Transcript 2. heamolymphatic stage

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 parasite
Vector: 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 distribution
Prevalence approximately - 50 mil.
20 – 50 thousand new cases per year
Approximately 55 thousand deaths/year
Belongs to so called neglected diseases
East 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
Site of inoculation
Local inflammation
Lymph, blood
Chronic inflammation of the
lymph system
CSF
Leptomeningitis
Variable Surface Antigens change = The
main mechanism of pathogenicity
• Variabile surface
coat VSG
(variabile glycoproteins)
• VSG protects from
phagocytosis and lysis by
alternative complement
pathway
• Trypanosomas
• Exhaustion of the
immune system
posses several
different genes coding
the surface antigens
• 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 skin
Intermitent 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
Anaemia
Polyneuropathy
sensitive, motoric
Weakness
kachexia
3. Meningoencefalic stage
Periferal polyneuropathy
(late hypersteasia after pressure on limbs and muscles, pruritus)
Headache
Inverse sleep
Personality, character changes
Chorea, 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.rhodesiensae
EPIDEMIOLOGY:
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
Fever
0, not always present
Slow onset up to 39°C
Present, large
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
Sleeping sickness
Current diagnostic approach and tools
I.
Screening:


II.
Serology (CATT, IFI, ELISA)
Cervical lymph node palpation
Diagnostic confirmation (parasitology):


I.
Cervical lymph node puncture
Detection of trypanosomes in blood
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
Pentamidin
Suramin
Suramin
Late phase
(cerebral)
Melarsoprol
Eflorithine
Nifurtimox
Melarsoprol
THERAPY
• 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 (JarischHerxheimer 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
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
Estimates of migrant residents from Chagas
disease endemic areas in nine studied European
countries
Basile et al, Eurosurveillance, 2009
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 bugs
The parasite is found within
feaces
Actively penetrates the skin
Transmitted 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/14/4/0
7-0489_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 nonendemic 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
Prognosis
Score 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 points
Risk 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 7
Prognostic 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 points
Risk 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 phase
Blood film
Concentration methods
Biopsy of the lymph nodes, CSF
PCR
Blood culture, xenodiagnostics
Chronic phase
Serology
HIV, congenital, transplantation
such as in acute phase
Positive skin test T. cruzi
XENODIAGNOSTICS
Chronic phase of infection
Therapy for acute or congenital disease,
reactivation or for children
• 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