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Simpozion Medical CYF Medical Diagnosticul Dirofilariozei [email protected] , pentru diagnostic metode de diagnostic si teste sunati la 0723318308.
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Dirofilaria infections in animals and
humans
Claudio Genchi, Med Vet, PhD, EVPC Dipl
Dept of Veterinary Science and Public Health, Università
degli Studi of Milano
Bucharest, June 14th, 2013
Biology and epidemiology of Dirofilaria infections throughout
Europe and risk for public health
Pathogenesis and clinical presentation: Dirofilaria immitis
versus Dirofilaria repens
New insights in the prevention and treatment of canine and
feline dirofilarial infections
Guidelines for the diagnosis of Dirofilaria infection in dogs and
cats
Dirofilaria and D. immitis, the cruel worm of the dog: 400
years of history
Francesco Birago, a nobleman living in Lomellina (Lombardy, Italy), in his Trattato Cinegetico ouero della Caccia(1626) made the first observation of heartworms during necropsy of an hunting dog and he wrote:
The dog suffers of one more disease, which is not possible to be cured …. Two worms develop in the kidney. They are long as an half harm (Dioctophyma renale) wide as a finger and red as the fire … they move and migrate to the heart (Dirofilaria immitis)…
In 1850, Joseph Leidy, a physician and naturalist from Philadelphia, described 3 worms found in the heart of a dog as Filaria canis cordis
In 1856, the same author redescribing the parasite, used for the first time the name of Filaria immitis
The genus Dirofilaria, from the Latin, dirus (bad, cruel) and filum (thin, filiform), was erected in 1911 by Raillet and Henry in 1911, two parasitologists at the the School of Veterinary Medicine of Alfort, Paris.
In Europe, 5 filarial species has been reported in dogs and cats:
Dirofilaria immitis Leidy, 1856, Dirofilaria repens Raillet and Henry,
1911, Dipetalonema dracunculoides Cobbold, 1870,
Acanthocheilonema (syn. Dipetalonema) reconditum Grassi, 1890
(but a complete description of developmental stages in the fleas
was done by Calandruccio, 1892), Cercopithifilaria (syn.
Acanthocheilonema) grassii Noé, 1907.
Filarial parasite VectorsPrepatent
period
Length of adult
wormsLocation of
adult worms
Dirofilaria immitisMosquitoes
(Culicidae)120-180 days
M: 12-18 cm
F: 25-30
cm
Pulmonary arteries/right
heart
Dirofilaria repensMosquitoes
(Culicidae)189-259 days
M: 5-7 cm
F: 10-17
cm
Subcutaneous
tissue/muscular
fasciae
Acanthocheilonema
(formerly Dipetalonema)
reconditum
Flies and ticks 427-476 days
M: 9-17 mm
F: 21-25
mm
Subcutaneous
tissue/muscular
fasciae,
peritoneal cavity,
kidney
Acanthocheilonema
(formerly Dipetalonema)
dracunculoides
Fleas and ticks (R.
sanguineus)120 days
M: 15-31 mm
F: 33-55
mm
Peritoneal cavity
Cercopithifilaria spp.Ticks (R.
sanguineus)?
M: unknown
F: 23-24
mm
Subcutaneous
tissue/muscular
fasciae
www.ESCCAP.org Guideline 6 VBD
Dirofilaria diseases are vector-borne parasitic infections
mainly of dogs and cats (and wild carnivores) that in
Europe are caused by Dirofilaria immitis and D. repens
and D. immitis only in the Americas.
D. immitis, the cruel worm of dogs, is the causative agent
of canine and feline heartworm disease.
D. repens, is the causative agent of subcutaneous
infections and its interest is mainly due to the high
zoonotic potential.
Distribution of Dirofilaria infection
The life cycle of both parasites consists of 5 larval stages developing
both within an intermediate mosquito host [from embryo - microfilaria
- to infective L3), that also acts as vector, and in a definitive
vertebrate host [from L3 to the adult worms].
Adult D. immitis worms occur in the pulmonary arteries and right
heart chambers, causing a severe condition known as canine and
feline heartworm disease, while D. repens is found mainly in
subcutaneous tissues (subcutaneous dirofilariosis). Adult parasites
released microfilariae in the blood stream where they are picked up
by mosquitoes during their blood meal.
The development from L3 to adult stages lasts 6-8 months.
