Larval source management: the missing link in vector control?

Julie Thwing MDAmerican Society of Tropical Medicine and Hygiene

Philadelphia, PADecember 6, 2011

Report on a Cochrane review in progress

Collaborators

• Rob Newman - WHO• John Gimnig - CDC• Julie Thwing - CDC• Steve Lindsay - LSHTM• Uli Fillinger - LSHTM• Lucy Tusting - LSHTM• Kimberly Bonner – CDC• Christian Bottomley - LSHTM

Objective

To compare mosquito larval source management (excluding biological control with fish) for malaria control with no larval source management, applied either alone or in combination with other malaria control interventions

Interventions considered• Interventions introduced with the objective of

reducing human malaria through the reduction of adult mosquito density by preventing the emergence of adult vectors from aquatic habitats– Habitat modification– Habitat manipulation– Biological control– Larviciding

Types of LSM (1)• Habitat modification: permanent change of land

and water, including– drainage of surface water– land reclamation and filling– coverage of water storage containers with mosquito-

proof lids– coverage of water surface with material impenetrable

to mosquitoes (expanded polystyrene beads)• Habitat manipulation: recurrent activity, such as

water-level manipulation, flushing, drain clearance, shading or exposing habitats to the sun

Types of LSM (2)• Biological control: introduction of natural enemies

into the aquatic habitats • Larviciding: regular application of biological or

chemical insecticides to water bodies to control mosquitoes– surface films– synthetic organic chemicals (eg temephos, pirimiphos-

methyl)– microbial toxins such as Bacillus thuringiensis israeliensis

(Bti), and Bacillus sphaericus (Bs)– insect-growth regulators (pyriproxyfen, methoprene,

diflubenzuron)– historically, Paris Green (copper acetoarsenite)

Interventions excluded

– Environmental interventions that do not target breeding sites (e.g. removal of vegetation around homes)

– Studies including larvivorous fish (to be covered by separate Cochrane review), unless both intervention and control areas are equally treated

– Non-standardized formulations of plant products

Types of articles considered

• Randomized controlled trials for which the unit of randomization is the cluster

• Non-randomized controlled trial for which the unit of allocation is the cluster

• Cross-over time series design

Exclusion criteria• No outcomes of interest reported• Intervention applied for < 1 year (or < 1 transmission season in

trials with strong seasonal transmission)• For non-RCTs, < 1 year (or in areas of highly seasonal

transmission, 1 transmission season) of baseline data• For cluster RCTs and non-randomized controlled trials:– Ecological, entomological, clinical baseline characteristics

and application of malaria control interventions in intervention and controls are non-comparable

• For cross-over time series:– Interventions likely to be permanent (e.g. habitat

modification)– Washout period inadequate for disappearance of larvicide

Search strategy• Electronic search: Cochrane Infectious Diseases Group

Specialized Register, Cochrane Central Register of Controlled Trials , CENTRAL, MEDLINE, EMBASE, CABS Abstracts, LILACS

• Hand searches:– Tropical Diseases Bulletin, 1900-2010– WHO Technical Documents pre c1983– Catalogue of the material of the WHO (stored in WHO

archives in microform) from 1946-1950 and 1950-1955, centralised files pre 1991

– Archives of the Parasitology Collection of the Communicable Diseases Documentation Centre at WHO Headquarters, ref code ARC007 - 1911 to date

– Literature Retrieval System of the US Armed Forces Pest Management Board

Search terms• ‘Malaria/Anopheles’ AND ‘Larval control’ • ‘Malaria/Anopheles’ AND ‘Larvicide’• ‘Malaria/Anopheles’ AND ‘Larvicide’• ‘Malaria/Anopheles’ AND ‘Bti’• ‘Malaria/Anopheles’ AND ‘Bs’• ‘Malaria/Anopheles’ AND ‘paris green’• ‘Malaria/Anopheles’ AND ‘temephos’• ‘Malaria/Anopheles’ AND ‘pyriproxifen’• ‘Malaria/Anopheles’ and ‘pirimiphos-methyl’• ‘Malaria/Anopheles’ AND ‘insect growth regulator’• ‘Malaria’/’Anopheles’ AND ‘Environmental management’ • ‘Malaria’/’Anopheles’ AND ‘Source reduction’• ‘Malaria’/’Anopheles’ AND ‘Biological control’• ‘Malaria’/’Anopheles’ AND ‘drainage’

Outcome measures  • Primary outcomes  – Prevalence of diagnostically confirmed

malaria (rapid diagnostic test or microscopy)– Incidence of diagnostically confirmed malaria

(rapid diagnostic test or microscopy)• Secondary outcomes  – Enlarged spleen rates in children–Vector biting rates (measured directly using

human baits or indirectly using light traps, knock-down catches or other proxy indicators)*

