Publications by authors named "Trentina Di Muccio"

33 Publications

Refractory mucocutaneous leishmaniasis resolved with combination treatment based on intravenous pentamidine, oral azole, aerosolized liposomal amphotericin B, and intralesional meglumine antimoniate.

Int J Infect Dis 2020 Aug 4;97:204-207. Epub 2020 Jun 4.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy; Referral Center for Tropical Diseases of Tuscany, Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy. Electronic address:

Introduction: Mucocutaneous leishmaniasis (MCL) is a complication of tegumentary leishmaniasis, causing potentially life-threatening lesions in the ear, nose, and throat (ENT) region, and most commonly due to Leishmania (Viannia) braziliensis. We report a case of relapsing MCL in an Italian traveler returning from Argentina.

Case Description: A 65-year-old Italian male patient with chronic kidney disease, arterial hypertension, prostatic hypertrophy, and type-2 diabetes mellitus was referred for severe relapsing MCL acquired in Argentina. ENT examination showed severe diffuse pharyngolaryngeal edema and erythema, partially obstructing the airways. A nasopharyngeal biopsy revealed a lymphoplasmacytic inflammation and presence of Leishmania amastigotes, subsequently identified as L. (V.) braziliensis by hsp70 PCR-RFLP analysis and sequencing. Despite receiving four courses of liposomal amphotericine B (L-AmB) and two courses of miltefosine over a 2-year period, the patient presented recurrence of symptoms a few months after the end of each course. After the patient was referred to us, a combined treatment was started with intravenous pentamidine 4 mg/kg on alternate days for 10 doses, followed by one dose per week for an additional seven doses, intralesional meglumine antimoniate on the nasal lesion once per week for six doses, oral azoles for three months, and aerosolized L-AmB on alternate days for three months. The treatment led to regression of mucosal lesions and respiratory symptoms. Renal function temporarily worsened, and the addition of insulin was required to maintain glycemic compensation after pentamidine discontinuation.

Conclusions: This case highlights the difficulties in managing a life-threatening refractory case of MCL in an Italian traveler with multiple comorbidities. Even though parenteral antimonial derivatives are traditionally considered the treatment of choice for MCL, they are relatively contraindicated in cases of chronic kidney disease.The required dose adjustment in cases of impaired renal function is unknown, therefore the use of alternative drugs is recommended. This case was resolved with combination treatment, including aerosolized L-AmB, which had never been used before for MCL.
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http://dx.doi.org/10.1016/j.ijid.2020.06.003DOI Listing
August 2020

Use of miltefosine in a patient with mucosal leishmaniasis and HIV-coinfection: a challenge in long-term management.

Infez Med 2019 12;27(4):452-455

Hospital Department of Specialized and Internal Medicine, Infectious Diseases Unit, University Hospital of Siena, Siena, Italy; Department of Medical Biotechnologies, University of Siena, Italy.

The management of mucosal leishmaniasis in immunocompromised patients is not standardized and limited data are available on the use of miltefosine for treatment and secondary prophylaxis. We describe a case of mucosal leishmaniasis in an HIV-coinfected patient treated with miltefosine due to a severe allergic reaction to liposomal amphotericin B.
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December 2019

Cutaneous leishmaniasis caused by Leishmania (Viannia) guyanensis complex in a traveller returning from Bolivia.

Travel Med Infect Dis 2019 Nov 21:101524. Epub 2019 Nov 21.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy; Referral Centre for Tropical Diseases of Tuscany, Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.tmaid.2019.101524DOI Listing
November 2019

Recent autochthonous cases of leishmaniasis in residents of the Republic of Dagestan, Russian Federation.

Int J Infect Dis 2019 Sep 10;86:171-174. Epub 2019 Jul 10.

Unit of Vector-Borne Diseases, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

Eighty years after the last published record of human leishmaniasis from Dagestan, Russian Federation, we report two recent cases which were most probably acquired locally: one case of visceral leishmaniasis in a 2-year old child, and one cutaneous leishmaniasis case in a 39-year-old man co-infected with HIV, both resident in Dagestan.
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http://dx.doi.org/10.1016/j.ijid.2019.07.005DOI Listing
September 2019

Emerging feline vector-borne pathogens in Italy.