Mosquito becomes infected taking blood from a microfilaraemic
host. Mf remain in the mosquito midgut for approximately 24 h,
then larvae become shorter and stouter (‘sausage’ stage). Larvae
molt to the second stage 8 -10 days after infection and again to
the third stage (L3) 2 - 3 days later. L3 perforate the distal ends
of the Malpighian tubules and migrate to the head and
mouthparts where they become infective (1100–1300 µm long).
The time required for the development of microfilariae to the
infective, third stage is temperature-dependent. At 27 °C and
80% relative humidity, development takes about 14 days.
Biology
Infective L3 are transmitted to the definitive host while the mosquito is
taking a blood meal: the tip of the labellum (fleshy part of the
mouthparts) ruptures and the L3 are deposited on the skin in a drop of
the mosquito’s haemolymph. Three days after infection, most of the
larvae are found in the subcutaneous tissues near their entry site. By
day 21, most of them have migrated to the abdomen of the dog,
The molt from L3 to L4 begins as early as day 3 days and as late as
day 9 - 12. L4 molt to the final stage [L5] at day 50 - 70; the first
worms entering the pulmonary artery on day 70 - 85 are 2 - 4 cm in
length. They become sexually mature (25-30 cm length) about day
120 post-infection. Dogs develop patent infections (circulating mf) as
early as 6 months, but usually by 7 - 9 months post-infection.
Biology
When juvenile heartworms first reach the lungs and the heart,
the pressure of venous blood forces them into the small
pulmonary arteries. As they increase in size, they migrate
upstream into larger arteries until the worms become fully
mature. The location of the adult worms depends on the size
of the dog and the worm burden.
A medium-sized dog with a low worm burden (i.e., 10) usually
has worms mainly in the lobar arteries and main pulmonary
artery. As the worm burden increases, worms are also located
in the right ventricle. Dogs with more than 40 worms are likely
to have caval syndrome, and most of worms migrate into the
right ventricle, right atrium and the caudal vena cava, thus
interfering with valvular function and/or blood flow.
Biology
Dog: aduld worms are able to survive until 7 years
mf: until 12-18 months
usually infected both by male and female worms
Cat: in most cases adult worms are able to survive 1½
year, but they can survive in asyptomatic cats until 4
years.
Most cats are amicrofilaraemic, when present, mf
can survive about 2 months
frequently infected by male or female worms only,
most infection abort (no adult worms in about 70% of
cats)
Biology
• Change in environmental ecology (global warming)
• Change in parasite ecology
• Decrease in natural resistance
• Economy
• Changed habit of human population
Factors affecting the spreading of parasitic
infections
The global average air temperature rose
0.74°± 0.18°C during the last 100 years
GLOBAL WARMING
Indeed, global climate change
will affect disease vector
behaviour, which in turn may
alter the current patterns of
vector-borne diseases
transmitted by the bite of
haematophagous arthropods
(Rogers and Randolph, 2006).
Arthropod vectors are cold-
blooded animals, meaning that
their internal temperature is
greatly affected by the
temperature of their
environment (Purse et al,
2005).
Factors for the spreading and establishment of infections
in pets
Furthermore, great concern has arisen following the introduction of less restrictions in the movement of pets throughout European countries, which can increase the risk of spreading of arthropod-borne diseases, such as filarial infections
In Practice 1999, 21: 482-491
Distibution of D. immitis in Italy: 1986-1988Genchi et al., 1988. Atti IV Seminario SCIVAC
Since the first
epidemiological studies,
north Italy, mainly the Po
River Valley, has been
shown the most endemic
area for canine HW
disease in Europe while
D. repens was distributed
mainly in central and
south regions of the
country
Starating and ending period of Dirofilaria transmisson risk in 74 Italian 1
provinces calculated for the decades 1980-1989, 1990-1999 and 2000-2012. 2
3
Decades
1980-1989
1990-1999
2000-2012
Transmission risk Number of weeks Number of days
strating-ending 16 Apr - 8 Oct
25
175
strating-ending 16 Apr - 29 Oct
28
196
strating-ending 2 Apr – 6 Nov
31
217
4
From south to north? From west to east?
