1. PBL SEMINAR FEVER IN A RETURNED TRAVELLER

2. 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

3. IMPORTANT 1. What’s common is common 2. The diagnosis is MALARIA MALARIA MALARIA until proven otherwise.

4. How to take a History from a Returned Traveller

5. Fever WWQQAAB

6. Travel History: CHOCOLATES Country of birth Housing Occupation Contacts Other drugs Leisure time Animals Travel Eating and Drinking Sexual history

7. HOPC CHOCOLATES Travel History: CHOCOLATES Take Jenny’s History

8. Travel History: CHOCOLATES Country of birth Housing Occupation Contacts Other drugs Leisure time Animals Travel Eating and Drinking Sexual history

9. Jenny’s History Jenny’s 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 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

10. TRAVEL SPECIFIC QUESTIONS 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 accommodation throughout recent travel Exposure to water, mosquitoes, 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

11. !~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!! !~Admit patient with rigors to hospital~!

12. Pyrexia of Unknown Origin (PUO) Approach: - identify cause ◦ Detailed history and regular examination ◦ Confirm temperature objectively, ?admission, ?physiological with circadian pattern ◦ Guide investigation based on initial test results  Blind investigation may be necessary  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  Empirical A/B therapy may mask an 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 Definition: In adults: T>38.3 for>3 weeks with no known origin despite appropriate Ix. Causes 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 Idiopathic

13. Examination of a Returned Traveller

14. Special points for an ID Ex Gen Inspection ◦ Room  Sputum cup  O2  IV – anything running  Drain tube  Catheter – check urine  Temp chart ◦ Patient  Distress (RR, diaphoretic, conscious state)  Rash – blanching/non-  Track marks IVDU  Any lines – sepsis?  Weight loss – chronic illness Hands ◦ Janeway ◦ Splinters ◦ Osler’s nodes ◦ Erythema ◦ Track marks ◦ Bruising, petechiae ◦ Phlebitis ◦ Arthropathy, raynauds - CTD Face ◦ Eyes – Roth spots (fundoscopy), pallor, jaundice (BW fever) ◦ Mouth – hygeine, ginigivitis, abscess ◦ Neck – lymphadenopathy Chest ◦ Crepitations, consolidation Praecordium ◦ New murmur Abdomen ◦ Tenderness? – localised? ◦ Organomegaly ◦ rashes Genitourinary ◦ Stool sample ◦ Urinalysis ◦ Discharge ◦ orchitis Legs ◦ Rash ◦ ulcers

15. Signs in a returned Traveller

16. 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.

17. 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 *NO FEVER RECORDED until day 5* ◦ 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 The Pattern of Fever

18. DDx??

19. 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.

20. 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 Tick typhus Viral haemorrhagic fevers other than Dengue World Wide Influenza Atypical pneumonia URTI/viral infection STI including acute HIV infection UTI Pyelonephritis

22. MalariaDengue Fever Typhoid Fever Hepatitis A DefinitionProtozoa 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 (G- bacillus), 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 TransmissionMosquito vector, transfusion, vertical, needlestick ‘Aedes’ mosquitoesFaecal-oral route, complicated by asymptomatic typhoid (unknowing carriers) Faecal-oral route, DIFFERENTIALS

23. Symptoms and signs MalariaDengueTyphoidHepatitis A non-specific flu-like symptoms: headache malaise myalgia anorexia fevers (periodic) chills faints rigors initially jaundice hepatomegaly splenomegaly

24. Symptoms and signs MalariaDengueTyphoidHepatitis A non-specific flu-like symptoms: headache malaise myalgia anorexia fevers (periodic) chills faints rigors initially jaundice hepatomegaly splenomegaly fever headache myalgia abdominal pain nausea vomiting diarrhoea rash

25. Symptoms and signs MalariaDengueTyphoidHepatitis A non-specific flu-like symptoms: headache malaise myalgia anorexia fevers (periodic) chills faints rigors initially jaundice hepatomegaly splenomegaly 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 bradycardia lymphadenopathy splenomegaly

26. Symptoms and signs MalariaDengueTyphoidHepatitis A non-specific flu-like symptoms: headache malaise myalgia anorexia fevers (periodic) chills faints rigors initially jaundice hepatomegaly splenomegaly 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 bradycardia lymphadenopathy splenomegaly fever malaise anorexia nausea arthralgia abdominal pain diarrhoea itching jaundice hepatomegaly splenomegaly

