American Trypanosomes (14-15)

Question 1

What is the prevalence of Trypanosoma cruzi Chagas disease?

Answer 1

8-10 million people infected in Latin America
Incidence of disease 500,000 new cases per year, 10,000 deaths per year
Highest burden of disability-adjusted life years (DALYs) lost among the NTDs (neglected tropical diseases)
Most important parasitic disease in Latin America
41% of 283 Andean mummies dates 9,000 years old positive for T. cruzi DNA
Humans are a very recent host - T. cruzi is >150 million years old

Question 2

What is the T. cruzi vector?

Answer 2

Vectors: reduviid or Triatominae bugs (kissing bug)
Order Hemiptera, Family Reduviidae, Subfamily Triatominae
→ can take up lots of parasites
→ 8-10x body weight in blood
→ need to shed exoskeleton to grow (moult) - required a blood meal

Question 3

What are the routes of transmission for T. cruzi?

Answer 3

Vector-borne by ‘kissing bug’ (80%)
Transfusion of infected blood (4-20%)
Congenital: mother to foetus (predominant form of transmission in US and Europe)
Accidental ingestion of infected sources (rare event)

Question 4

What is the transmission cycle for T. cruzi?

Answer 4

1. Triatomine (kissing) bug takes a blood meal → passes metacyclic trypomastigotes in fees, trypomastigotes enter bite wound or mucosal membranes such as the conjunctiva
2. Metacyclic trypomastigotes penetrate various cells at bite wound site → inside cells they transform into amastigotes
3. Amastigotes multiply by binary fission in cells or infected tissues
4. Intracellular amastigotes transform into trypomastigotes then burst out of the cell and enter the bloodstream
   → trypomastigotes can infect other cells and transform into intracellular amastigotes in new infection sites, clinical manifestations can result from this infective cycle
5. Triatomine bug takes a blood meal → trypomastigotes ingested
6. Epimastigote stage in midgut
7. Multiplies in midgut
8. Metacyclic trypamsatigotes in hindgut
9. Triatomne bug takes a blood meal passing it to humans

(not saliva transmission (not efficient) - takes a blood meal, scratches site of bite, trypomastigotes in faeces enter)

Question 5

What are the key triatomine species responsible for T. cruzi transmission?

Answer 5

~20 triatomic species responsible for T. cruzi transmission
key species: Rhodnius prolixus. Triatoma brasiliensis, Panstrongylus meglstus, Triatoma infestans, Triatoma dimidiata
→ T. Infestans highly domesticated vector in Southern Cone countries

Question 6

What is the epidemiology of T. cruzi?

Answer 6

8 million people are infected
>10,000 deaths per year
Remains one of the biggest public health problems in 21 Latin American countries
In recent decades has spread beyond Latin America
Endemic to Latin America → reservoirs, vectors and contact between them - urbanisation
Non endemic regions → migration - risk for congenital transmission
USA: 300,000 infected persons live in USA, most of whom are migrants from Latin America
Enzootic T. cruzi transmission has been reported across the southern half of the US but locally acquired cases in humans are rare

Question 7

What is the global distribution of T. cruzi?

Answer 7

Risk associated with migration
Chagas is long-lived infection with asymptomatic chronic carriers
Leads to unusual global distribution linked not only to transmission but migration
Subsequent (autochthonous) transmission is not vector-borne → rather mainly congenital, also blood transfusions and infected organ transplants
68,000-123,000 infected immigrants in Europe e.g. Bolivian’s make up 80% of immigrants in Spain

Question 8

How did T. cruzi spread from wild animals to domestic animals and human beings?

Answer 8

T. cruzi was strictly a rural disease for decades but socio-economic changes, rural exodus, deforestation and urbanisation have transformed the epidemiological profile of the disease
→ led to expansion of endemic regions at the start of the 20th century - now large urban/peri-urban burdens

Triatomine bugs typically live in the wall or roof cracks of poorly constructed homes in rural or suburban areas - becoming active at night, biting exposed areas of skin, then defecating close to the bite

Question 9

What are the epidemiological risk factors for T. cruzi?

