schizont (usually asymptomatic at this stage)
• Liver schizonts rupture after 6-30 days → releases “daughter” merozoites which can infect red cells → replicate in red cells forming new schizonts and rupturing in infected red cells → develop symptoms when red cells infected
• Some merozoites differentiate into male or female gametocytes. If these gametocytes are ingested by a female during feeding they can then complete their life cycle in the gut before migrating back to the salivary glands

Question 9

Clinical features malaria infection

Answer 9

• Suspect in anyone with a fever >37.5 who has recently visited a malaria endemic area
• Clinical features limited value in distinguishing malaria from non-malarial causes of fever
• Patients who have had repeated malaria exposure through living in an endemic area will have partial immunity and can have asymptomatic paristaemia → there is no test that can differentiate symptomatic from asymptomatic parasitaemia

Question 10

Diagnosis of malaria

Answer 10

• Clues on CBC → thrombocytopaenia non specific
• Microscopy → thick films (screening) and thin films (density and speciation) → in patients with a high clinical suspicion, repeat testing for 3 days required before excluding disease
• Antigen based rapid diagnostic tests (RDTs)
  
  • Some genus specific, and some able to distinguish P. falciparum from P. vivax
  • Unable to determine parasite density
  • RDTs can stay positive for several weeks after successful treatment
  • Increases reports of mutations in antigen encoding genes

Question 11

Notes on severe anaemia

Answer 11

Features

• Anaemia
• Jaundice
• Seizures
• Kidney injury
• Shock
• Impaired consciousness

Causes

Most P. falciparum, P vivax and P knowlesi also cause severe disease

Medical emergency

Management

Artemisinin combination drugs clear parasitaemia faster than quinine and reduce mortality

Supportive care → hypoglycaemia common, careful treatment of shock as excess IV fluids → pulmonary and cerebral oedema

Question 12

Notes on P. knowlesi

Answer 12

• Human infection typically acquired in forest areas or forest-fringe areas in SE Asia
• Can cause uncomplicated infection and severe disease
  
  • Jaundice, AKI, respiratory distress and shock
  • Coma and seizures rare
• Diagnosis requires microscopy
  
  • Parasite density lower than other species for severity of disease → beware false negative slides
  • Requires confirmatory PCR for species
  • RDTs have poor sensitivity

Question 13

Notes on artemisinin resistance in malaria

Answer 13

• Increasingly common in SEA - Thai-Cambodian border
• Artemether monotherapy driven mutations in Kelch 13 gene
• Clonal spread through SEA, also development of parallel resistance
• Resistance = slower parasite clearance → requires prolonged courses of treatment (not necessarily associated with treatment failure)
• Avoid artemether monotherapy

Question 14

Notes on P. vivax/P. ovale malaria and erradication of hypnozoites

Answer 14

• Life cycle of both contain dormant hypnozoites → can cause relapse months to years after initial infection
• Should consider erradication in all patients with P. vivax or ovale → primaquine 7-14 days (must have normal G6PD or → life threatening haemolysis)
• New data on tafenoquine as single dose, also need G6PD assay showing >70% function

Question 15

Notes on malaria vaccine

Answer 15

• Recombinant fusion protein from P.falciparum sporozoite and an antigen derived from the Hepatitis B surface antigen → roll out 2022 Malaria endemic countries

Question 16

Enteric fever → basics, epidemiology, clinical features

Answer 16

• Salmonella enterica serotypes Typhi, and Paratyphi A, B, C
• High incidence regions → Southern Asia, SEA, Southern Africa.
• Medium incidence → Oceania including Samoa and Fiji
• Humans only reservoir and transmission direct contact with an infected person, or through contaminated food or water

Clinical features

• Incubation period 5-21 days
• Classic presentation
  
  • Week 1: Rising, stepwise fever, relative bradycardia
  • Week 2: Abdominal pain and rose spots
  • Week 3: Septic shock, intestinal perforation, hepato-splenomegaly
• Usual presentation: persistent fevers, GI, neurological and respiratory symptoms variable
• Chronic carriage 1-6% - A/W biliary tract disease, higher in women

Question 17

Diagnosis of enteric fever

Answer 17

• Suspect if fever and epidemiologic exposure - esp. GI symptoms, or fever >3 days
• Stool and blood cultures
  
  • Sensitivity blood culture 50%
  • Bone marrow culture most sensitive but not usually warranted
• Widal test - not routine
  
  • Positive result may indicate past exposure (common in endemic areas)

Question 18

Enteric fever and anti-microbial resistance

Answer 18

• MDR typhoid common → resistant to amoxicillin, TMP-SMX, chloramphenicol
• Quinolone resistance increasing - up to 80% South Asia
• Most strains susceptible to ceftriaxone and azithromycin
• Emergence of ESBL produing S. enterica Typhi

Question 19

Treatment of enteric fever

Answer 19

• Empiric: axithro or ceftriaxone
• Acquired in Pakistan → carbapenem (?ESBL)
• Dexamethasone adjunct in severe disease
• Assess for chronic carriage and erradication e.g. ciprofloxacin
• Vaccination
  
  • Injectable and oral - none provide complete protection. None prevent infection with paratyphoid. Not yet a valid global control strategy but recommended for travellers.