Austria Germany Switzerland Serbia Albania Bulgaria Ucraine Czech Republic Hungary
Hinaidy et al., J. Vet. Med., B 1987 34: 326-332 Reuther, Wschr Thierheilk 1888; 32: 429-430 Wenzel and Fallbericht, Kleintierpraxis 1898 34: 27-28 Leuterer and Gothe, Kleintierpraxis 1993 38: 633-646 Wohlsein and Brandes, Kleintierpraxis 1996 41: 367-374 Zahller et al., Tierärztl Prax 1997 25: 388-392. Arnold et al., Schweiz Arch Tierheilk 1994 136: 265-269 Deplazes et al., Schweiz Arch Tierheilk 1995 137:172-179 Bucklar et al., Schweiz Arch Tierheilk 1998 10 Tasić et al., Parasitol Res 2008 103: 1297-1302 Rapti and Rehbein, Parasitol Res 2010 107: 481-485 Georgieva et al., Bulgarian J Vet Med 1999 2: 121-124 Georgieva et al., Bulgarian J Vet Med 2001 4: 231-236 Mazurkevich et al., Vet Rec 2004 155: 638-639 Svobodova and Mišoňova, Vet Paasitol 2005 128: 137-140 Boros et al., Magyar Allatorvosok Lapja 1982 121 : 313-316 Zahler et al., Tierztlic. Praxis, 1997 25: 388-392 Szell et al., Magyar Allatorvosok Lapja 1999 121 : 100-104 Kleiter et al., Kleintierpraxis 2001 46: 283-288 Farkas, Helmithological Colloquium, 14th Nov, Vienna 2003
Country
Year
Prevalence (%)
No. of cases
Reference
Switzerland
1998
1.6% 8/479
Bucklar et al., Schweiz Arch Tierheilk 1998 140:255-260
Germany June 1993 - May 1996
72 Zahller et al., Tierärztl Prax 1997 25: 388-392
The Netherlands 1992-1993 1982-1992
7 9
Meyer et al., Vet. Quartely 1994 16: 169-174
Tourism-associated canine Dirofilaria infection in northern
Europe
Until recently, interest in Dirofilaria infections has been
focused primarily on D. immitis because of its
pathogenicity in companion animals.
However, the increasing spread of D. repens towards
eastern and northern Europe has renewed the interest for
this species. Furthermore, human infections caused by D.
repens are dramatically increasing in Europe.
To note …
Main factors allow the spread of Dirofilaria infection around
the world including socio/economic factors conditioning
the abundance and movement animal reservoirs able
to acts as donors of microfilariae to mosquitoes throughout
a blood meal and mosquito species and abundance,
however temperature plays a key role:
environmental temperature maintains/increases the
abundance of competent mosquitoes
temperature is critical for the development of mf and for
the duration of infection transmission season to new hosts
Worming and introduction
of exotic mosquito
species in Italy as a
consequence of trade
exchanges
1990: Aedes albopictus
1996: Aedes atroparvus
2011: Aedes koreicus
Distribution
D. immitis
D. repens
Anophelinae Anopheles claviger*
N, S, Si, Sa
-
-
Anopheles maculipennis N, S, Si mol/field mol/field
Culicinae Aedes albopictus
N, S, Sa
mol/field
mol/filed
Aedes cantans* N - - Aedes caspius* N, S, Si, Sa - - Aedes cinereus N mol/abd - Aedes geniculatus N, S, Si, Sa mol/abd - Aedes detritus N, S, Si, Sa mol/abd - Aedes punctor N, S mol/abd - Aedes vexans* N, S, Si, Sa - - Coquillettidia richiardii* N, S, Si, Sa mol/field - Culiseta annulata* N, S, Si, Sa - - Culex modestus N, S, Si, Sa mol/abd - Culex pipiens N, S, Si, Sa mol/field mol/field Culex torrentium N mol/abd - Culex territans* N, S - -
Proven or suspected Culicidae vectors of D. immitis and D. repens
in Italy
(North: N; South: S; Sicily: Si; Sardinia: Sa); studies by dissection or PCR of field collected samples
(mol/field). PCR positive abdomens (mol/abd) do not proving vector competence are also reported.
Central Italy: mosquitoes CO2 trapped and PCR for
Dirofilaria worms [2002-2003]
Tested
PCR positive
Mosquitoes
Individuals
Pools
head-torax
abdomen
%
Cx. pipiens Cx. hirritans Ae. albopictus Ae. caspius Ae. cinereus Cs. annulata
1,108
1 436 29 1 1
412
31 0 43 0 0 0
32 0 24
0 0 0
0.54
1.37
1 two D. repens, one D. immitis
2 one D. repens, two D. immitis
3 two D. repens, one D. immitis and D. repens
4 one D. repens and D. immitis
Cancrini et al, 2007
Aedes albopictus: introduced in Italy in 1991 and proved Dirofilaria vector in 2003
Cx. pipiens: 1 two D. repens and one D. immitis, 2 one D. repens and two D. immitis
Ae. albopictus: 3 two D. repens, one D. immitis; 4 one D. repens and one D. immitis
The rate of Dirofilaria maturation to infective third-
stage larvae (L3) in the mosquito vector(s)
depends mainly on the environmental
temperature, and there is a threshold of about
14°C below which development will not proceed.
