25/10/2017. Summary. Mosquito-borne Diseases. Malaria The Disease 1. Malaria The Disease. Malaria The Disease. Malaria Flaviviruses.

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Summary Mosquito-borne Diseases Dr Bernie Hudson Microbiology & Infectious Diseases, Royal North Shore Hospital, Sydney A/Professor, James Cook University, Townsville Malaria Flaviviruses Dengue

1 Summary Mosquito-borne Diseases Dr Bernie Hudson Microbiology & Infectious Diseases, Royal North Shore Hospital, Sydney A/Professor, James Cook University, Townsville Malaria Flaviviruses Dengue Japanese Encephalitis Yellow Fever Zika Alphaviruses Chikungunya Malaria The Disease 1 Protozoan genus Plasmodium: 5 species infect humans: Life cycle Malaria The Disease Species Predominance Disease Prevalence globally Characteristics P. falciparum Africa Most severe Highest Highest mortality P. vivax Asia Severe High (esp. in Australian cases) Relapse cycles P. ovale Africa Severe Low Relapse cycles P. malariae Global Mild Low Long dormant periods P. knowlesi South-East Asia Severe Normally found in macaques Can infect humans Transmitted by bite of infected female Anopheles mosquitoes Adapted from: Centers for Disease Control (CDC): Malaria Biology. (accessed April 2014) 1. Centers for Disease Control and Prevention (CDC) Malaria Malaria The Disease 1 Types of disease Malaria The Disease Acute febrile illness UNCOMPLICATED SEVERE All symptoms are triggered by Plasmodium s asexual development stage in erythrocytes Plasmodium species dependent characteristics: Attack cycles (2 or 3 days) Incubation period from 7 days (P. falciparum) to 30+ days (P. malariae may be years) Relapses caused by dormant liver stages of P. vivax and P. ovale (after months or years) Attacks consisting of cold, hot and sweating stage Frequency of attacks depends on the parasite species General symptoms: Fever Chills Sweats Headaches Nausea, vomiting, diarrhoea Body aches General malaise Additional symptoms: Splenomegaly Mild jaundice Enlargement of the liver Increased respiratory rate Infections complicated by serious organ failures or abnormalities Severe disease symptoms often are medical emergencies Manifestations include: Cerebral malaria Hemoglobinuria Abnormal behaviour Acute respiratory distress syndrome Seizures Low blood pressure due to Coma cardiovascular collapse Severe anemia Acute kidney failure High risk groups to develop severe disease when infected: Children Pregnant women Elderly Travellers Late onset (especially in non-endemic countries) can lead to misdiagnosis 1. Centers for Disease Control and Prevention (CDC) Malaria 5 Adapted from the Centers for Disease Control and Prevention (CDC) :Malaria Disease 6 1

Epidemiology in Australia Malaria in Travellers >600,000 Australians travel to malaria endemic countries each year 1 400-600 Australian cases of imported malaria are reported annually (414 cases in

Yung et al, Manual of Travel Medicine 3rd ed 2011 IP Communications 2. National Notifiable Disease Surveillance System, http://www9.health.gov.au/cda/source/rpt_3_sel.

especially between dusk and dawn C: Take anti-malarial drugs (Chemoprophylaxis) when appropriate, to prevent infection from developing into clinical disease D: Immediately seek Diagnosis & treatment

Protection against vectors Avoidance of outside activities between dusk and dawn Insect repellent Mosquito nets - Permethrin impregnated Protective clothing - Long and light-coloured - Permethrin

