Human African trypanosomiasis one of the neglected tropical diseases

1. Human African
Trypanosomiasis
Otile Jacob MBChB 3
20th/June/2018

2. Outline
• Definition
• Introduction
• Epidemiology
• Pathophysiology
• Clinical features
• Investigations
• Ddx
• Management & follow-up

3. Definition
• Trypanosomiasis is one of the neglected tropical diseases caused by Trypanosoma
brucei spp.

4. Introduction
• Sleeping sickness or human African trypanosomiasis (HAT) is still an
important health problem in Africa
• Caused by sub-species of the protozoan Trypanosoma brucei, which is transmitted to
humans by tsetse flies.
• The disease occurs in two clinically and epidemiologically distinct forms: West
(gambiense) and East African (rhodesiense) sleeping sickness
• An established infection invariably has a lethal outcome if left untreated.
• Proper diagnosis and correct patient management are therefore crucial.
• Dx & Rx, however, is difficult and complicated by many drug-related side effects

5. Epidemiology
• 60m people in 36 countries are at risk, but fewer than 4m are under professional &
constant surveillance.
• T.b. gambiense accounts for 97% of cases.
• However, the most affected areas are nearly inaccessible for epidemiological surveys
• Major epid. 1896-1906 in Uganda & Congo Basin
• Most recent 1970 and lasted till late 90s
• 1998 almost 40k cases were reported but estimated 300k cases were undiagnosed &
hence untreated.
• Most recent epid. Prev. was 50% in Angola, DRC, South Sudan &was 1st/2nd cause of
mortality ahead of HIV.
• In last 10yrs over 70% cases occurred in DRC & is the only country that currently reports
> 1k new cases annually=84% cases reported in 2015
• CAR declared 100-200 new cases in 2015.

7. Transmission
• Mainly, MOT is through the bite of infected tsetse flies (Glossina spp., order Diptera)
• Although congenital,
• Blood-borne eg sexual contact.
• Mechanical transmission have been occasionally reported (other blood sucking
insects but difficult to asses epid. impact)
• Accidental infections in labs through needles
NB
• Tsetse are biologically unique insects, which only occur in Africa.

9. The life cycle
• During the blood meal of infected mammalian host, the tsetse fly takes up trypanosomes
into its mid-gut, develop into procyclic forms and multiply.
• After about 2/52, they migrate to salivary glands as epimastigotes, where they finally
develop into infective metacyclic forms.
• With the next blood meal, they are then injected into the new vertebrate host.

11. Pathophysiology
• Metacyclic trypomastigotes inoculated transform into bloodstream trypomastigotes, which
multiply by binary fission.
• Spread through the lymphatics and bloodstream.
• Blood trypomastigotes multiply until specific Abs produced by the host sharply reduce
parasite levels.
• However, a subset of parasites escape immune destruction by a change in their variant
surface glycoprotein and start a new multiplication cycle.

12. Patho. Cont..
• The cycle of multiplication and lysis repeats.
• Late in the course, trypanosomes appear in the interstitial fluid of many organs,
including the myocardium and eventually the CNS.
• The cycle is continued when a tsetse fly bites an infected human.
• Humans are the main reservoir of T. b. gambiense, but this species may also reside in
animals. Wild game animals are the main reservoir of T. b. rhodesiense.

13. HAT StageI
Haemolymphatic stage:
• After local multiplication at inoculation site, invade the haemolymphatic system, where they can
be detected 7 to 10 days after the bite of the infective fly.
• Period of systemic spread
• Exposed to vigorous defense mechanisms of the host (which they evade by constant
Ag. variation)
• Hyper-IgG can reach extreme levels as a result of polyclonal activation of Igs.
• The IgM serum levels detected in trypanosomiasis are among the highest observed in any
infectious disease.
• In addition autochthonous production of IgM is commenced in the CSF.
• This continuous battle btn Ag. switches & humoral defence= undulating parasitemia with
parasite numbers frequently decreasing below detection level esp. in Gambiense

14. HAT Stage I features
• The cyclic release of cytokines during periods of increased cell lysis results in intermittent,
non-specific symptoms:
• Fever, chills, rigor, headache and joint pains.
• Hepatosplenomegaly & generalized lymphadenopathy are common, indicating activation
and hyperplasia of the RES.
NB: misdiagnosis common

15. Stage I features cont..
T.b. gambiense
• The early stage usually has fewer symptoms. Febrile episodes become less severe as the
disease progresses.
• Winterbottom’s sign
• Puffy face syndrome (pale skin) a myxedematous infiltration of connective tissue ‘
• A fugitive patchy rash
• Kérandel’s sign, inconspicuous periostitis of the tibia with delayed hyperaesthesia
In T.b. rhodesiense;
• Usually very pronounced with severe, acute symptoms and
• Heavy bouts of recurrent fever, frequently resulting in early death through myocarditis.