Answer 9

Poverty / course construction → triatomic bugs favour habitats in poorly constructed houses
Deforestation and human colonisation of Triatomine habitats → provides abundant / stationary blood sources
Rural to urban migration → blood transfusions e.g. blood bank prevalence of 1.7% (Sao Paulo, Brazil) to 53% (santa Cruz, Bolivia)
Congenital transmission → e.g. 2-15% urban and 23-81% rural Bolivia

Question 10

What is the time course from T. cruzi infection to chronic Chagas disease?

Answer 10

Infection
1-2 weeks → acute stage (asymptomatic/mild) - weeks/months

Chronic stage → life-long, asymptomatic Chagas disease (70-75% of infected subjects)

Latency of 10-20 years
Symptomatic Chagas disease (25-30% of infected individuals) → Chagas heart disease (85-95% of symptomatic subjects), chagas gastro-intestinal disease (5-10%), chugs heart/gastrointestinal disease

Question 11

What occurs in the acute phase of Chagas disease?

Answer 11

Acute (symptomatic) form (4-8 weeks) - most often seen in children
→ fever, swelling lymph glands, liver and spleen enlargement, local inflammation of inoculation site (e.g. Romama’s sign)
→ abundant parasites in the blood stream (easy to diagnose)
→ mostly mild, self-limited symptoms e.g. fever that doesn’t come to medical attention
→ can be severe acute infection - myocarditis, meningoencephalitis - both life threatening
→ case fatality rate is estimated to be 0.25-0.5%

Question 12

What occurs in chronic phase Chagas disease?

Answer 12

Chronic phase without treatment is life long
Cardiomyopathy (diseases of heart muscle) in 20-30% of chronically infected individuals
Develop digestive damage (megaviscera)
Peripheral nervous involvement
→ difficult to treat

Question 13

How is Chagas disease diagnosed?

Answer 13

In the acute and early congenital phase → high parasitaemia - microscopy of stained blood smear - PCR or hemoculture

Chronic phase → parasitaemia levels drops, amastigotes remain in cardiac/skeletal muscle/macrophages, scarce trypomastigotes in blood
→ two serological IgG antibody tests due to low sensitivity
→ no satisfactory test to define parasitological cure (low PCR sensitivity)
→ no gold standard

Question 14

What are the 2 effective drugs for treating Chagas disease?

Answer 14

Nifurtimox, Benznidazole
→ effective again acute and early chronicle phases only
→ serious / frequent side-effects (40%), more common with increasing age
In acute phase treatment reduces and shortens clinical severity and duration of detectable parasitemia - parasitological cure in 60-85% of patients treated in the acute phase
→ WHO recommends treatment for acute, congenital and reactivated T. cruzi infection, and for children (up to 18) with chronic infection

Question 15

What are the drawbacks of the drugs for Chagas disease?

Answer 15

No drugs are effective for chronic phase
→ debate over usefulness in adults with long-standing infections - despite an impact on parasite serological parameters, a randomised trial of benznidazole did not significantly reduce levels of cardiac clinical deterioration over 5 year follow up
Clinical trials in progress for new drugs but hindered by no accepted reference assay to detect chronic T. cruzi infection (3x serological tests used) - PCR insensitive, antibody decay post cure is very slow
Drugs cannot be administered during pregnancy
Specific treatment to alleviate symptoms needed for cardiac, or digestive or neurological symptoms - but will not give parasitological cure
Serious side effects
Access: less than 1% of patients have access to Benznidazole
Only recommended in areas with vector control or non-endemic → due to re-infection and risks associated with treatment - governments dont mobilise benzidazol unless vector control implemented (re-infection makes it not cost effective)
Disease is poorly understood by health professionals in non-endemic areas → making detection difficult
Desperately need new drugs and to improve parasitological detection

Question 16

What are some approaches to control of Chagas disease?