2 Epidemiology in Australia Malaria in Travellers >600,000 Australians travel to malaria endemic countries each year Australian cases of imported malaria are reported annually (414 cases in 2013) 2 Estimated 1.5/1000 Australian travellers develop malaria 1 (endemic country travel) Non-immune travellers from malaria-free areas are very vulnerable to the disease 1 1. Yung et al, Manual of Travel Medicine 3rd ed 2011 IP Communications 2. National Notifiable Disease Surveillance System, accessed 25/3/ WHO The ABCD of malaria prevention 1 A: Be Aware of the risk, incubation period, possibility of delayed onset, and the main symptoms B: Avoid being Bitten by mosquitoes especially between dusk and dawn C: Take anti-malarial drugs (Chemoprophylaxis) when appropriate, to prevent infection from developing into clinical disease D: Immediately seek Diagnosis & treatment if a fever develops 1 week or more after entering an area where there is a malaria risk and up to 3 months (or, rarely, later) after departure from a risk area Personal Protective Measures (PPM) 1,2 Protection against vectors Avoidance of outside activities between dusk and dawn Insect repellent Mosquito nets - Permethrin impregnated Protective clothing - Long and light-coloured - Permethrin impregnated Image source: Use of insecticide aerosols in rooms before retiring at night 1. World Health Organization (WHO). International travel and health Geneva 9 1. World Health Organization (WHO). International travel and health Geneva 2. Yung et al, Manual of Travel Medicine 3rd edition 2011 IP Communications 10 Repellents Pros & Cons Repellent Advantages Disadvantages DEET (N,N-diethyl-3- methylbenzamide) Icardin (piperidine derivate) EBAAP (ethylbutylacetylaminopropionate) Citriodiol (made from Eucalyptus/Corymbia citrodora oil) Mosiguard Natural oils (Citronella, Neem etc) Widely used and tested; effective; 20% protects for >5 hrs 19.2% prep. similar protection to DEET; best against An. gambiae ; Less irritating than DEET Mean duration of protection 23 minutes; good cosmetic properties 96% protection for up to 4 hours; plant based repellent, well tolerated Field trials as good as 15-20% DEET Bio -well accepted May damage fabrics and plastics Inter-individual variation Variation in efficacy Inter-individual variation; only recommended natural product (CDC) (very) short protection duration 11 Drug Mechanism of Action Based on stages of the Plasmodium life cycle RELAPSE CAUSAL 1 DORMANT 1 P. vivax & P. ovale Primary liver phase hypnozoites in liver Atovaquone-Proguanil Primary attack Dormant stage Primaquine Primaquine Proguanil (Limited: Doxycycline) SUPPRESSIVE 1 Erythrocytic cycle Atovaquone-Proguanil Chloroquine Doxycycline Recrudescence Mefloquine Proguanil Adapted from: The Centers for Disease Control (CDC): Malaria biology ndex.html (accessed April 2014) 1. Yung et al, Manual of Travel Medicine 3rd ed 2011 IP Communications 12 2

Adult dosing Chemoprophylaxis Palette* Adult dosing Dosage of Chemoprophylaxis* Options against P.

Chloroquine 300 mg weekly + Proguanil 200 mg daily Primaquine 30 mg base daily 1-6 *No malarial prophylaxis gives complete protection.

Lariam Product Information 2. Vibramycin Product Information 3. Doxylin Product Information 4. Malarone Product Information 5.

Malarone Product Information 2. World Health Organization: International Travel and Health, 2012 edition 3. Vibramycin Product Information 4. Doxylin Product Information 5.

