African and American trypanosomiasis Jarmila Kliescikova, MD, 1 st Faculty of Medicine, Charles...

African and American trypanosomiasis

Jarmila Kliescikova, MD, 1st Faculty of Medicine, Charles University in Prague

Sleeping sickness

Sleeping sickness• Kinetoplastida: Salivaria

Trypanosoma brucei gambiense

Western and central Africa (chronic disease)

Trypanosoma brucei rhodensiense

East and SE Africa (acute disease)

Extracellular parasiteVector: tse-tse fly (Glossina)

DRC, Angola, CAR, South Sudan - prevalence up to 50%.

1. or 2. most common cause of death in these countries

In Africa, patients with sleeping sickness are poor live in remote / poor / unstable / neglected areas

Patient prognosis is dependent on accurate and early diagnosis and staging

The incidence of sleeping sickness has decreased in the most affected countries since 2000 ( elimination ?)

The maintenance of vertical programmes are more difficult to justify and fund integration into existing health structures is the trend practical and cheap diagnostic tools must be used

Epidemiology

Distribution: tropical Africa (Chad, Congo, Cote de Ivoire, Guinea, Malawi, Uganda, Tanzania, CAR)

Botswana, Swaziland and Namibia – trasmission seems interruped

Connected to the vector distributionPrevalence approximately - 50 mil.

20 – 50 thousand new cases per year

Approximately 55 thousand deaths/year

Belongs to so called neglected diseasesEast African form rarely imported to Europe – infection usually during safari

Simarro et al., 2010

The vector = Glossina spp. – both genders able to transmit the disease

T. b. gambiensae

Gl.palpalis/tachinoides – River glossina

The maximum is the end of dry season

Antroponoosis – human is the main reservoir, rarely dog,

swine, sheep, cattle,..

T. b. rhodesiensae

Gl. morsitans/fuscipes Savannah glossina

Zoonosis – reservoir antelope, lions, cattle, sheeps, dogs

Life cycle

Pathogenity

CSF Leptomeningitis

Site of inoculation

Lymph, blood

Local inflammation

Chronic inflammation of the lymph system

Variable Surface Antigens change = The main mechanism of pathogenicity

• Variabile surface coat VSG

(variabile glycoproteins)

• Trypanosomas posses several different genes coding the surface antigens

• VSG protects from phagocytosis and lysis by alternative complement pathway

• Exhaustion of the immune system

• Toxic and end metabolic products of trypanosomas released in the organism

The surface antigen changes

Alteration of the human immune response

Malvy and Chappuis, 2011

Clinical infection: I.Local reaction

IP 6-14 days

Local reaction at inoculation site: oedema, erythema

„chancre“ formation (Grafs chancre) (trypanozomas found in the secret)

Hyperpigmentation of skinIntermitent fever

Loal lymphadenopathy

Graafs chancre

Malvy and Chappuis, 2011

2. Heamolytical stage:

Lymfadenitis

Cervical nodes

Generalisation

• Intermittent fever generalized weakness, headache

2. Haemolymphatic stage:

Posterior

cervical

lymphadenopathy

Nodes are soft, non dolorous, elastic

Winterbotts sign

2. heamolymphatic stage

Hepatosplenomegy

Subcutaneous oedemas(face, lids)

Exantema – tripanid

2. Heamolymphatic stage:

Myocarditis tachycardia (100-140/min); heart failure

AnaemiaPolyneuropathy

sensitive, motoric

Weakness kachexia

3. Meningoencefalic stage

Periferal polyneuropathy (late hypersteasia after pressure on limbs and muscles, pruritus)

HeadacheInverse sleep

Personality, character changesChorea, atetosis, dyskinesis, tremor, ataxia, tonic-clonic seizures

Sexual behaviour dysfunctions, endocrinne dysregulation

Wasting syndrome

CT, NMR:

Atrophic changes, hydrocephalus, thickening of meninges

T.b gambiensae T.b.rhodesiensaeEPIDEMIOLOGY: Middle, West Africa East. Africa

Rezervoir Human, (dog, pig, ..) Antelopes, cattle

Vector River glossina Savannah glossina

Clinical course Chronic Acute

Incubation period 1 – 3 weeks 1 – 3 weeks

Chancre 0, not always present Present, large

Fever Slow onset up to 39°C Acute, chills, > 39°C

Lymph nodes Enlarged Insignificat

Oedemas insignificant Present, esp. In children

Myokarditis Not always Very common

Invasion of CNS After 1 – 2 years after 3-6 months., earliest in 1 month

Inflammatory CNS reaction

High Weak

Fatal without treat. 1-6 years Within 1 year

Rat infection Mild course Fatal

Laboratory• ESR (> 100 mm/h)

• Blood count• Anaemia: severe, normochromatic• Lymphocytosis and monocytosis with relative

neutropenia• Trombocythopenia

• Serum protein• Total increase• Hypergamaglobulineamia and macroglobulinaemia (↑ IgM)• Elevation of α2-globulins