Study review and data abstraction• All abstracts reviewed by two co-authors• Any abstract selected by either co-author pulled for

review• All studies reviewed for eligibility by two co-authors• All disagreements resolved by third co-author• Data from selected studies abstracted by two co-

authors• Disagreements resolved by discussion or if agreement

not reached by discussion, by third co-author • All data abstraction reviewed by senior co-author• Calculated percent reduction and 95% CI for each

outcome measure

Results

• 2255 abstracts identified by electronic search strategy, 587 from hand search

• 344 abstracts selected from electronic search, 181 from hand search

• 526 unique studies identified and assessed for eligibility

• 14 studies included

Issues

• Many very old or obscure reports• Most studies of low quality design– Historical program reports– Uncontrolled demonstration projects

• Most studies have high risk of bias• Heterogeneity• Meta-analysis not possible• Solution: present individual study results in

tables

Primary outcome 1: Parasite prevalenceStudy Study 

type Intervention Setting Population % reduction  (95% CI)

Yapabandara 2001 RCT Larviciding Sri-Lanka, forest gem-mining pits all 89.5% (80.3-94.4)

Majambere 2010 cross-over Larviciding Gambia, savanna floodplain 6 mo - 10 yrs -36.4% (-217.1-41.3)

Balfour 1936NRCT

Larviciding Greece, urban and rural school children 45.4% (15.8-64.6)

Samnotra 1980NRCT

Larviciding India, rural, forest All ages 56.1% (49.6 – 61.7)

Santiago 1960NRCT Environmental

management Phillipines, urban 2-10 years 97.4% (94.3-98.8)

Sharma 2008NRCT Environmental

management India, rural, forest All ages 74.6% (60.6-83.6)

Geissbulher 2009 NRCT Larviciding Dar-es-Salaam, Tanzania 0 to 5yrs OR: 0.28

Castro 2009 NRCT Integrated vector management

Dar-es-Salaam, Tanzania All ages OR: 0.23

NRCT: non-randomized pre-test/post-test control group

Primary outcome 2: Malaria incidence

Study Study type Intervention Setting Population % reduction  

(95% CI)

Yapabandara 2001 RCT Larviciding Sri-Lanka, forest gem-mining pits All ages 73.8% (66.6-79.4)

Yapabandara 2004 RCT Larviciding Sri-Lanka, rural villages in irrigation program All ages 70.0% (55.0-80.1)

Majambere 2010 Cross-over LarvicidingGambia, lowland savanna floodplain

6m to 10 yrs -66.1% (-1141.9-77.8)

Fillinger 2009 NRCT Larviciding Kenya, rural 6m to 10 years 46.3% (-2.2 – 71.7)

Samnotra 1980 NRCT Larviciding India, urban All ages 79.2% (76.2-81.8)

Sharma 2008 NRCT Environmental management India, rural, forest All ages 61.2 (41.8-74.1)

NRCT: non-randomized pre-test/post-test control group

Splenomegaly prevalence

Study Study type Intervention Setting Population % reduction  

(95% CI)

Majambere 2010 Cross-over Larviciding

Gambia, lowland savanna floodplain

6m to 10 yrs-2.4% (-260.2 – 70.9)

Balfour 1936 NRCT Larviciding Greece, urban and rural school children 42.0% (33.3 – 49.6)

Santiago 1960 NRCT Environmental management Phillipines, urban 2-10 yrs 95.6% (92.0-97.6)

NRCT: non-randomized pre-test/post-test control group

Next steps

• Finalize abstraction of all possible studies• Submit draft review• GRADE study quality• Finalize and publish Cochrane review

Discussion• Very few quality trials• In selected places, where vector ecology

(localized stable breeding sites, etc.) is appropriate, appears that it may be effective

• Man-made breeding sites (pits, dams, etc.)• Need to know more about a variety of settings• Combination with other interventions• Cost-effectiveness• Real world implementation

RBM Global Malaria Action Plan 2008• More work is needed before LSM ‘can be considered on par with

LLINs and IRS’ • Where malaria transmission is low to moderate, and seasonal or

focal, targeted approach in addition to LLINs and/or IRS, especially during the phase of sustained control ‘as the burden goes down and targeted approaches towards breeding sites can be very effective in reducing vector populations’.

• …‘sustainability relies on the ability to conduct continuously reliable surveillance and mapping activities to identify areas where these interventions are most appropriate’.

• Operational research ‘where larviciding may be feasible’ and more ‘applications where larviciding can be feasible in regions where LSM was previously thought inappropriate’ are encouraged.

• Research priority for elimination: ‘applications of larviciding and environmental management in various transmission settings’

Thank you!