Malaria Elimination Initiative Overview of Malaria Epidemiology and the Impacts of P. vivax Andrew Lover, MSc MPH PhD WHO Training Course On Malaria Elimination in The Greater Mekong Subregion August 2015 Chiang Mai, Thailand Agenda 1. General overview of malaria parasitology and epidemiology, including P. vivax Why? What biological and epidemiological features of P. vivax and P. falciparum favour or hinder elimination? Or, what factors influence influence malaria elimination? Vectors and parasites Human hosts Eco-geographical factors 2. Questions and discussion 2 2 3 Malaria burden estimates The Lancet (2012) 379, 41331 World Malaria Report, 2014 IHME: Deaths, global 1,238,000 [95% CI: 929,000 to 1,685,000] (2010) Deaths, outside of SSA 104,000 [45,000 to 191,000] (2010) WHO: Deaths, global 655,000 [95% CI: 539,000 to 906,000] (2010) 584,000 [95% CI: 367,000 to 755,000] (2013) 3 4 Background: the parasites Plasmodium falciparum- majority of global morbidity and mortality P. vivax- benign tertian P. malariae- less severe. P. ovale- Rare, also relapsing. (East Africa, Papua) P. knowlesi- monkey malaria, zoonosis in SE Asia P. cynomolgi- zoonosis in SE Asia (?) 4 P. vivax trophozoites (US CDC) 5 Plasmodium lifecycle (simplified) The Lancet, Why does malaria persist? Interconnected factors: biologic factors cultural factors socioeconomic factors environmental factors Barriers 6 Interconnected barriers to elimination 7 The vector Anopheles freeborni Eggs (1-2 days) Larvae (wigglers) Pupae (2-4 days) 8 400+ species of Anopheles; ~ 70+ can transmit malaria; are important vectors. 5-6 species complexes account for majority of global burden Eggs larvae pupae adult is ~ 7-10 days at the equator (but highly variable). After a blood meal, the vector rests this is the reason IRS is successful Major session later on entomology The vector 9 Incubation generally 7-14 days (up to 40+) Infection Acute febrile illness Asymptomatic or mild in people living in endemic regions Generally more severe in unexposed May be severe in P. falciparum and vivax malaria Relapses in vivax and ovale malaria (months to several years later) Human hosts 10 characterized by acute febrile attacks (malaria paroxysms) periodic episodes of fever alternating with symptom-free periods manifestations and severity depend on species and host immunity, nutritional status and genetics can develop severe complications (especially P. falciparum; P. vivax in some areas) Clinical picture Images from: Bruce-Chwatt, Rise and Fall of Malaria in Europe 11 Four key processes of Plasmodium in humans Process Host organ Host cellStages involvedDuration Dormancy (Pv and Po only) liverhepatocytehypnozoite Months to years; usually 5-18 months Exo-erythrocytic schizogony (all species) liverhepatocyte exo-erythrocytic schizont -> merozoite 6-15 days, depending on the species Erythrocytic schizogony (all species) blood red blood cell merozoite -> trophozoite -> schizont -> merozoite-> etc. a number of cycles, each of 2 or 3 days duration Gametocytogony (all species) blood red blood cell merozoite -> gametocytes (male and female) days/weeks Critical intervals for P. falciparum and P. vivax CharacteristicsP. falciparumP. vivax Prepatency (from inoculation to the appearance of microscopy detectable parasitaemia) 7-10 days11-13 days Incubation: short (from inoculation to the appearance of symptoms) 8-14 days10-21 days Incubation: long (from inoculation to the appearance of symptoms) Not applicable5-18-months Minimum time to appearance of mature gametocytes after the appearance of parasitaemia 12 days0 days Maximum time of disappearance of circulating gametocytes (after treatment with blood schizontocides) 8 weeks< 1 day Asexual cycle in the blood48 hours (tertian) Typical duration of untreated infectionOne year or less in about 80% of cases years (rarely, up to 5 years) Stable transmission Holoendemic Under-5 year Spleen rate >75% Under-5 year old Parasitaemia 60-70% Mortality highest in the 1st and 2nd year of life Anaemia most severe in early life Transmission is very high, but stable. Hyperendemic Under-5 year Spleen rate 50 to 70 % Under-5 year Parasitaemia 50 to 70 % Malaria more common in older children Seasonal and intense, but can still be considered stable. 14 Unstable transmission Mesoendemic Under-5 Spleen rate 20 to 50 % Under-5 Parasitaemia < 20 % Transmission is seasonal under normal rainfall Cerebral malaria common, infection tolerated well in adults Seasonal debilitation seen in all population groups Hypoendemic Under-5 Spleen rate 0 to 10% Under-5 Parasitaemia 0 to 10% Only periodic transmission following unusual rainfall Severe clinical outbreaks in children and adults, mortality high in all population segments 15 Alternative view High transmission = hyper- and holoendemic malaria (parasite prevalence in children aged 29 years > 50%), moderate transmission = mesoendemic malaria (parasite prevalence 1050%) low transmission = hypoendemic malaria (parasite prevalence < 10%). The threshold of 10% is generally used to characterize low transmission, but