• CSF (v II. stage)• Proteinrhachia (up to 10% IgM)• Mononuclear cells

Diagnostics – direct methods

• Biopsy of ulcus, local lymph nodes

• Blood film, thick film

• Concentration techniques

• CSF examination

Current diagnostic approach and tools

Sleeping sickness

I. Screening: Serology (CATT, IFI, ELISA) Cervical lymph node palpation

II. Diagnostic confirmation (parasitology): Cervical lymph node puncture Detection of trypanosomes in blood

I. Stage determination: CSF examination (LP): Search for trypanosomes (centrifugation) WBC/mm3 > 5 Raised IgM

Blood film

Brun at al., 2010

Serology

Agglutination tests:

Paper stripes

Only for T.b.gambiense

THERAPY

T. b. gambiensae

T. b. rhodesiensae

Early phase PentamidinSuramin

Suramin

Late phase (cerebral)

MelarsoprolEflorithineNifurtimox

Melarsoprol

• Acute trypanosomiasis• Suramin (BAYER 205, ANTRYPOL)

• 5 mg/kg v 5-10 ml H2O slow i.v. 1. day• 10 mg/kg v 10 ml H2O slow i.v. 3. day• 20 mg/kg v 10 ml H2O i.v. 5.,11.,17.,23.and 30. d

• Pentamidin isethionate (PENTACARINATE)• 3-4 mg/kg (150-300 mg)/day i.m. or i.v

Every other day, together 7-10 doses

• Chronic trypanosomiasis• Melarsoprol (MEL B, ARSOBAL)

Strictly i.v. slow injection with increasing dosage, max. 3,6 mg/kg/day in several (3-4) 3-4 day cycles

• Before malarsoprol use suraminem or pentaminidine (Jarisch-Herxheimer reaction)

• High toxicity (5-10% fatal) arsenic encephalopathy• Mannitol i.v. in isotonic glucose á 6 hours.• Prednisolon 50 mg/day, dexametason 6-8 mg/day i.v.EFLORITHINE -2 weeks 4 infusions per day

THERAPY

Vector control

http://influentialpoints.com/Gallery/Tsetse-flies_Louse-flies_and_Lice.htm

American trypanosomiasis

Trypanosoma cruzi – Kinetoplastida: Stercoraria

• Vector: Triatoma; Rhodnius• Chagas disease• Rezervoir: human, live stock• Transmission: by vector transfusion/transplantation transplacentary

Where are we now: 2012

• Transmission by Triatoma infestans halted in 1999 in Uruguay, 1999 in Chile, 2006 in Brazil and 2009 in Guatemala

• Triatoma eliminated also from some parts of Argentina and Paraguay

• Disease now „common“ in non-endemic areas: Europe and USA

• WHO launched an initiative for controlling of disease in non-endemic areas

• USA Food and Drug Administration approved the first serological screening for blood donors

• Emergence of secondary domestic and peridomestic vectors

• 8-11 mil people infected predominantly in Mexico, Central and South America

• Incidence has dropped from 700 000 new cases per year to 40 000

• The number of deaths has dropped from approximately 45 thousand to 12 500 (chronic kardiomyopathy)

Europe and Chagas disease

3 periods:

Description of Chagas disease and in 1980 first case description in Europe

Description of non-endemic transmission via transfusion or congenital transmission (southern

Europe, Spain)

Chagas disease recognized as global problem – transmission reported in 28 countries worldwide

Basile et al, Eurosurveillance, 2009

Estimates of migrant residents from Chagas disease endemic areas in nine studied European countries

Source: Basile at al, Eurosurvaillence, 2009

Estimated number of migrants infected with Chagas disease

Basile et al., Eurosurveillance 2009

Underdiagnosis of Chagas disease in Europe

Basile et al., Eurosurveillance 2009

Estimated congenital transmission in Europe

Basile et al., Eurosurveillance 2009

Endemic Chagas disease distribution 2011

Triatoma/Rhodnius

Blood sucking bed bugsThe parasite is found within

feaces

Actively penetrates the skinTransmitted by adults and progeny

Biting at night

Typical sites of vector multiplication

Typical sites of vector multiplication

The vector can live in the crevices that are common in the mud and wood used to build walls and floor

Chagas Disease in a Domestic Transmission Cycle in Southern Texas, USA

real and predicted distribution of Triatoma gerstaeckeri

Beard et al, 2003 from CDC

Life cycle

Trypanosoma cruzi

• Intracellular parasite• Spread by blood to different

organs• Preference: RES heart cells muscle cells neuroglia• In blood the flagellated forms are

found• Intracellulary amastigotes are

found

Chagas disease has two phases

Acute phase:

Local or diffuse inflammation of myocardium

Chronic phase

Inflammatory fibrotic reaction damaging the cardiac muscle and conduction network and

the enteric nervous system

Pathofyziology

• Autoimmune mechanisms: molecular mimicry, release of cryptic antigens, polyclonal lymphocyte activation, epitope spread

• But the role is still controversial (immunosuppresion, HIV…)

