Malaria and travellers health. Dr Behzad (Baz) Nadjm
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1 Malaria and travellers health Dr Behzad (Baz) Nadjm
2 Outline of talks Malaria 101 Developments in treatment Cases throughout
3 Ms C M 30 Yr Old Arrived from Cameroon 2 weeks ago Forestry research Feeling unwell 4-5 days Fevers, sweats, vomiting
4
5 Ms C M 30 Yr Old Arrived from Cameroon 2 weeks ago Forestry research Feeling unwell 4-5 days Fevers, sweats, vomiting
6 O/E Temp 39 9 C GCS 10, localising pain Tachycardic, tachypnoeic, not shocked No meningism, no rash, no focal CNS signs Jaundiced Very dark urine
7 Investigations Haem Chem Hb 95 Na 129 WCC 5.5 K 4.1 PLT 56 Ur 6.1 PT 1.1 Cr 91 ABG ph 7.43 po pco BE - 5.6
8 Differential Diagnosis Malaria (falciparum) Meningoencephalitis Enteric fever Other bacterial sepsis +/- Cerebral venous sinus thombosis African Trypanosomiasis VHF
9 Thick Film Parisitaemia 1% with schizonts
10 Initial Management Admitted to HDU Fluid rehydration IV quinine, loading dose given
11 Clinical Course Parasitaemia rose to 15% overnight Remained haemodynamically stable Urea and Creatinine rose, but good urine output maintained Hb dropped to transfused
12 By 48 hrs Clinical Course Parasitaemia down to 0.4% Acidosis improving GCS But QTc up to 480msec - responded to IV Mg 2+ By 72 hrs Bili up to 180 Creat improving Remained febrile
13 Clinical Course Doxycycline added on day 3, Parasites cleared by day 4 Discharged after 6 days
14 Points for Review Severe disease & low parasitaemia Parasite count rise despite adequate therapy Reduced GCS and AKI early complications
15 Severe Malaria in Adults requiring ICU: Marks et al. BMC ID 2013
16 Marks et al. BMC ID 2013
17 5 species Malaria Plasmodium falciparum P. vivax & P ovale P malariae P knowlesii Broad spread throughout tropics & sub tropics Transmission by female anopheles mosquito
18 18
19 With thanks to Tom Doherty
20 Pf schizont
21 Falciparum malaria 0.5 1m deaths annually worldwide Significant mortality in returning travellers Prophylaxis highly effective against P falciparum Pathogenesis multifactorial Infection of all ages of RBC Rosetting & sequestration Altered rheology of infected/uninfected cells Cytokine driven pathology
22 Symptoms/signs Fever and / or Rigors Headache Myalgia N & V Arthralgia Dark Urine Cough Diarrhoea Drowsiness Confusion
23 Diagnosis blood films
24 Diagnosis Rapid Diagnostic Tests
25 Classification severe disease Any one of Neurological dysfunction Severe anaemia Acidosis Renal failure Hypoglycaemia ARDS/pulmonary oedema Bleeding/DIC Blackwater fever Shock Parasitaemia >10% (2% or peripheral schizonts for IV) (Pregnancy) (Elderly)
26 Treatment severe disease Artesunate Survival advantage over quinine Quinine Remains the mainstay of treatment in Africa Second agent in all cases (ACT, doxycycline, clindamycin) No patient should wait untreated for artesunate
27 General management Liaise with specialist centres early Avoid over-filling Monitor blood glucose (2hrly during infusion) Broad spectrum antibiotics if shock/other evidence of bacterial infection Appropriate level of care
28 Pitfalls I lived there/had malaria before, I m immune I thought he had flu/gastroenteritis/hepatitis/meningitis He was in for a broken leg We were waiting for quinine/artesunate/a monitored bed Elderly
29 Non-severe Pf (UK) Artemether-lumefantrine DHA-piperaquine Atovaquone-proguanill Oral quinine sulphate for 5-7 days plus doxycycline or clindamycin for 7 days