Temperature dictates the development of
Dirofilaria larvae in the intermediate hosts
Temperature
Dirofilaria immitis
Dirofilaria repens
in Aedes spp. 28-30 °C 26 °C 22 °C 18 °C
8-9 days 10-14 days
17 days 29 days
8-10 days 10-11 days 16-20 days ~ 28 days
in Ae. albopictus 26 °C
14-18 days
16-18 days
Time requirements for Dirofilaria mf development to infective stage
at different temperatures
Temperature dictates the seasonal occurrence
of heartworm transmission in temperate
latitudes
The total environment heat required for
development may be expressed in terms of
degrees days in excess of this threshold
[Dirofilaria Development Units – DDUs]
The seasonal Dirofilaria transmission model
assumes a requirement of 130 Heartworm DUs for
larvae to reach infectivity and a maximum life
expectancy of 30 days for a vector mosquito (Slocombe et al., 1989; Lok and Knight, 1998)
Rationale
•A program was developed in order to calculate the
DDUs for 2556 European Meteorological Stations in
Europe
• Threshold value of 130 cumulative DDUs was
accepted only if it was reached in 30 consecutive days.
•Data interpolated utilizing the Linear Kriging of GIS
Model: Europe
1971-2000: 854 examined meteorological stations
Meteorological stations reaching the 130DDUs based on
the average temperature of the 15 studied years
May: 112 June: 356 July: 548
August: 550 September: 299 October: 65
Monthly average
predicted number of
HW generation
obtained by Linear
Kriging interpolation
May - November
ESCCAP Guideline 5, 2012
Control of vector-borne diseases
in dogs and cats
As for HW infection, D.
repens until recently was
mainly present in
northern Italy and
southern of France.
From 2000, the infection
was more and more
often diagnosed in
northern-eastern
countries.
Currently subcutaneous D. repens infection is
diagnosed in Italy, France, Spain, Switzerland, Austria,
Germany, The Netherlands, Poland, Czech Republic,
Hungary, Croatia, Slovakia, Serbia, Romania, Greece,
Russia
Interestingly, in several countries the spreading of
infection was firstly reported through human cases
Pantchev et al: Diagnosis of imported
canine filarial infections in Germany 2008-
2011. Pasitol Res 109 S61-S67 2011
Host
D. immitis
D. repens
A. reconditum
Reference
Dog [Vojvodina]
7.2%
49.2%
2.1%
Tasić et al 2008
Humans
>29 cases; most
ocular and periocular
Kranijčić-Zec et al 1998 Džamić et al 2004 Džamić et al 2009 Tasić et al 2011
Serbia
5.1%
38.3%
18.5%
2%
D. immitis
D. repens
Location
Reference
35% 23%
presence 3.5%
3.5% (1) 7%
0-31% (2)
presence
n.d. n.d. 81%
presence (1) 17% n.d.
whole country
Bucharest area whole country Timiş County whole country
south-western areas whole country
Olteanu et al, 1996 Coman et al, 2007 Fernoagă et al, 2010 Ciocan et al, 2012 Hammer et al, 2012 Ilie et al., 2012 Micean et al, 2012
(1) Dogs imported from Romania to Germany (2) Depending on the region
Prevalence of Dirofilaria infections in Romania
Geographic distribution of D. immitis in Romania [Ag Elisa]
Mircean et al, 2012 Vector-Borne Zoon Dis 12: 595-604
Humans are susceptible hosts for dirofilarial worms
[accidental hosts]
Usually the worm does not develop into adult stage and
humans are not microfilaremic, although at four cases of
microfilaraemic zoonotic infections have been reported
in Europe.
The severity of the infection depends on the localization
of the parasite
Though the first case of D. immitis human infection has
been found in Italy (histology and PCR), D. repens is the
most frequent cause of zoonotic infection in Europe and
Asia (more than 1500 cases vs 300-350 cases of HW
human infections in USA and Japan)
Human Dirofilaria repens infection in Europe: from
emergency to endemicity?