27. Jenny’s symptoms and signs MalariaDengueTyphoidHepatitis A non-specific flu-like symptoms: headache malaise myalgia anorexia fevers chills faints rigors jaundice hepatomegaly splenomegaly fever headache myalgia abdominal pain nausea vomiting diarrhoea rash fever malaise headache abdominal pains dry cough constipation or diarrhoea rose spots on trunk bradycardia lymphadenopathy splenomegaly fevers malaise anorexia nausea arthralgia abdominal pain diarrhoea itching jaundice hepatomegaly splenomegaly

28. Fever in the tropical traveller <14 days14 days – 6 weeks> 6 weeks undifferentiated fever Malaria Typhoid Leptospirosis Dengue fever Rickettsiae Acute HIV infection 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 fever with CNS signs Viral/bacterial meningitis + encephalitis East African Trypanosomiasis Poliomyelitis East African Trypanosomiasis Rabies fever with chest signs Influenza Legionellosis Q fever Acute histoplasmosis SARS Tuberculosis Q fever Tuberculosis

29. 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

30. Incubation Periods MalariaDengueTyphoidHepatitis A P. falciparum 6-21d (typically 7-10d) P. vivax 10-17d P. ovale 10-17d P. malariae 18-40d 3-14 days3-21 days2-6 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 daystypically 28 days

31. MalariaDengue Fever Typhoid Fever Hepatitis A DefinitionProtozoa parasite.RNA flavivirusBacterial infectionHepatits A virus (HAV) Mode of TransmissionMosquito vector, transfusion, vertical, needlestick ‘Aedes’ mosquitoesFaecal-oral route, complicated by asymptomatic typhoid (unknowing carriers) Faecal-oral route, Incubation period P. falciparum 6-21d (typically 7-10d) P. vivax 10-17d P. ovale 10-17d P. malariae 18-40d 3-14 days3-21 days2-6 weeks Signs and Symptomsnon-specific flu-like symptoms: headache malaise myalgia anorexia fevers (periodic) chills faints rigors initially jaundice hepatomegaly splenomegaly 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 bradycardia lymphadenopathy splenomegaly fever malaise anorexia nausea arthralgia abdominal pain diarrhoea itching jaundice hepatomegaly splenomegaly DIFFERENTIALS

32. 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. STRAINS OF MALARIA

33. THE MALARIAL CYCLE 1) MOSQUITO VECTOR 2) EXTRA- ERYTHROCYTIC 3) ERYTHROCYTIC PHASE

34. 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 Malarial Immunology

35. Investigations of a Returned Traveller

36. MalariaDengue FeverTyphoid FeverHepatitis A DefinitionProtozoa parasite.RNA flavivirusBacterial infectionHepatits A virus (HAV) Mode of TransmissionMosquito vector, transfusion, vertical, needlestick ‘Aedes’ mosquitoesFaecal-oral route, complicated by asymptomatic typhoid (unknowing carriers) Faecal-oral route, Incubation period P. falciparum 6-21d (typically 7-10d) … 3-14 days3-21 days2-6 weeks Signs and symptoms non-specific flu-like symptoms: headache malaise myalgia … fever headache myalgia abdominal pain nausea … fever (progresses slowly) malaise headache abdominal pains … fever malaise anorexia nausea arthralgia … Ix and Common Findings Basic principles: Parasite = microscopy Bacteria = culture Virus = serology Thick and Thin Blood films Serology (e.g. arbovirus serology) and PCR studies Cultures - bone marrow, blood, stool, urine - bone marrow culture has highest yield Serology for anti HepA IgM DIFFERENTIALS

37. Jenny’s Ix Findings FBE ◦ HB 110, WCC 7.0, Plt 110 ◦ HB 100, WCC 7.3, Plt 90 ◦ HB 90, WCC 7.2, Plt 96 ◦ HB 95, WCC 7.2, Plt 115 UECs ◦ Na 140, K 4.0, Ur 7.0, Cr 110 LFTs ◦ Mildly elevated ALT and bilirubin, otherwise normal Atypical pneumonia - Legionella, Chlamydia species, Mycoplasma pneumoniae, Pneumocystis jiroveci serology - pending CXR - clear Malarial Thick and Thin Film ◦ Negative ◦ Positive for plasmodium falciparum, parasite count 0.2% ◦ parasite count 0.1% ◦ parasite count 0% Hep A serology - Total Ab positive, IgM negative Hep B serology - Surface Antibody positive, surface negative Arbovirus (dengue) serology - negative HIV serology - negative Pregnancy Test - negative

