Visceral Leishmaniasis in Araatuba

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Visceral Leishmaniasis in Araçatuba

• Control of Canine Leishmaniasis Reducing
  Canine-Vector Interaction

Danielle Bivanco de Lima, Rei Nakagawa, Travy
Saveria, Joanna Tan
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Outline

• Background
• Current regulations and programs
• Analysis of Situation
• Methods to reduce dog-vector interaction
• Literature Review
• Recommendations
• Integrated Strategy
• Prevention Measures RCT
• Control of dog population
• Summary and further studies

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Background Key Biological Components of Disease
Host Human
Vector L. longipalpis
Parasite L. (infantum) chagasi
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Background

• Visceral Leishmaniasis (VL) in the world
• 500,000 cases/yr
• 59,000 deaths/yr
• Brazil reports most cases in Latin America
  (3,500/yr)
• Socio-economic trends 80 of victims live on
  
• Drastic increase in cases
• 1980-2003 51,222 cases
• Lethality at 10
• BLCP (Brazilian Leishmaniasis Control Program)
• No change in practices since 1950
• Diagnosis and treatment of human cases
• Immunoscreening and culling of seropositive dogs
• Insecticide spraying against sandflies
• Despite this, Brazil continues to see an increase
  in cases/yr

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Spread of Visceral Leishmaniasis (VL) in Araçatuba
Araçatuba
1997 sandfly 1998 1st dog case 1999 1st human
case
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Background

• No apparent correlation between sandfly density
  and human cases in Araçatuba
• High correlation between human and canine cases
• Thus, control of canine leishmaniasis is a
  primary concern

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BackgroundCurrent Strategies

• No treatment because of recurrent relapses (up
  to 74) concerns about drugs resistance remain
  parasitologically positive and infectious to
  sandfly vector

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Background

• Human population 172,000
• Dog population 32,000
• Current dogs to people ratio 14
• Ideal dogs to people ratio 110
• Average 4-7 of dogs are L chagasi
• 294 () / 9983 sampled (2006)
• Previously controlled rabies successfully
• Last human case in 1999
• Strategies can provide learning points for VL
• Experience shows Araçatuba has capability to
  control zoonosis

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Analysis of Situation

• Brazil has spent more money on VL programs than
  any other country
• However, success has been limited
• Challenges
• No human vaccine
• Efficacy of canine vaccine
• Cultural and behavioral practices
• High dog population (1 dog / 4 persons) and high
  turnover rates ( 2 yrs)
• Multiple dogs per household
• Many dogs kept outdoors
• Mindset of dependence on government
• Owners unwillingness to spend money on their
  pets health
• Lack of knowledge

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Methods to Eliminate Dog-Vector Interactions

• Vaccination of dogs
• Deltamethrin-medicated baths
• Insecticide-impregnated dog collars
• Topical application of insecticide (ointments or
  repellant sprays)

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Literature Review

• Current gaps in literature
• Currently little research on preventive measures
  in Brazil
• Most focused on epidemiology and serology
• Most studies on single preventive measures only,
  little comparison of measures
• e.g. between collars and ointments
• Many studies are laboratory-based rather than
  community-based
• Extrapolation of lab-based findings to reality
  may be limited
• Different species of sandflies and parasites were
  tested in overseas studies

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Literature Review Vaccination of dogs

• Vaccine is a fucose mannose ligand antigen of
  Leishmania donovani

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Literature Review Vaccination of dogs

• Vaccine experimentally used as immunotherapy
• 5 dogs infected with L. donovani and 21 with L
  chagasi
• 22 months of follow up
• Vaccines group 90 asymptomatic and parasite
  free vs control group 37 of deaths due to
  illness
• Interruption of transmission of the disease
• 11 months of follow up
• Technical Report of Ministry of Health 2005
• Lack of data about the reduction of transmission
  of disease
• Confounding serologic surveys in finding infected
  dogs
• Should not be used as a public health control
  tool

Borja-Cabrera,GP et al. Vaccine
200422(17-18)2234-43. Nogueira, FS et al.
Vaccine 2005 23 (40) 4805-10. Nota Tecnica do
Ministerio da Saude 2005.
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Literature Review Deltamethrin-medicated baths

• Effective for 104 days reduces sandflies blood
  feeding rate (62 control group vs 4 bath group)
  
• In a community-based trial in China, transmission
  was reduced after semestral baths for 2 years (no
  controls)

• Guangua X Changfa J et al . Endemic Disease
  Bulletin 1994932-4.
• Guangua X Changfa J et al Chinese Journal of
  Parasitology and Parasitic Diseases
  199513178-81.