3 Adult dosing Chemoprophylaxis Palette* Adult dosing Dosage of Chemoprophylaxis* Options against P. falciparum (in chloroquine resistant areas) 1-6 Mefloquine mg weekly Doxycycline 2,3 100 mg daily Malarone 4 (Atovaquone/Proguanil) 250mg/100mg daily 2-4, 6 2,5,6 Alternatives include 5,6 : Chloroquine 300 mg weekly + Proguanil 200 mg daily Primaquine 30 mg base daily 1-6 *No malarial prophylaxis gives complete protection. Chemoprophylaxis should be prescribed with bite prevention measures 2,6 *No malarial prophylaxis gives complete protection. Chemoprophylaxis should be prescribed with bite prevention measures 1. Lariam Product Information 2. Vibramycin Product Information 3. Doxylin Product Information 4. Malarone Product Information 5. Centers for Disease C ontrol (CDC) Health Information for International Travel 2014: The Yellow Book 6. Yung et al, Manual of Travel Medicine 3rd ed 2011 IP Communications Malarone Product Information 2. World Health Organization: International Travel and Health, 2012 edition 3. Vibramycin Product Information 4. Doxylin Product Information 5. Lariam Product Information 6. Centers For Disease Control (CDC), Health Information for International Travel 2014 : The Yellow Book 14 Compliance is Important Non-compliance increases risk of infection 2- to 4-fold 1 Rate varies between 30-70% of travellers 1 Factors that affect compliance include 1,2,3 : Complexity of regime Duration of therapy Side effect profile The length of post-travel regimen has a significant impact on compliance 3 Chemoprophylaxis Comparative overview Dosing Malarone 1 (Atovaquone-Proguanil) Doxycycline 2,3 Lariam 4 (Mefloquine) Pre-trip Daily, 1-2 days before Daily, 1-2 days before Weekly, 2 weeks before Trip Daily Daily Weekly Post-trip Daily for 1 week Daily for 2-4 weeks* Weekly for 2-4 weeks* Paediatric use Presentations available in Australia Paediatric formulation available, Indicated for use in children >11 kg** 12 Tablet pack (250/100 mg) 24 Tablet pack (250/100 mg) 12 Tablet pack Junior (62.5/25mg) No paediatric formulation available, Indicated for use in children >8 years 7 Tablet pack (100 mg) 25 Tablet pack (50 mg) No paediatric formulation available, Indicated for use in children >14 years & 45 kg** 8 Tablet pack (250 mg) *Recommendations vary for duration of post-trip prophylaxis (between 2-4 weeks). 2-6 The latest advice from the WHO and CDC is that doxycycline and mefloquine be taken for 4 weeks after leaving a malaria endemic area. 5,6 1. Yung et al, Manual of Travel Medicine 3rd ed 2011 IP Communications 2. Aurelie MA et al. J Travel Med 2010; 17: Goodyer J et al. Journal of Travel Medicine 2011; Volume 18 (4): 245 2, Malarone Product Information 2. Doxylin Product Information 3. Vibramycin Product Information 4.Lariam Product Information 5. World Health Organization: International Travel and Health, 2012 edition 6. Centers For Disease Control (CDC), Health Information for International Travel 2014 : The Yellow Book 16 Duration of use Malarone Prophylaxis of Plasmodium falciparum malaria Start 1-2 days before leaving Once a day whilst in endemic country Once per day for one week after leaving endemic area Newer data Only take for 1 day after leaving malaria area Intermittent dosing Needs validation 87% of 485 travellers* stopped Malarone 1 day after leaving malaria area None developed malaria How long does Malarone prophylaxis need to be taken post-exposure?? *cumulative exposure 4,979 days In clinical trials of prophylaxis Subjects received Malarone for up to 12 weeks But many countries have no upper limit on duration Malarone Product Information 17 3

4 Doxycycline Prophylaxis Chemoprophylaxis Efficacy (U.K.) Prophylaxis Many rickettsial infections GI infections - some, not all Post-exposure prophylaxis Scrub typhus - 100mg stat Leptospirosis mg stat Doxycycline and the gastrointestinal system Microbial flora upset MDR GUT bacteria risk Weight gain on doxycycline Risk of P falciparum by Chemoprophylaxis Expressed as Rate/100,000 Prescriptions Atovaquone/proguanil * Doxycycline * Mefloquine * *If VFRs excluded Zuckerman J TMID Nov 2009 Angelakis E. AAC Long term doxycycline Chemoprophylaxis v. Standby Emergency Treatment (SBET) SBET & antimosquito measures rather than chemoprophylaxis If APR < 10/1000 Stand by Treatment Options Lariam 3 tabs, then 2 tabs + artesunate 100mg stat, then 50mg bd 5 days Malarone (atovaquone 250mg + proguanil 100mg) 4 tabs/day 3 days Riamet (artemether + lumefantrine) 4 tabs bd for 3 days GOLD STANDARD = ACT (artemether combination therapy) 11 November 2003 NOVARTIS 24 4

5 Sent Home from ED 1000 hours Represented to ED 2300 hours same day Arboviruses & Travel Many Not detected or considered or readily available test Illness not characterised Flaviviruses Dengue Japanese Encephalitis West Nile Yellow Fever Zika Alphaviruses Chikungunya 5