38. Malarial Thick and Thin Blood Films 3 thick and thin smears 12-24hrs apart should be obtained Highest yield of peripheral parasites occurs during or soon after a fever spike; however smears should not be delayed to await a fever spike. Thin Films - qualitative (speciation) Thick Films - quantitative (parasite count)

39. Determining types of malaria Histological Differences

41. Slides Plasmodium falciparum P vivax P ovale P malariae Normal

42. Epidemiology and Risk Factors of Malaria

43. Incidence 3 billion people (1/2 world’s population) living in areas at risk 1-2 million deaths per year 5 th most common cause of death from infection worldwide 2 nd most common cause of death from infection in Africa

44. Where malaria occurs Most countries in the tropics 107 countries

45. Transmission patterns Stable transmissionUnstable transmission FluctuationYear round infectionLower levels of infection Climate Warmer conditions Less seasonal variation Closer to the equator Temperature a bit cooler Climate varies with season Clinical manifestation Children affected the most Mostly asymptomatic in adults Symptomatic disease occurs at all ages ImmunityHighLow EpidemicUnlikelyLikely Efficiency of mosquitoEfficient vectorInefficient vector Main parasiteP. falciparumP. vivax Social and Economic Toll Cost to individuals Cost to government

50. 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

51. Treatment of Malaria

52. Treatment Many different antimalarials The decision of which to use is dependent on:  Setting of treatment: remote region with fewer resources  The resistances of the parasite  Individual: age, pregnancy status  Cost

53. Antimalarials Prophylaxis Atovaquone + Proguanil Doxycycline Mefloquine Treatment Artemesinin and derivatives Quinine salt + Doxycycline or Clindamycin Chloroquine - Resistance - Less expensive - P. ovale, P. vivax, P. malariae Treatment Artemisinin and derivatives Atovaquone + proguanil Quinine salt + Doxycycline or Clindamycin

54. Prophylaxis 1. Atovaquone + proguanil DailyStart 1-2 days before, stop 7 days after 1. DoxycyclineDailyStart 2 days before, stop 4 weeks after 1. MefloquineWeeklyStart 2-3 weeks before, stop 4 weeks after Doxycycline: oesophagitis, photosensitivity, thrush Mefloquine: contraindicated in: neuropsychiatric disorders, epilepsy, cardiac conduction defects Prophylaxis not always effective Prophylaxis Atovaquone + Proguanil Doxycycline Mefloquine

55. Australian Therapeutic Guidelines Uncomplicated P. falciparum Oral therapy 1. Artemether + lumefantrine 2. Atovaquone + proguanil 3. Quinine sulphate + Doxycyline Or Clindamycin (pregnancy & chidren) Treatment Artemisinin and derivatives Atovaquone + proguanil Quinine salt + Doxycycline or Clindamycin

56. Severe malaria Altered conscious state Jaundice Oliguria Severe anaemia or hypoglycaemia Parasite count >2% of RBCs Acidotic

57. Australian Therapeutic Guidelines Severe P. falciparum IV therapy 1. Artesunate 2.4mg/kg on admission Repeat at 12hr, 24hr, then once daily 2. Quinine dihydrochloride Loading dose, then maintenance dose Treatment Artemisinin and derivatives Atovaquone + proguanil Quinine salt + Doxycycline or Clindamycin

58. Complications of Malaria

59. 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

60. 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

61. 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

62. 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/  L) Hb <5g/L Creatinine >265  mol/L Malaria pigment >5% neutrophils Complicating infection DIC >20% of parasites are mature trophozoites or shizonts

63. The main criteria for poor prognosis: The species of Malaria: P. Falciparum The number of parasites: >5% of RBCs

64. Pre-Travel Advice

65. Traveller’s Advice Risk assessment Administer vaccinations Malaria prevention Essential preventive behaviours

66. Risk assessment: 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

67. Administer Immunisations – Routine vaccinations – Travel vaccinations

68. Malaria Prevention

69. Essential preventive behaviours 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

70. OBJECTIVES RED FLAGS ◦ Rigors = hospital admission HOW TO TAKE A HISTORY IN A RETURNED TRAVELLER ◦ Afebrile doesn’t rule out infection MALARIA ◦ Diagnosis ◦ Pathophysiology ◦ Management COUNSELLING A PROSPECTIVE TRAVELLER