needs to be decided locally. WHO, Disease surveillance for malaria elimination: an operational manual Biological aspects related to human host Susceptibility to malaria is universal in humans. Only exception: People lacking the Duffy antigen on red cell surfaces are refractory to P. vivax. This genotype is widespread among Africans (especially West Africa) Therefore, a sufficient pool of susceptible individuals to vivax do not exist Thats why vivax transmission is limited in Africa 17 Some haemoglobinopathies (gene polymorphisms) offer some protection: Haemoglobin S (causing sickle cell disease) Thalassemias (alpha-thalassemia): missing genes that affect how the body makes hemoglobin. RBC weak and destroyed Ovalocytosis (oval-shaped blood cells) Glycose-6-phosphate dehydrogenase (G6PD) deficiency: the enzyme is important for red blood cell metabolism Most of these gene polymorphisms are linked to intensity of malaria transmission Biological aspects related to human host 18 Acquired malaria immunity Clinical immunity develops by age, but is poorly understood Offers partial protection Determines the clinical epidemiology in an area Strongly dependent on malaria exposure (transmission intensity) throughout life Clinical infections peak earlier in Pv Biological aspects related to human host 19 Complex immunology These curves are for stable high-transmission settings. 20 So, what does it look like in a community? Hyperendemic: Seasonally intense malaria transmission with disease in all age groups. Holoendemic: Perennial intense transmission with protective clinical immunity among adults Mesoendemic: Variable transmission that fluctuates with changes in one or many local conditions, e.g., weather or disturbance to the environment. Hypoendemic: Little transmission, and the effects of malaria on the community are unimportant. 21 A. Low endemicity B. Moderate endemicity C. High endemicity D. Hyperendemicity E. Epidemic Incidence by age and transmission level 22 How is everything related? adapted from Epi. Methods for the Study of Infectious Dis, 2001 Ross-Macdonald model where : N = size of human population M = size vector population m = M/N, number of mosquitoes per human host a = human biting rate (by single mosquito) b = transmission probability from infected An. to a human c = transmission probability from infected human to mosquito r = recovery rate in human hosts = daily mortality in Anopheles t = extrinsic incubation period (days) 23 Eco-geographical factors Historically, malaria was seasonal in the US, Northern Europe, the UK, Russia, and as far N as Finland. Range of Pf transmission Malaria Journal 2011, 10:378 25 Geographical factors Temperature The most important factor for mosquito and parasite (in mosquito) development Mosquitoes less sensitive to low temperatures than parasites anophelines can breed at temperature above 10 C where the lower threshold of sporogony is 16 C Lower threshold for P. vivax sporozoite development is 16 C, for P. falciparum it is 18C Optimum temperature for mosquito development is 25-27C and maximum is 40C Optimum temperature for parasite development is 27C Extremely high temperature is deleterious to vectors and parasites (38 C and above) Average daily temperature (ADT) is main meteorological indicator 26 27 Time for parasite development in vectors EMRO- Guidelines on the elimination of residual foci of malaria transmission, Duration (in days) = C / (average daily temperature B) Duration (in days) = C / (average daily temperature B) For example, at 19C, the development of P. vivax would take C / (19 B) = 105 / (19 14.5) = 23 days. C / (19 B) = 105 / (19 14.5) = 23 days. Only days with temperatures above the threshold (A) are counted, i.e. above 16C for P. vivax and above 18C for other species. P. vivax 28 29 But vivax malaria isnt serious Conventional wisdom P. vivax is not a major source of morbidity and contributes essentially no mortality. Recent data Can, and does, cause both severe disease and mortality. e.g. Village cohorts: Severe malaria occurred amongst 342 (6.1%) and 100 (6.2%) patients with P. falciparum and P. vivax mono-infections, respectively [OR 0.99; 95% CI: 0.78 to 1.24]. (PNG) 29 Lancet Infect Dis (2009) 9, 55566. Clin Infect Dis (2012) 55(8), e Clin Microbiol Rev (2013) 26(1), 30 New P. vivax technical strategy Am J Hyg (1950) 5(1), Why vivax and why now? Recent local transmission Singapore: 2009 (20 cases in three clusters) Greece: 2011 (20 cases); 2012 (40-70 cases); 2013 (several) Re-endemic South Korea: 2010 (1,721 cases); 2013 (440 cases) (North Korea): 2013 (~14,000 cases) Parasite evolution Evolving towards increased virulence Ann NY Acad Science (2015) 61 Evolving to invade into Duffy-negative populations PNAS (2010), 107(13), 59675971 Zoonosis(?) P. vivax has been found in multiple wild NHP populations Memrias do Instituto Oswaldo Cruz (2014), 109(5), 32 Severe Pv Case series: 20-27% of patients with severe malaria have PCR-confirmed vivax mono-infection (PNG, Indonesia, Thailand, India) Curr Opin Infect Dis (2009), 22, 4305. Retrospective cohorts: No difference in aOR for miscarriage in both asymptomatic Pf or Pv [2.7; 95% CI, 2.0 to 3.6] or symptomatic Pf or Pv [4.0; 95% CI, 3.1 to 5.1] in the first trimester, relative to uninfected women. (Thailand) Lancet Infect Dis (2012) 12(5), 38896 Village cohorts: Severe malaria occurred among 342 (6.1%) and 100 (6.2%) patients with P. falciparum and P. vivax mono- infections, respectively [OR 0.99; 95% CI: 0.78 to 1.24]. (PNG) Clin Microbiol Rev (2013) 26(1), 3657 32 Plasmodium vivax lifecycle 33 The Lancet, Lancet ID 2009 34 P. vivax- geographic range (2010, modeled) 34 PLoS Negl Trop Dis (2012) 6(9), e1814 Lancet Infect Dis (2004) 4(6), % of global population at risk, with ~ 132 million clinical cases per year. ? 