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Literature Review Insecticide-impregnated dog
collars

• Scalibor US4 (R6) per month
• Italy clinical trial in 1998 and 1999 in 4 towns
• used deltametrin- impregnated collars

Maroli, M Mizzon V et al. Med Vet Entomol
200115(4)358-63.
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Literature Review Insecticide-impregnated dog
collars

• Iran clinical trial with 18 villages paired for
  1 year
• All dogs in intervention villages were provided
  collars with deltamethrin
• Rate of seroconversion in children was 1.49 in
  intervention group (17/1141 children) and 2.41
  in control (26/1078) RR 0.57 (95 CI 0.36-0.90)
• Rate of seroconversion in dogs RR 0.46 95 CI
  0.30-0.70
• Andradina, Brazil Intervention study
• 2 years follow up
• Reduced incidence of disease in humans and
  prevalence in dogs
• Human incidence 2001 23.3 vs 2004 3.6
• Dogs prevalence 2002 10.8 vs 2004 4.8

Gavgani, AS et al. Lancet 2002 Camargo-Neves, VLF
et al BEPA 2004
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Literature Review Topical application of
insecticide (ointments or repellant sprays)

• Advantix US26 - 40 (R44 - 68) / mo
• Several small studies showing some effective
  repellant and insecticide effects
• Effective for 21-30 days
• Effect of permethrin with imidacloprid repellent
  effect varies 97.7 - 74 (1-29 days) and
  insecticidal effect varies 53.2 - 2.9 (1-29
  days)
• Miro et al (2007)
• Spraying permethrin with pyriproxyfen
  significant protection (p
  21-28 days for adult dogs and 15 days for puppies
• Mercier et al (2003)

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Literature Review

• Comparison of insecticide-impregnated dog collars
  and insecticide lotions
• Parana-Brazil clinical trial with 17 dogs and L.
  intermedia and L. whitmani

Deltamethrin collars were more effective than
permethrin and fenthion
Reithinger, R Teodoro, U et al. Emerging
Infectious Diseases 2001 7(5)872-7.
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Recommendations

• Current initiatives are fragmented and
  uncoordinated
• Holistic approach required
• Active collaboration of agencies necessary for
  success
• SUCEN, Municipals, Ministério da Saúde, CCZ,
  Ministry of Agriculture, Livestock Food Supply,
  Animal Protection Society
• SUCEN could spearhead strategy
• An integrated, multi-prong strategy is proposed

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Framework of Integrated Strategy
Regulations licensing Inspection and policing
Control dog population through incentives for
sterilization
Preventive measures Collars vs Ointments?
Public education, active community participation
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Prevention Measures RCT

• Objective
• Pilot study to evaluate effectiveness and
  practicality of collars vs topical insecticide in
  reducing dog vector transmission
• Rationale
• Insecticide-impregnated collars and topical
  insecticide ointment seem most feasible and
  acceptable
• None of the prior studies considered cost
  effectiveness

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Prevention Measures RCT

• Time period
• 2 yrs
• account for seasonal changes and lag in
  effectiveness
• Start in June/July
• account for lead time required for ointment to be
  effective
• Outcomes
• of seropositive dogs
• of infected humans

in the test neighborhoods and surrounding
neighborhoods
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Prevention Measures RCT

• Methodology
• No change to existing policies and practices
• 6 neighborhoods randomized to collar, topical
  or control groups (2 neighborhoods for each
  group)
• Choice of neighborhoods
• Neighborhoods matched for disease incidence,
  socio-economic status and size of dog/human
  populations within each group
• High prevalence of seropositive dogs
• All groups educated about environmental control
• Intervention groups
• Dog owners provided collars or ointments
  periodically
• Calendars provided as memory aide for new
  applications
• Education on use of products

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Prevention Measures RCT

• Evaluation
• Serology exam of dogs every 6 months
• Compliance
• Results analyzed as intention-to-treat
• Collect used/left over supply of ointment
• Qualitative interview on satisfaction and
  challenges faced
• Monitor and compare human cases
• Close analysis of nearest neighborhoods
• Other Considerations
• Confounding factors (income, weather, surrounding
  neighborhoods)
• Funding
• Ethical / Authority approval
• Human resources

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Prevention Measures RCT

• Cost-Effective Analysis will be conducted to
  compare the 2 modes of prevention
• Policy recommendation will be made based on
  cost-effective analysis

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Control of Dog Population

• ? dog culling
• Rationale
• Human disease incidence strongly correlated with
  dog population
• Large number of dogs increases size of reservoir
• Many households own multiple dogs
• decreases owners budget and ability to care for
  each dog (e.g. time, collars, vaccines, etc)

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Control of Dog Population

• Change incentive structure of current
  sterilization policies
• Currently have to pay to sterilize dogs ( 1 mth
  rent)
• Important to provide incentives for owners to
  sterilize dogs through, e.g. free vaccines,
  identification collars, etc.
• Licensing dogs as possible policy consideration
• Voluntary via incentives or mandatory via
  regulations
• More dogmatic regulations to limit number of
  dogs per household
• Any regulation must be supported by inspections
  and appropriate penalties to be effective