• The role of Th8 lymphocytes (shift to another population when treated)

Pathophysiology • Host response can cause tissue damage

(Th8 lymphocytes producing granzymes and other cytokines)

• Progression to symptomatic disease involves imbalance between T-helper 1 and 2 responses

• Heart: conduct system, parasympatic nerve

• Hypertrophy, fibrosis, thinning of the left ventricular wall, aneurysma, thrombes formation

Clinical symptoms.Primary leasion

• Induration at entry point – inoculative chagoma: local inflammation, amastigotes in lipocytes

• Inudrated erythematous papule (1-3 cm) local lymphadenopathy

• Romaña sign – oedema of lids, conjunctivitis

French female with Romana sign after visiting her parents

from French Guzana, Source: CDC

http://wwwnc.cdc.gov/eid/article/14/4/07-0489_article.htm

Indeterminate Chagas disease

• Seropositivity for Ch. disease

• Normal chest radiograph and EKG

• Abscence of clinical signs and symptoms

• One third of patients progresses to symptomatic disease

Some patients: abnormal contractility on Echo, Areas of cardiac fibrosis…

Acute phase

• ID: 2-3 weeks• Asymptomatic vs symptomatic• Continuous fever 38 C, max evening (38-40 C)• Local vs generalised lymphadenopathy• Morbilliform rash (chest, stomach)• Mild hepatosplenomegaly• Subcutaneous oedema – face, limbs• Myocarditis, endocarditis, pericarditis heart

failure• Meningoencefalitis – mortality less than 5%

(children)• Acute phase will disappear within 2-3 months

Silva N et al. J Acquir Immune Defic Syndr Hum Retrovirol, 1999.

Two thirds of patients – cardiac form, one third GIT form

Progression 10-30 years after infection

Cardiac disease

Early: malaise, palpitations, syncope, abdominal pain (right upper quandrant),

jugular venous distension, peripheral oedema, stroke

Late: Atypical chest pain, syncopal episodes, sudden cardiac death, dyspnoea,

orthopnoea, fatigue, murmurs, stroke

GIT disease

• Megaoesophagus: dysphagia, regurgitation, odynophagia, oesophagitis, aspiratory pneumonia, hiccups

• Megacolon: chronic constipation, meteorism, chronic abdominal pain, bacterial overgrowth syndrome, malabsorbtion, ileus – toxické megacolon

• Megaureteres

Congenital disease

• Increased by increased pregnancies, high maternal parasitemia…

• Risk of approximately 5% in endemic and non-endemic areas

• 10-30% babies symptomatic, 10% die within first 2 days without treatment

• Prematurity, low birthweight, hepatomegaly, splenomegaly, jaundice, oedema, RDS, meningoencephalitis

Transplanation

• Kidney – 20-35%

• Live and haemopoietic cells

• Reactivation after transplantation: heart (20-75%), liver and haemopoietic cells

• Myocarditis, Meningoencephalitis, nodules and plaques on skin

Chagas disease and HIV+

• Reactivation of latent infection

• CNS – 75% cases

• Hypodense leasions; necrohaemorrhagic leasions,

• Fever, cefalea, seazures, vomiting, focal neurological deficiency

• Treatment must be early and continued for 30-60 days

PrognosisScore for the progression of cardiac involvement• Age older than 50 years; 2 points• Systolic diameter more than 40 mm; 3 points• Intraventricular conduction disorders; 2 points• Sustained ventricular tachycardia; 3 points• Benznidazole treatment; –2 pointsRisk of progression is• 3 ・ 6% for a score of 0• 6 ・ 9% for a score between 1 and 3• 16% for a score between 4 and 6• 52 ・ 5% for a score above 7Prognostic score for mortality from Chagas disease• New York Heart Association III–IV; 5 points• Cardiomegaly; 5 points• Wall motion disorders; 3 points• Non-sustained ventricular tachycardia; 3 points• Broadened QRS complex; 2 points• Male sex; 2 pointsRisk of death is• 2% at 5 years and 10% at 10 years for a score between 0 and 6 points• 18% at 5 years and 44% at 10 years for a score between 7 and 11 points• 63% at 5 years and 84% at 10 years for a score between 12 and 20 points

Diagnostics

Acute phaseBlood film

Concentration methods

Biopsy of the lymph nodes, CSF

PCR

Blood culture, xenodiagnostics

Chronic phaseSerology

HIV, congenital, transplantation

such as in acute phase

Positive skin test T. cruzi

Chronic phase of infection

XENODIAGNOSTICS

• Nifurtimox (LAMPIT)• 2,6 – 3,6 mg/kg (children 3-5 mg/kg) p.o. 3x

day 90 days

• Benznidazol (RADANIL)• 2,5 – 3,5 mg/kg (children 5 mg/kg) p.o. 2x

day 60 days• Also effective in early chronic phase

• Allopurinol

• Symptomatic treatment of chronic phase

• Follow up by decline of antibodies levels

Therapy for acute or congenital disease, reactivation or for children