35 Natural history of P. vivax 35 Mosquito exposure Parasitemia Clinical illness Resolution of symptoms Renewed symptoms? Pre-patent period Incubation period Relapse / Re-infection / Recrudescence Sub- patentcy Short latency type Long latency type Am J Hyg (1950) 5(1), 36 Conventional wisdom- what do we know? Vivax infections acquired in different parts of the world show striking differences in the duration of the incubation period and the occurrence of periods of latency. These differences have been broadly correlated with climactic zones. Essential Malariology, Prog Clin Parasitol. (1989) 1, 119. 37 Pv lagging control (Brazil) 37 Memrias do Instituto Oswaldo Cruz. 2014;109: 618633 Same trends observed in Sri Lanka, India, and the GMS. 38 Pv lagging control 38 World Malaria Report, 2013 Why does Pv control take longer to control than Pf? Relapse and long-latency Temperature range (shorter extrinsic incubation period) Vectors (compatibility; biting patterns in the GMS) Gametocytemia is rapid, even before symptoms Diagnostics But. comparing the ratio/proportions of reported cases from each parasite can give important insight into progress 39 P. vivax- challenges for surveillance Am J Trop Med Hyg (5), Historical epidemic in California, Korean strain (N=35). 39 40 Pv challenges for diagnosis - microscopy 40 Parasitemia in infections with P. vivax is much lower than for Pf. Pv: Average of ~ 20,000 (2%); max ~50,000 per uL Pf: Average of ~20, ,000 per uL; maximum of 2,000,000 However, Pv enlarges infected red blood cells, making identification easier. Essential Malariology, 2003 41 Pv and Pf - microscopy 41 The Primate Malarias, Figs. 17, 18. Mature trophozoites. Figs Early schizonts. Figs. 22, 23. Developing schizonts. Figs Nearly mature/mature schizonts. Figs Nearly mature/mature macrogametocytes. Fig.30. Mature microgametocyte. Figs Mature trophozoites. Figs Developing schizonts. Figs Nearly mature/mature schizonts. Figs. 27, 28. Mature macrogametocytes. Figs. 29, 30. Mature microgametocytes. 42 Pv challenges for diagnosis- RDTs 42 Parasitemia in infections with P. vivax is much lower than for Pf. Additionally, while RDTs have improved greatly in the past several years false negative will happen with Pv Assuming sufficient parasite density: Pf: 1 false (-) test for every 350 true (+) tested Pv: 1 false (-) test for every 22 true (+) tested Why imported vivax and not falciparum? Vectors! P vivax is readily transmitted by a wide range of vectors from other geographic areas Pv development is supported by a much wider range of vectors than Pf = major challenge for prevention of reintroduction. eg,Virginia, USA Other vector issues: vectors throughout the GMS are exophilic and exophagic, limiting effectiveness of standard interventions. 43 44 G6PD Deficiency and Primaquine 44 Glucose-6-phosphate is an enzyme important for red blood cells; some populations have a genetic mutation that leads to low levels (G6PD) Low enzyme levels can cause mild or severe hemolysis after exposure to certain drugs or food (fava beans) Only approved hypnozoiticidal drug (primaquine) can cause hemolysis Recent statement from ERG (Aug 2015):Where feasible all patients should be tested for G6PD deficiency before administering primaquine. Testing for G6PD deficiency in vivax malaria cases should be seen as an integral part of ensuring universal access to diagnosis and treatment. Several rapid tests in field testing currently 45 G6P Deficiency- where is it? 45 Malaria J, 2013;12: 418. 46 The other resistance story- CQ 46 The Lancet Infectious Diseases. 2014;14: 982991 Efficacy X Access X Targeting Accuracy X Provider Compliance X Consumer Adherence = Effectiveness 50% x 80% x 75% X 75% 18% x 80% Efficacy x Coverage = Effectiveness Health System Factors Slide courtesy of Marcel Tanner Why interventions lose traction 47 Final thoughts. 48 Local malaria problems must be solved largely on the basis of local data. It is rarely safe to assume that the variables in one area will behave in the same way as they do in another area, however closely the two regions may seem to resemble each other in topography and climate. Large sums of money have been wasted in attempted malaria control when malariologists have forgotten this fundamental fact. - Paul F. Russell, 1946. Discussion 49 An. minimus Additional slides 51