JE The Disease Japanese Encephalitis Flavivirus Mosquito-borne Perspective Clinical illness very rare in travellers Prevention Vaccine efficacy good Immunity Mosquito avoidance JE The Disease

Neurological sequelae: 40-80% Complete recovery: 10-15% Source: CDC. Yellow Book 2014, Japanese Encephalitis JE Vaccine: Which Travellers?

season, or anticipated to be repeated, and/or where there is considerable outdoor activity, and/or accommodation is not mosquito-proof More than 1 year in Asia (except Singapore) even if much of the

6 JE The Disease Japanese Encephalitis Flavivirus Mosquito-borne Perspective Clinical illness very rare in travellers Prevention Vaccine efficacy good Immunity Mosquito avoidance JE The Disease Japanese Encephalitis: Risk Areas Many cases asymptomatic Very rare in travellers Very rare in expats (but OH&S) Annual global incidence 15,000 / year Case fatality: 10-30% Long term disability: 30% Neurological sequelae: 40-80% Complete recovery: 10-15% Source: CDC. Yellow Book 2014, Japanese Encephalitis JE Vaccine: Which Travellers? Recommended for travellers 1 year old: More than 1 month in rural areas of high-risk countries in Asia and Papua New Guinea Consider vaccination for shorter term travellers, particularly in the wet season, or anticipated to be repeated, and/or where there is considerable outdoor activity, and/or accommodation is not mosquito-proof More than 1 year in Asia (except Singapore) even if much of the stay is in urban areas All travellers should take appropriate measures to avoid mosquito bites Balance rare illness v. catastrophic outcomes cf recent Australian cases, UK cases, push for more vaccination 1. NHMRC. The Australian Immunisation Handbook, 10th Edition,

JE vaccines Imojev Live attenuated chimeric vaccine using yellow fever virus backbone Single dose IM (protective Abs @ 14 days) Jespect Vero cell cultured, inactivated vaccine 2 doses IM: day 0,

Brasil, others) Mosquito transmitted Flavi-Virus Monkey reservoir Jungle - urban Africa, South & Central America, T&T Not Asia Yellow Fever Vaccine Self-Protection active areas International

7 JE vaccines Imojev Live attenuated chimeric vaccine using yellow fever virus backbone Single dose IM (protective 14 days) Jespect Vero cell cultured, inactivated vaccine 2 doses IM: day 0, 28 (or 0,7) All year Transmission Seasonal Transmission Source: WHO International Travel & Health Yellow Fever Yellow Fever Globally - 200,000 cases/year Outbreaks in (Angola, Brasil, others) Mosquito transmitted Flavi-Virus Monkey reservoir Jungle - urban Africa, South & Central America, T&T Not Asia Yellow Fever Vaccine Self-Protection active areas International regulations WHO & CDC advise for return from active areas Many countries insist on the old endemic zone Receptive countries cautious WHO now advises 1 dose = lifelong protection No boosters required 7

Contraindications Allergy egg, polymixin, neomycin < 6, 9 or 12 (?4) months of age Cancer, immunosuppressed, Pregnant HIV (< 200 CD4) Thymic Disorders (ever) Risk of YF vs.

8 Contraindications Allergy egg, polymixin, neomycin < 6, 9 or 12 (?4) months of age Cancer, immunosuppressed, Pregnant HIV (< 200 CD4) Thymic Disorders (ever) Risk of YF vs. Risk of YFV Yellow Fever - Vaccine Deaths Non-allergic causes related to complications of the (usual) YFV strain viraemia Viscerotropism (YF-AVD or MSOF) Neurotropism (YF-AND) YFV Serious AE risk increases with age 7.5 /100,000 aged 70 years or more 4 /100,000 aged years age Not Immunocompromised Not seen with booster doses Yellow Fever Vaccine Risk YFV - Risk of YF v. Risk of YFV Get up to date data on active transmission (lags) Change itinerary or even go somewhere else Exemption/Waiver Certificate Age > 60 years & Low Risk Travel But if risk significant - may still need YFV Anaphylaxis rate: 1/130,000 Summary: Biologics Compared re Infections Agent/ Condition Mode of TB Action Screen Live* Vaccines Killed # Vaccines TNF Inhibitors IL-1 Inhibitors anti-tnf anti-il1 Bacterial, Granulomatous, Intracellular, Viral Yes No Yes Bacterial, Granulomatous, Intracellular, Viral Yes No Yes Arbovirus General Rituximab CD20, B cells Bacterial, HBV, Other viral?no No Yes Abatacept CD86,80,28T cells Bacterial, Granulomatous, Intracellular, Viral Yes No Yes Newer agents Various???? No Spectrum may change with more usage *Avoid for > 3mths after cessation of biologic; #Reduced Ig response to Killed Vaccines 8

