Gastro-intestinal (soiltransmitted) nematodes
 GI nematodes infect half of the world’s population, mortality is
low however, considerable morbidity of heavy chronic
infections especially in children slowing physical and
intellectual growth (public health programs)
 Biology of Ascaris & hook worms
 Pathogenesis of hook worms
 Expulsion of GI nematodes depends on lymphocytes
 The T-cell response makes choices and polarizes to respond
appropriately (TH1 or TH2)
 Protective responses to worms are usually of the TH2-type and
produce immunological as well as physiological changes to
combat the worm
 Lack of helminth infection may result in an immune system with
a less robust feedback control and be a factor in the higher
prevalence of autoimmunity and allergy (Hygiene hypothesis)
Filaria and filariasis
Tissue dwelling nematodes with adults
and L1 present in the human host
Arthropode vector which takes up L1 and
transmits L3
Onchocerciasis, Lymphatic filariasis,
(Loiasis)
onchocerciasis
 A progressive inflammatory
eye and skin disease
 River blindness
 18 million people infected of
which 770,000 already have
impaired vision with 250,000
blind (estimates for 2003)
 Caused by infection with the
filarial nematode
Onchocerca volvulus
onchocerciasis
 The disease was most
prevalent in West Africa,
but now has been
dramatically reduced
there
 Significant transmission
still occurs in several
central African countries
 Transmission on the
American continent is
now reduced to a few
very small foci.
onchocerciasis
 Infection occurs in
proximity to fast moving
water (river blindness)
 At the beginning of the
river blindness
campaign 25 years ago
many West African
villages in close
proximity of rivers were
deserted because
people feared blindness
 in some communities up
to 90% of inhabitants
tested positive for filaria
onchocercosis
 Adult worms (macrofilaria)
live in nodules under the
skin of the human host
 The female is ovovivipar
and releases L1
(microfilaria)
 Microfilaria migrate
through he cutis
 Black flies take up
microfilaria through the
blood meal, the worms
settle in the fly thorax
muscle and develop into
infectious L3
onchocerciasis
 Onchocerca is transmitted by
black flies (Simulium spec.,
especially S. damnosum)
 Black flies are small diptera
with a fly like habitus (but
they are Nematocerca (closer
related to mosquitoes)) and
only the females bite)
 Larvae and pupae are
aquatic filter feeders, living in
fast flowing oxygen rich
waters
onchocerciasis
 Black flies do not have deep
penetrating mouthparts
 They make a relatively small
incision with their mandibles
and maxillae and take up
the lymph and blood
collecting in this wound
(pool feeding)
 This is how they take up
microfilaria (L1)
 L3 invade the labium, and
break through the thin
membrane during blood
feeding and enter the
wound
onchocerciasis
 L1 and L2 develop in the
flight muscle in the thorax
 These stages are
intracellular similar to the
Trichinella larvae in
mammalian muscle that we
discussed earlier
onchocerciasis
The adult worms form nodules in the cutis which are enclosed by
the host with a fibrotic granuloma (onchocercoma). Inflammatory
reaction against macrofilaria is very mild. Onchocercomas are
easily spotted especially when over bone or strong muscle
onchocerciasis
 Microfilaria migrate through the
connective tissue especially the
dermis of the skin and cause most
of the pathology (unsheated,
tapered and sharply bend hind end)
 Living migrating microfilaria seem
to cause little or no inflammation
 Dead microfilaria however
stimulate potent inflammatory
reactions (treatment can have
therefore severe side effects, (mild
with Ivermectin but can be
pronounced with DEC)
onchocerciasis
 The response in the skin
(and the eyes) is mainly a
TH2 polarized response
 The inflammatory
reaction causes
progressive pathological
changes of the skin
 These are in part due to
the reaction to
microfilaria and in part to
secondary bacterial
infection
onchocerciasis
 Inflammation in the skin
causes an unbearable
itch provoking
scratching which is the
main source of
additional secondary
infection of the skin
 Chronic scratching also
mechanically stresses
the skin
onchocerciasis
Inflammation and
constant scratching
often leads to
depigmentation of
skin (leopard skin)
which is especially
visible on dark skin,
and progressive loss
of elasticity resulting
in skin hardening
onchocerciasis
Late stages can
present a hardened
and cracked skin
surface
(lichenification)
Hanging groin and
elephantiasis of the
genitals are additional
severe manifestations
onchocerciasis
 Microfilaria also migrate
through the eye
 Again inflammatory
reactions around dead
microfilaria seem to do
the most damage
 Progressive chronic
scaring of the cornea and
to a lesser extend of the
retina and optical nerve
lead to vision impairment
onchocerciasis
 Chronic microfilaremia in the
eye leads to sclerotizing
ceratitis (a hardening
inflammation of the clear
front part of the eye)
 The cornea becomes
opaque resulting in gradual
loss of sight
 Nodules directly on the head
seem to result in higher mf
burden for the eyes and fast
progression to blindness
even in children
Are endosymbionts involved in
filarial pathogenesis?
