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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
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