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Summary and Further Studies

• Integrated strategy necessary to reduce
  canine-vector transmission
• Issues requiring further studies
• Dogs are the main but not the only reservoir.
  There could be other sources, e.g. foxes,
  opossums and cats, which could become more
  important in the future
• ? correlation between human cases and vector
  density
• ? effectiveness of vaccines on canine infection

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References

• Manual de Vigilancia e Controle da Leishmaniose
  Visceral Americana do Estado de Sao Paulo. 2006.
• Manzillo V, F. et al. Deltamethrin-impregnated
  collars for the conrol of canine leishmaniasis
  evaluation of the protective effect and influence
  on the clinical outcome of Leishmania infection
  in kennelled stray dogs. Vet Prasitology. 2006.
  Nov 30 142(1-2) 142-5.
• Zhongguo, JS. et al. Studies on the
  deltamethrin-medicated bath of domestic dogs for
  interrupting visceral leishmaniasis transmission.
  1995 13(3)178-81.
• Palatinik-de-Sousa, CB. et al. Impact of Canine
  control of the epidemiology of canine and human
  visceral Leishmaniasis in Brazil. Am J. Trop.
  Med. Hyg. 2001 65(5)510-517.
• Reithinger, R. et al. Are insecticide-impregnated
  dog collars a feasible alternative to dog culling
  as a strategy for controlling canine visceral
  Leishmaniasis in Brazil? Int J. for Parasitology.
  2004 34(1)55-62.
• Reithinger, R. et al. Topical insecticide
  treatments to protect dogs from sand fly vectors
  of leishaniasis. Emerg Infect Dis. 2001
  7(5)872-6.
• Dantas-Torres, F. The role of dogs as reservoirs
  of Leishmania parasites, with emphasis on
  Leishmania (Leishmania) infantum and Leishmania
  (Viannia) braziliensis. Veterinary Parasitology.
  2007, doi10.10.16/j.vetpar.2007.07.007.
• Dantas-Torres, F. and Brandao-Filho, SP.
  Leishmaniasis in Brazil Revisiting paradigms of
  epidemiology and control. Rev. Inst. Med. Trop.
  S. Paulo. 2006 48(3)151-156.
• Gavgani, AS Hodjati, MH et al Effect of
  insecticide-impregnated dog collars on incidence
  of zoonotic visceral leishmaniasis in Iranian
  children a matched-cluster randomised trial.
  Lancet 2002 360374-9.

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References

• Borja-Cabrera, GP et al. Long lasting protection
  against canine kala-azar using the FML-QuilA
  saponin vaccine in a endemic area of the Brazil.
  Vaccine 200220(27-28)3277-84.
• Silva, VO Borja-Cabrera,GP et al. A phase III
  trial of efficacy of the FML-vaccine against
  canine vaccine in a endemic area of the Brazil
  .Vaccine 200019(9-10)1082-92.
• Borja-Cabrera,GP et al. Effective immunotherapy
  against canine visceral leishmaniasis with the
  FML-vaccine Vaccine 200422(17-18)2234-43.
• Nogueira, FS et al. .Leishmune vaccine blocks
  the transmission of canine visceral leishmaniasis
  Absence of Leishmania parasites in blood, skin
  and lymph nodes of vaccinated exposed dogs
  Vaccine 2005 23 (40) 4805-10.
• Camargo-Neves, VLF et al Avaliacao da efetividade
  da utilizacao de coleiras impregnadas com
  deltametrina a 4 para o controle da
  leishmaniose visceral americana no Estado de Sao
  Paulo resultados preliminares. BEPA 20048-14.
• Nota Tecnica do Ministerio da Saude 2005.
• Guangua X Changfa J et al Deltametrin bath of
  domestic dog in the prevention of sandfly bite.
  Endemic Disease Bulletin 1994932-4.
• Guangua X Changfa J et al Studies on
  deltametrin-medicated bath of domestic dogs for
  interrupting visceral leishmaniasis transmission.
  Chinese Journal of Parasitology and Parasitic
  Diseases 199513178-81
• Maroli, M Mizzon V et al Evidence for an impact
  on the incidence of canine leishmaniasis by the
  mass use of deltamethrin-impregnated dog collars
  in southern Italy. Med Vet Entomol
  200115(4)358-63.
• Miro G Galvez, R et al. Evaluation of the
  efficacy of a topically administered combination
  of imidacloprid and permethrin against
  Phlebotomus perniciosus in dog. Vet Parasitol
  2007143(3-4)375-9.
• Mercier, P Jasmin,P et al. Prevention of sand
  fly attack by topical application of a
  permethrin/pyriproxyfen combination on dogs. Vet
  Ther 20034(3)309-16
• Reithinger, R Teodoro, U et al. Topical
  insecticide treatments to protect dogs from dand
  fly vectors of leishmaniasis. Emerging Infectious
  Diseases 2001 7(5)872-7.

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Obrigada - Thank You

• QA Discussion