16. HAT stage II
Meningo-encephalitic stage
• Within weeks (T.b. rhod) & months (T.b. gam)
• Insidious CNS involvement, Cross the BBB
• More rapid sleeping sickness progression in children
• Increasing headache,
• Marked change in behaviour and personality.

17. HAT stage II cont..
• Gradually, focal or generalized, depending on the site of cellular damage in the
central nervous system.
• Convulsions are common (poor prognosis) .
• Periods of confusion and agitation slowly evolve towards a stage of distinct apathy
when individuals lose interest in their surroundings and their own situation.
• Sleep abnormalities result finally in a somnolent and comatose state.
• Progressive wasting and dehydration follow the inability to eat and drink

18. • Perivascular infiltration of inflammatory cells (‘cuffing’) and glial proliferation can be
detected suggesting an immune-mediated endarteritis.
• Cerebral involvement xterized by morular cells of Mott in brain tissue and CSF
(activated plasma cells with characteristic eosinophilic inclusions)

19. Clinical features
• Often, insidious onset, but will almost invariably kill, if not treated in time
• The natural course of sleeping sickness can be divided into different and distinct stages
The trypanosomal chancre
• Leave a small, self-healing mark.
• In event of trypanosomal infection, local reaction quite pronounced and longer lasting.
• A small raised papule develops after about 5/7, which increases rapidly in size. surrounded
by a heavy erythematous tissue reaction with local oedema and regional lymphadenopathy
• In T.b. rhodesiense infection, trypanosomal chancres occur in about half of the cases

22. Investigations
1. Non specific
• CBC (Anaemia and thrombocytopenia (TNF-alpha)
• Hyper IgG (polyclonal activation)
• IgM (highest in any infectious disease)
2. Specific
• Parasite in the aspirate from a chancre, blood, lymph juice (x400 stat), CSF
A. Wet preparation, thin and thick blood film
• Unstained wet
• Stained, thick stain (Giemsa or Field) preparations.

23. Invx cont..
B. CSF (minimum of 5mls, protein 37mg/100mls(dye-binding protein), Lymp,
5c/mm3=CNS involvement, eosinophilic inclusion morular cells of mott,). Latex IgM test
advance disease.
2. Concentration methods
• Quantitative buffy coat (QBC) (Accumulate just above the buffy coat layer after
centrifugation)
• m-AECT (mini anion exchange column technique) where trypanosomes are concentrated
after passage through a cellulose column=best result
• Capillary tube centrifugation widely used in the field
•

25. Invx cont..
3. Serological assays
• Detects Abs against trypanosomiasis.
• ELISA technique or immunofluorescence but provide reliable results only in T.b. gambiense
infection.
• CATT (card agglutination test for trypanosomiasis) is an excellent tool in areas of T.b.
gambiense infection.
• A visible agglutination in the CATT suggests the existence of Abs, but does not necessarily
mean florid disease.
4. LP for the examination of about 5 ml of CSF has to be performed in every patient (stage II)

26. Treatment
• Can be cured, if the diagnosis is made early.

28. Some adverse drug effects
Suramin (allergic rxn)
A/E of suramin are dependent on the nutritional status, concomitant illnesses (especially
onchocerciasis) and the general clinical condition of the patient.
Pentamidine (gen well tolareted)
• Adverse effects are related to the route of administration and/or its dose. They are usually
reversible.
• I V infusion on, given in normal saline over two hours, might be used instead.

29. Some adverse drug effects
Melarsoprol (reactive encephalopathy)
• Acute encephalopathy occurring in 5 to 14 per cent of all patients under treatment.
• ? immune-mediated precipitated by the release of parasitic Ag in the first days of
treatment.
• Prednisolone 1 mg/kg body weight
Eflornithine
• Less toxic than Melarsoprol
• Nirfurtimox + Eflornithine (introduced in 2009)

30. Follow-up
• Patients with sleeping sickness are often severely ill due to malnutrition and
concomitant infections.
• Good medical and nursing care will be decisive for the final outcome.
• Depending on the extent of cellular damage, some neurological symptoms will only be
partially reversible.
• Sequelae have to be distinguished from persisting infections as a result of resistant or
incompletely treated trypanosomes.
• Even re-infections have to be considered in endemic areas, as there is no reliable and
lasting immunity after infection.
• For reasons of individual care and epidemiological surveillance, patients have to be re-
examined regularly.
• In patients with late-stage disease, repeated LP are necessary in order to assess the
efficacy of treatment, preferably 1, 3 and 6 months after the end of Rx

31. Ddx
Causes of PUO
• Malaria,
• Brucellosis
• Enteric fever
• CCM
• Tuberculosis

32. References
• Principles of Medicine in Africa 4th Ed [PDF][tahir99] VRG
• WHO (www.who.int) 16th/Feb/2018
• CDC(http://www.dpd.cdc.gov/dpdx)

33. Thank you