 Wolbachia bacteria are
found as intracellular
endosymbionts in the
hypodermal lateral chord
and the uterus of many
parasitic nematodes
(here Brugia malayi)
 The bacteria seem
important for nematode
development as antibiotic
treatment results in
sterility (and maybe even
death) of the adults
Are endosymbionts involved in
filarial pathogenesis?
 Sections through onchocercomas in
untreated (upper) and antibiotic
treated patients (11 months after a 6
weeks course of doxycyclin)
 Note that Wolbachia detected by red
stain are absent in the treated patient
 In addition the treated worms show no
healthy eggs or embryos
 This suggest that antibiotics might
provide new therapeutic approaches
for the treatment of filariasis
 There are also studies that suggest
that the bacterial antigens might be
responsible for the strong
inflammation and hence pathology
onchocerciasis
 Diagnosis: skin snip,
demonstration of
microfilaria in the cutis. A
small piece of skin is cut
and placed into saline.
Microfilaria emerging
from the sample can be
observed microscopically
 Antibody tests suitable
for large scale
epidemiology are also
available now
onchocerciasis
Nodulectomy: adult
worms can be
removed surgically to
reduce microfilarial
load to alleviate
symptoms
onchocerciasis
 Onchocerciasis has been the
target of several long standing
(>25 years) highly successful
control programs
 The carter center is a major
organizer of this program
(check out
http://www.cartercenter.org/he
althprograms/healthpgm.htm
for excellent information on
this and other parasite control
programs of the CC)
 One arm of the program has
been vector control mainly by
large scale application of
larvicides on target rivers
onchocerciasis
 The second arm has been
treatment
 Diethylcarbamazine DEC (kills
microfilaria and in some
species macrofilaria slowly
with unknown mechanism)
 Sudden death of many MF can
lead to severe inflammatory
reaction of skin and eye
 Ivermectin (paralysis of worms
by interfering with neural
ionchannels), does not kill
macrofiliaria but dramatically
reduce MF number and has
milder side effects than DEC
 Pretreatment with steroids can
reduce side effects
onchocercosis
 Annual community mass
treatment is used to alleviate
pathology due to microfilaria
and to reduce the number of
new infections
 The most successful model
developed for this programs
is Community Directed
Treatment (the affected
community assumes full
responsibility for
distribution, collection and
reporting of the drug and
also shares in the cost)
 Pharmaceutical companies
have donated free drugs for
this purpose
Onchocercosis: is there
drug resistance in humans?
 Large scale treatment programs could select for the emergence of
drug resistance
 Resistance to ivermectin (and other antihelmintica) is rampant in
nematodes that infect livestock (especially in small ruminants and
horses)
 So far ivermectin remains effective in the treatment of Onchocerca
 However, there are several studies that claim to detect the early
emergence of drug resistance.