1900 - 1994: 267 cases 56/year
1995 - 1999: 264 cases 53/year
2000 - 2013: 1782 cases 137/year
Country
No.
cases
Ocular
Pulmonary
Other unusual and seriousness localization
France Greece Hungary Italy Ukraine Poland Russia (Siberia included) Turkey Other countries²
81 36 31
324 932 18
109¹
22 229
22 7
19 62 18
44
12 120
2 1
23 2
intradural tumor like scrotum abdominal cavity spermatic cord, spermatic duct, scrotum intravitreal, 7 intra-oral cases in Sri Lanka, 16 scrotal, 2 spermatic cord, 1 testis, 1 epididymis, 1 associated with meningoencephalitis (surgery in Germany)
Total
1782
305
27
¹ Sergiev et al [65] reported of worms from 140 individuals identified as D. repens; such a
figure has not been added to Russian cases because of incomplete description.
² Albania, Bulgaria, Croatia, Dubai, Former Yugoslavia, Georgia, Kazakhstan, Kenya, India,
Iran, Israel, Japan, Malaysia, Poland, Romania, Serbia and Montenegro, Slovenia, Spain, Sri
Lanka (more than 132 cases), Tunisia, Turkmenistan, Uzbekistan, USA
Human D. repens infections published from 1900-2013
Subcutaneous nodules
Deep localizations intraperitoneal in lungs mimicking
tumors
Ocular localization with impaired vision and floater-
like mobile shadow seem to be the most frequent
symptoms, but infection is seldom accompanied by
loss of vision or serious ocular complications;
intravitreal ocular infection is quite rare but possible
The severity of the infection depends on the
localization of the parasite
Human infection
Gherman 1967 (pers comm): hand dorsum
Olteanu 1997: many human cases, probably D. repens
Panaitescu et al, 2000: no data
Mănescu et al, 2009: a subcongiuntival nodule caused by D. repens
Popescu et al, 2012: unusual and severe clinical manifestations that
mimicked pathological conditions like cellulitis or deep venous
thrombosis. The diagnosis was performed by histology and PCR.
Romania
Typical features of D. repens are the external longitudinal ridges, the thick
cuticula, and the well-developed musculature. Around the parasite a
marked inflammatory reaction with numerous eosinophils, neutrophils,
lymphocytes, plasma cells, and macrophages. Many IgE-positive plasma
cells are present in the infiltration and near to the surface of the parasite
… and recently the first case of Dirofilaria autochtonous
infection in has been diagnosed in Poland
Most studies have reported D. repens in animals
mainly from north-eastern European countries (i.e.:
north eastern Austria, Germany, The Netherlands,
Hungary, Poland) and even when D. immitis is
present, D. repens shows higher prevalences (i.e.:
northern Serbia and Hungary).
Human D. repens infections showed the same trend:
the more recent and severe cases have been reported
from north eastern countries such as Hungary, Slovak
Republic, Poland, Russia and Romania.
Why D. repens is spreading more rapidly than D.
immitis?
Intermediate hosts competence? D. repens microfilariae are more
easily destroyed by the bucco-pharyngeal armature of some
mosquito species (e.g.: Culex pipiens). Very few mf can develop to
infective stage. In such a way, both the mosquito fitness and their
ability to transmit the infection are not affected.
The spreading throughout Europe of Ae. albopictus. This species
has shown to be infected by Dirofilaria larvae 2.5 times more than
C. pipens, which is a proven intermediate hosts for dirofilarial
worms.
D. repens has been found, when first established in the host, to be
able to stimulate a specific immune response able to reduce the
ability of D. immitis to develop into adult worms.
Some hypothesis
Most D. repens infections in dogs are asymptomatic while
HW infections usually cause severe clinical disease. It is
thus likely that dogs who travelled to endemic areas of
southern Europe become infected and when they return to
northern areas, having no apparent symptoms, act as
donors of microfilariae to local mosquito populations. On the
contrary, dogs with heartworm infection are usually referred
to veterinary clinics and cured. If such an hypothesis is
confirmed, considering that an increasing number of dogs
travel for holidays or relocation and that pet travel is now
facilitated by the new schemes in many European countries,
subcutaneous dirofilarial infection could continue its spread.
Some hypothesis
Dirofilaria immitis
Severe clinical signs
Mf in the blood by Knott test
Ag serology in dogs and Ab in
cats by Elisa
Very effective preventative drugs
Adulticide tharapy
Apparently uncommon
zoonotic infections in Europe
Dirofilaria repens
Mostly no clinical signs
Mf in the blood by Knott test
No serology
Only moxidectin has been confirmed as an effective preventative
No adulticide therapy
Most common agent of human
dirofilariosis in Europe