Answer 16

No vaccine
Endemic regions → sustained vector control of intra-domiciliary vectors in Latin America - prevent vector borne transmission
→ promote engagement with vector control activities
Endemic and non-endemic regions → screen blood transfusions and organ donation worldwide
→ screen pregnant women and children to control congenital transmission worldwide
→ promote health seeking behaviour and awareness among health professionals

Question 17

What is the focus of control for Chagas disease?

Answer 17

Focus on prevention, interrupt transmission by:
→ controlling intra-domiciliary vectors in Latin America
→ screening blood banks for transfusions
→ screening organs for transplantation
→ screening for congenital infection (testing pregnant women)

This is because:
→ no vaccine
→ chemotherapy cannot be relied upon to prevent spread of infection - no solution to chronic infections (asymptomatic carriers), not widely available (expensive, distribution issues), vector infestation leads to high levels of re-infection

Question 18

How is vector control used to control Chagas disease?

Answer 18

Indoor residual spraying → classic control - use of chemicals, important for delivery dose to be at correct level
→ contact insecticides - must lands on wall, must be inside
Insecticide impregnated nets (ITNs) (or curtains)
House improvement (environmental management) → plastering of walls - earth, cow dung, lime or cement mixes to seal gaps (vectors hide in the cracks)
Social interventions (education and community participation) → school teachers, community leaders, focus groups, meetings and house visits
→ sustainability is a key parameter in community participation
→ ‘good practices’ may be acquired, but abandoned if regarded low priority
Integrated Vector Management and political commitment → country wide approach

Question 19

What is an example of successful vector control programme for Chagas disease?

Answer 19

Southern Cone Initiative → launched in 1991
→ Argentina, Bolivia, Brazil, Chile, Paraguay and Uruguay
→ domestic vector elimination
→ serological screening blood
→ housing improvement
→ international collaboration

Interruption of transmission achieved in… Uruguay - 1997, Chile - 1999, Brazil - 2002, Argentina - 2002, Bolivia - 2005, Paraguay - 2005

Question 20

What is the domesticated vector for Chagas disease?

Answer 20

Triatoma infestans → highly domesticated - moved into houses

Question 21

Where has seen re-emergence of Chagas disease?

Answer 21

Despite Southern Cone Initiative showing great success, Gran Chaco region has re-emergence
→ Argentina, Bolivia, Paraguay
→ 1.3 million km2
→ indigenous communities - marginalised communities often ignored by politicians
→ highest transmission
→ house infestation 82-100%
→ T. infestans infection with T. cruzi - 50%
→ typical living conditions - hot, dry, houses made out of framework of sticks and mud - cracks and spaces for vectors to hide

Question 22

What rates of Chagas disease is present in Bolivian Chaco (Santa Cruz Department - largest of the 9 departments of Bolivia)?

Answer 22

→ house infestation index (proportion of houses infested): 18-73%
→ Triatomine infection prevalence with T. cruzi: 29-82%
→ house construction (wall crevices) main risk factor for persistent infestation
→ 20-30% infection prevalence in children <18yrs
→ 86-97% infection prevalence in adults >30yrs
→ 45% T. infestans populations variably resistant to IRS chemicals

Question 23

Why is a higher prevalence of Chagas disease seen in pregnant women in rural community (Camiri) than less endemic state (Santa Cruz)?

Answer 23

Repeat vector infection exposure in Camiri sustains inflammatory responses at higher chronic levels, increasing cardiac morbidity, but possibly enabling exposed women to control parasitemia even in the face of pregnancy-induced Th2 polarisation

Question 24

What is the method of surveillance for Chagas disease vectors?

Answer 24

Timed manual capture (TMC: 1 person looking for 30mins)
→ poor reproducibility

Question 25

What is required for community treatment of Chagas disease?