30 P. vivax & P. ovale: P. vivax - Asia, South America P. ovale - West & Central Africa P. ovale curtisi P. ovale wallikeri Benign disease - parasitaemia never > 2% Relapsing malaria Hypnozoites - dormant liver stage
31 With thanks to Tom Doherty
32 P. vivax & P. ovale: P. vivax - Asia, South America P. ovale - West & Central Africa P. ovale curtisi P. ovale wallikeri Benign disease - parasitaemia never > 2% Relapsing malaria Hypnozoites responsible for relapses
33 Flower et al Lancet 2011
34 P. malariae: Least common Never causes severe disease May persist for decades Rare cause of nephrotic syndrome
35 P. knowlesi Borneo & SE Asia Zoonosis (macaques) 24 hour erythrocytic cycle Can cause severe disease
36 Treatment of benign malaria: P. vivax & ovale: Chloroquine + Primaquine (hypnozoites) (Primaquine causes haemolysis with G6PD) P. malariae & P. knowlesi Chloroquine alone.but anything will do
37 Case 32 year old man No previous medical history Fever, lethargy, dyspnoea, ankle swelling 4 months backpacking in Togo, West Africa Jarvis et al. Lancet 2013
38 Case Episode of malaria diagnosed in Togo 15d ago Hb 130g/L Artemether IM x 3days plus 3 days DHA-PQ Symptomatic response
39 Case 2 days later Fever, dyspnoea, ankle swelling Hb 110g/L 3 days deterioration Hb dropped to 70g/L IV Ofloxacin + PO Doxycycline Evacuated to HTD
40 Case On Arrival 38.5C Tachycardic, jaundiced, pale, hepatosplenomegaly Brown urine Hb 41g/L WCC 4.2x10 9 /L Plt 112x10 9 /L Haemoglobinuria on dip
41 Case reticulocytes, bilirubin, LDH Haptoglobin Malaria HRP2 test pos, malaria slides neg No haemoglobinopathy, normal G6PD Direct coombs test negative Normal Iron, B12, Folate
42 Case Full infection screen negative Bone marrow erythroid hyperplasia No auto-antibodies/agglutinins etc PET scan unremarkable
43 Case Diagnosis Post artemisinin delayed haemolysis 4 blood transfusions over 6 days Haemolysis spontaneously resolved Jarvis et al. Lancet 2013
44 Post Artemisinin Delayed Haemolysis Now well described Occurs 7-14 days after parenteral artemisinin therapy Probably relates to pitting of erythrocytes infected with young rings stages However unclear why anaemia can be refractory to transfusion InjectableArtesunateExpertGroupMeeting.pdf
45 Post Artemisinin Delayed Implications: Haemolysis Lifesaving benefit outweighs risk Consider check Hb 2 weeks post artesunate (UK guidance)
46 Artemisinin Resistance
47 Early Signs 28 day treatment success 79% in Eastern Thailand (2003) Similar reports from Western Cambodia Vijaykadga et al Trop Med Int Health 2006 Denis et al Trop Med Int Health 2006
48 Dondorp et al NEJM 2009
49 Image Credit: BBC News
50 Dondorp et al NEJM 2011
51 Artemisinin Resistance Difficult to track Required clinical studies Refined by quantitative PCR Possibility of genetic markers Kelch protein on Chromosome 13 K13-propellor mutations Currently confined to SEA 51
52 Artemisinin Resistance Implications Severe malaria Few Non-severe malaria Longer course of ACT? TACT (Triple ACT DHAP- MQ)? New drugs
53 New Drugs Cipargamin (KAE 609) Tafenoquine
54 Cipargamin Under development by Novartis Completed Phase 2 studies in Thailand Very rapid clearance of Pf & Pv infections No safety issues as yet White et al NEJM 2014:371 (5)
55 Tafenoquine Under development by GSK Single dose treatment of hypnozoites Similar problems as primaquine Undergoing phase 3 trials
56 Any Questions?
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