 Quick recrudescence of microfiliaria in some treated individuals
 Genetic studies that suggest that drug treated worm populations
are under selection
 None of these studies offers final hard proof and they have many
critics, however they warrant concern and demand tight
surveillance of efficacy and also heighten the need for additional
new drugs/vaccines with different mode of action
lymphatic filariasis
 Long known disease
which only in a minority
of cases results in severe
elephantiasis
 120 million people
infected of which 40
million show symptoms
(1996)
 Caused by three species
of filaria: Wucheria
bancrofti, Brugia malayi,
B. timori
lymphatic filariasis
Wucheria bancrofti
Brugia malayi
lymphatic filariasis
 Adult worms
(macrofilariae) live in the
lymphatic vessels and
lymph nodes of the lower
body half
 Females are
ovoviviparous producing
L1 larvae still in the egg
membrane (the sheath)
lymphatic filariasis
 L1 lavae or microfilariae
are swept into the blood
stream and circulate
 W.b. microfilariae are
sheated and the nuclei
do not reach the tip of the
tail
 Microfilariae remain
viable and infective for
several months
lymphatic filariasis
 Microfilaria show diurnal
rhythm
 Wucheria and Brugia
microfilariae are found in the
peripheral blood during night
time whereas Loa is found
during the day hours
 This is phenomenon is not
linked to egg production but
to the behavior of the MF
 The benefit (of absence from
the peripheral blood during
the day is unclear)
lymphatic filariasis
Culex quiquefasciatus
W. bancrofti L1 in mosquito flight muscle
 Mircofilariae are taken up
by mosquitoes with the
blood meal
 Broad spectrum of night
active vectors (Culex,
Aedes, Anopheles,
Mansonia)
 Microfilaria leave sheath
in the mosquito midgut,
penetrate the midgut wall
and migrate to the flight
muscle where they molt
twice (the develop intracellularly)
lymphatic filariasis
Brugia pahangi, courtesy of Sara Erickson &
Bruce Christensen, U-Wisconsin Madison
 L3 migrate through
hemolymph until they find
the labium, which they
penetrate when they
sense that the mosquito
is feeding
 They move onto the skin
and into the wound
puncture
 Development in mosquito
takes about two weeks
lymphatic filariasis
 Maturing larvae and adults
provoke strong inflammatory
reaction
 Acute symptoms are painful
lymphnode and lymphchannel
inflammation and swelling
which is often accompanied by
fever
 Brugia infection is very similar
to Wucheria
 Acute reactions are more
pronounced (e.g. formation of
abscesses)
 Elephantiasis tends to affect
arms instead of legs
lymphatic filariasis
 Progessive chronic
disease can lead to wide
spread fibrosis and
damage of lymphatic
vessels, which can result
in rupture and discharge
of lymph into the urinary
system (chyluria) or the
scrotum
lymphatic filariasis
 In men chronic infection often
results in hydrocele, a painful
swelling of the scrotum due to
blockage and inflammation of
the adjacent draining lymph
vessels
 Up to 20% of all grown man in
certain communities in Haiti
suffer from hydrocele
 No effects on fertility, but wide
spread sexual disability
 Profound effects on patients
self esteem and family life
lymphatic filariasis
Adult filaria can be
detected in the scrotal
lymph vessels of men
with hydrocele by
ultra sound
Macrofilaria can be
identified easily by
there mobility
lymphatic filariasis
 Chronic disease has complex
inflammatory etiology
 Dieing filaria are especially
potent in triggering inflammation,
and death of worms if followed
by episodes of fever, pain and
acute inflammation
 Recent work suggests that, in
addition to adult worms,
secondary bacterial and fungal
infections play an important role
in acute episodes and chronic
progression of the disease
lymphatic filariasis
Only a minority of
patients progresses
to elephantiasis and
the factors
contributing to their
susceptibility are not
well understood
©WHO-TDR
lymphatic filariasis
Diagnosis:
 Demonstration of
microfilaria in blood, or
lymph (has to be done at
night!)
 Antibody and antigen
capture assays (dip stick
format)
 Demonstration of adult
worms by ultra sound
lymphatic filariasis
Oedema of arm and
hand in this patient
with filariasis
Leasons between
fingers and toes are
especially vulnerable
to bacterial infection
lymphatic filariasis
 Chemotherapy can be
used to kill microfilaria but
does not affect adult
worms (antibiotic treatment
targeting Wolbachia may
hold promise here)
 However strict antiseptic
regimens using soap and
antibacterial ointments can
greatly reduce swelling,
pain and other symptoms
and even revert many
severe symptoms
lymphatic filariasis
http://www.who.int/tdr/media/video/productions.htm