9 Incubation periods up to 14 days May be itchy NO aspirin or NSAIDs until dengue excluded 9

10 Dengue 10

Dengue Practice Points Incubation Period Usually 3-7 days, maximum 14 days 4 serotypes, immunity after infection only to that serotype Underdiagnosed Serology can takes 4 weeks to become (+) Antigen

recommended for travellers yet Advice if Dengue serology (+) Risk of DHF (?

humans Nigeria then 1950s-80s tropical Africa, SEAsia, India Zika Zika Practice Points Brasil outbreak Guillain-Barre (as in French Polynesia0 Foetal abnormalities (microcephaly) Causal association 1

11 Dengue Practice Points Incubation Period Usually 3-7 days, maximum 14 days 4 serotypes, immunity after infection only to that serotype Underdiagnosed Serology can takes 4 weeks to become (+) Antigen test (NSA) makes diagnosis easier Most get better, but post-infection fatigue common Haemorrhagic Fever is rare (NO ASPIRIN/NSAIDs) Be aware of warning signs early referral Vaccine developed but not recommended for travellers yet Advice if Dengue serology (+) Risk of DHF (?lifelong) Cuban experience DHF (17yrs), but can get DHF with 1 o infection Consider also Zika & Chikungunya, and co-infection Zika First detected in 1947 (monkeys in Ziika Forest Uganda), then 1954 humans Nigeria then 1950s-80s tropical Africa, SEAsia, India Zika Zika Practice Points Brasil outbreak Guillain-Barre (as in French Polynesia0 Foetal abnormalities (microcephaly) Causal association 1 st & 2 nd trimestre likely highest risk to foetus 3 rd trimestre, congenital clinical foetal illness Up to 2 years of age, neural progenitor cells still developing (?avoid travel) Incubation period usually 2-7 days (range 3-14 days) Pregnancy RANZCOG guidelines WHO, CDC Guidelines Conception after exposure women 8 weeks, males 6 months Sexual transmissible Partners travelling back from endemic areas (6 months in semen) Prevention Avoid travel Mosquito avoidance 11

Chikungunya Chikungunya Diagnosis Chikungunya Rash Itchy

not cause itchy rash except scabies, larva migrans & some

monkeys 1952-53 Makonde Plateau, Tanzania That which bends

days, range 1-12 days Arthritis often prominent Chronic

following Chikungunya Strong family history of

12 Chikungunya Chikungunya Diagnosis Chikungunya Rash Itchy Reunion: 20% Kerala : 80% Beware the rule infections do not cause itchy rash except scabies, larva migrans & some others Chikungunya Practice Points First isolated from monkeys Makonde Plateau, Tanzania That which bends up (Makonde or Swahili word) Incubation period usually 2-4 days, range 1-12 days Arthritis often prominent Chronic arthritis may supervene Rheumatoid arthritis has developed following Chikungunya Strong family history of rheumatological illness Avoid travel Prevention Avoid travel Mosquito avoidance 12

Symptoms of Malaria. Young children, pregnant women, immunosuppressed and elderly travellers are particularly at risk of severe malaria.

Symptoms of Malaria. Young children, pregnant women, immunosuppressed and elderly travellers are particularly at risk of severe malaria. Preventing Malaria 1 Malaria is the world s most prevalent parasitic disease, accounting for an estimated 216 million cases with 655,000 deaths annually. Many people acquire malaria during travel to tropical