Answer 25

Surveillance → household infestation threshold to trigger vector control by IRS
→ IRS “attack phase’ conducted typically until reduced to <5% of houses infested; infestation indicated by TMC

Vector control → successful vector control is required to trigger human treatment
→ treatment of childhood infection is recommended only if area is under affective vector control commonly defined as: house infestation index: <3% houses in community infested, and absence of infestation in case households

Question 26

What are some issues with IRS (indoor residual spraying)?

Answer 26

Stuff everywhere → bugs inside posters, blankets, mattresses
Difficult to deliver insecticide → often below target insecticide delivery dose

Question 27

How can IRS (indoor residual spraying) for vector control of Chagas disease be improved?

Answer 27

IRS campaign sustained, supervised, community-based vector control and housing improvement
→ sustainable house construction improvement - reduces crevices and increases surface adhesion of IRS insecticides

Question 28

What are the complications with vector control for Chagas disease?

Answer 28

~20 triatomic species responsible for T. cruzi transmission
→ don’t know much about reservoir host
The different species have different behaviours:
Rhodnius prolixus → mostly peri-/domestic, some syllabic populations
→ prefers huts with palm-thatch roofs and perideomestic palms
Triatoma dimidiata → sylvatic (occurring in, affecting or transmitted by wild animals) and domestic colonisers
→ hides in dirt floors

Question 29

Does insecticide resistance affect vector control for Chagas disease?

Answer 29

Triatomine resistance to insecticides is patchy - insecticides:
→ DDT is not effective against Triatomids
→ Organophosphates (Dieldrin), organochlorines (benzene hexachloride), carbamates (propoxur)
→ Synthetic pyrethroids (cypermethrin, cyfluthrin, deltamethrin, permethrin, lambdacyhalothrin)

Most resistance has been observed so far in the highly endemic Gran Chaco region (45% of populations)
→ no apparent association with time or IRS pressure

Question 30

Has Latin America seen improvements with Chagas control?

Answer 30

→ incidence declines from 700,000 to 40,000 cases per year in 25 years
→ mortality decline: 45,000 to 12,500 deaths
→ still annual cost of US 8billion
→ elimination of T. infestans in majority of region

Question 31

What are WHO/PAHO’s goals for endemic and non-medic countries for Chagas control?

Answer 31

2020 goals → interruption of intradomiliciliary (within homes) vector transmission in the Americas
→ interruption of transmission by blood/blood products in the Americas, Europe and W. Pacific

New WHO goals 2021-2030
→ elimination as a public health problem - in 20 endemic countries + 75% access to treatment
→ interruption of intradomiciliary (vectorial) transmission (0% infestation index 0% T. cruzi human infection incidence)
→ elimination of blood transfusion and tissue transplant transmission (100% of target countries)
→ interruption of congenital transmission - 90% screening coverage and treatment of women, and when infected, screening of their new-borns and siblings

Question 32

What are the overall challenges for controlling Chagas disease?

Answer 32

Dissemination → Chagas disease has spread in areas where the disease was previously non-endemic, such as Europe, due to population mobility
→ knowledge and experience of the disease are limited here, thus insufficient surveillance and control measures in place
Diagnosis and treatment → even with substantial reductions in transmission, millions of infected people remain without access to adequate diagnosis and care
Co-infection and co-morbidities → Chagas disease is mainly a chronic condition, this with disease urbanisation and the increase in life expectancy is increasing the number of co-infections and co-morbidities being seen
Sustainability → maintain and consolidate advances, particularly in areas where endemicity is low
→ this challenge has been called ‘the punishment of success’ - occurs when political interest (and resources) decline after transmission has been controlled
Persistance and emergence → transmission in these areas mainly involves wild vectors, rather than domestic ones, and may include local oral outbreaks of food-borne disease
→ disease emergence has been recently described in areas previously considered to be free of the disease - such as the Amazon basin
Persistence and re-emergence → the disease re-emergence has been observed in regions where Chagas disease control had been in progress - such as the Chaco region of Argentina and Bolivia
→ extensive extra-domestic populations of the main vector, and some resistance foci, among others