Question 20

Notes on Dengue haemorrhagic fever

Answer 20

• Most serious manifestation of infection with dengue virus (DENV) → can lead to shock
• Virus transmitted by Aedes aegypti mosquito (vector borne illness)
• Incubation 7 days
• 4 cardinal features:
  
  • Increased vascular permeability
  • Fever
  • Haeorrhagic manifestations
  • Marked thrombocytopaenia
• Plasma leakage is the most specific and life-threatening feature usually occurs over a period of 24-48 hours

Question 21

Virology and vectors of dengue, zika, chikungunya

Answer 21

• Dengue and Zika → flaviviruses (same family as yellow fever, Japenese encephalitis)
  
  • Dengue - 4 serotypes and mutliple lineages in each
• Chikungunya → alphavirus → 4 lineages
• Same vectors fr all three - Aedes aegypti (tropical areas) and A. albopictus (cooler climates)
• Recent increases in all three viruses driven by urbanisation, high population density, travel, climate change and increasing vectors

Question 22

Dengue - epidemiology, transmission, pathogenesis of severe disease

Answer 22

• Most tropical and subtropical populated areas
• Risk varies widely between countries, year to year and season to season
• Tranmission from bite of infected mosquito - may occur via blood transfusion, needle stick, mucosal splashes. Vertical transmission if viraemic at delivery

Pathogenesis of severe disease

• Infection → type specfic antibodies → long term immunity to that serotype + cross reactive antibodies → cross protection against other 3 serotypes for up to 2 years
• 2nd infection → cross reactive antibodies - bind to the different Dengue virus to facilitate virus entry through Fc receptors on target cells e.g. macrophages (antibody dependent enchancement - ADE) → not universal among universal infections
• Viral protein NS1 may also play a role in pathogenesis - disrupt endothelial glycocalyc which increases vascular permeability - dengue shock syndrome

Question 23

Clinical features and investigations for Dengue fever

Answer 23

• Incubation period 2-5 days
• Many asymptomatic or minor illness. 25% febrile illness
• Classic → sudden onset high fever, malaise, myalgia, retro-orbital headache, low back pain, GI disturbance
• Diffuse erythematous rash in initial febrile phase
• Saddleback pattern fever
• Most defervescence on day 4 to 5 → can develop complications at this point
  
  • Vasculopathy, plasma leakage, IV volume depletion. Diastolic BP may rise while systolic maintained
  • Rare → myocarditis, bradycardia, fulminant hepatitis, encephalitis, Guillain-Barre, retinal vasculopathy, optic neuropathy

Investigations

• Leucopaenia, often significant thrombocytopaenia
• Coagulation derangements → raised APTT, low fibrinogen
• Mild to moderate tranaminase increase AST > ALT
• Choice of diagnostic test dependent on time since fever onset
  
  • <5 days → PCR or NS1 antigen
  • ?otherwise serology

Question 24

Management of Dengue, outcomes, vaccine

Answer 24

• Supportive. Avoid aspirin, NSAIDs
• Daily monitor platelets haematocrit
• 84% cases severe Dengue → secondary infections
• Vaccine
  
  • Live
  • Increased risk severe disease in those seronegative at time of receipt. Only licensed for those seropositive

Question 25

Epidemiology and transmission of Zika virus

Answer 25

* 2007 outbreak Micronesia → Pacific. 2014 → Brazil and rapid spread through americas and Caribbean. * Now outbreaks have subsided - sporadic cases continue * Humans and non-human primates are reservoirs * Transmission mosquitos. Also documented intrauterine, intrapartum from a viraemic mother, sexual transmission, blood transfusion and lab exposure * Sexual transmission most commonly male → female. Can occur with asymptomatic infection. * Prolonged viraemia detected in pregnant women * Contraception 3 months in men, 2 months in women after at risk travel

Question 26

Clinical features Zika virus

Answer 26

* Incubation 3-14 days * 20% symptomatic * Mild self limiting illness with symptoms lasting 4-7 days * Rash, pruritus, headache, arthralgia, myalgi, non-purulent conjunctivitis * Fever in 50% * No increased susceptibility or increased severity in pregnant women * Generally mild in children **Complications** * Guillain-Barre * Median 5-10 days after onset Zika symptoms * Sporadic Zika virus → cases of myelitis, meningoencephalitis, uveitis, ocular complications * Congenital infection - microcephaly with partially collapsed skull, thin cerebral cortices with calcifications, macular scarring and focal retinal mottling, congenital contractures, marked early hypertonia and extrapyramidal involvement → all stages of pregnancy but 1st trimester highest risk

Question 27

Zike virus diagnosis and management

Answer 27

* PCR \< 7 days, serology \> 7 days * Problems with cross-reactivity with other flaviviruses * Pregnancy → serial ultrasounds

Question 28

Notes on Chikungunya

Answer 28

* Central and South America, Indian Ocean, Samoa, Cook Islands, Tonga * Predominantly urban disease * Perinatal infection has been documented * Incubation 3-7 days * Acute phase: fever, itchy rash, joint pain (can get severe B/L symmetric distal synovitis. Headache, myalgia, conjunctivities, GI symptoms. Treatment → analgesia. No steroids * Post acute (4-12 weeks) - fatigue, joint symptoms * Chronic → joint stiffness and pain. * Diagnosis → PCR up to 8 days, serology after 7 days