Parasit Vectors 2019 May 2;12(1):193. Epub 2019 May 2.

Department of Infectious Diseases, Unit of Vector-borne Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.

Background: The epidemiology of feline vector-borne pathogens (FeVBPs) has been less investigated in cats than in dogs. The present study assessed the prevalence of Rickettsia spp., Babesia spp., Cytauxzoon spp. and Leishmania infantum infections in cat populations living in central Italy, by molecular and serological tools.

Results: A total of 286 healthy cats were randomly selected from catteries and colonies in central Italy. Peripheral blood and conjunctival swab (CS) samples were collected during surgical procedures for regional neutering projects. Sera were analysed by IFAT to detect anti-Rickettsia felis, R. conorii, Babesia microti and Leishmania IgG antibodies using commercial and home-made antigens. DNA extracted from buffy coats (BCs) was tested for Rickettsia spp., and Piroplasmida species, including Cytauxzoon spp. and Babesia spp. by PCR. Buffy coats and CS samples were assayed by a nested (n)-PCR for Leishmania spp. Sixty-two cats (21.67%) were seropositive to at least one of the tested pathogens. The serological assay revealed 23 (8.04%) and 18 (6.29%) positive cats for R. felis and R. conorii, respectively, with low titers (1/64-1/128). No antibodies against B. microti were detected. Neither Rickettsia nor Piroplasmida DNA were amplified using the specific PCR assays. Thirty-one cats (10.83%) tested positive to anti-Leishmania IgG, with titers ranging from 1:40 to 1:160 and 45 animals (15.73%) tested positive to Leishmania CS n-PCR, whereas none of the animals tested positive to BC n-PCR. Considering the results obtained by IFAT and CS n-PCR, a moderate agreement between the two tests was detected (κ = 0.27).

Conclusions: The results of the serological and molecular surveys showed a moderate exposure to Leishmania in the investigated cats and highlighted the limited molecular diagnostic value of BC versus CS samples for this pathogen. Conversely no evidence supported the circulation of Cytauxzoon spp. in domestic cats, in contrast with previous detections in European wild cats in the same areas monitored. The low positive titres for R. felis in association with no DNA BC amplification prevent speculation on the exposure of feline populations to this FeVBP due to the cross-reactivity existing within spotted fever group rickettsiosis (SFGR).
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http://dx.doi.org/10.1186/s13071-019-3409-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498675PMC
May 2019

Structure-guided approach to identify a novel class of anti-leishmaniasis diaryl sulfide compounds targeting the trypanothione metabolism.

Amino Acids 2020 Feb 29;52(2):247-259. Epub 2019 Apr 29.

Istituto di Biologia e Patologia Molecolari, Consiglio Nazionale delle Ricerche, IBPM-CNR, c/o Dip. Scienze Biochimiche Università Sapienza, P.le Aldo Moro 5, 00185, Rome, Italy.

Leishmania protozoans are the causative agent of leishmaniasis, a neglected tropical disease consisting of three major clinical forms: visceral leishmaniasis (VL), cutaneous leishmaniasis, and mucocutaneous leishmaniasis. VL is caused by Leishmania donovani in East Africa and the Indian subcontinent and by Leishmania infantum in Europe, North Africa, and Latin America, and causes an estimated 60,000 deaths per year. Trypanothione reductase (TR) is considered to be one of the best targets to find new drugs against leishmaniasis. This enzyme is fundamental for parasite survival in the human host since it reduces trypanothione, a molecule used by the tryparedoxin/tryparedoxin peroxidase system of Leishmania to neutralize the hydrogen peroxide produced by host macrophages during infection. Recently, we solved the X-ray structure of TR in complex with the diaryl sulfide compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine), which impairs the parasite defense against the reactive oxygen species by inhibiting TR with high efficiency. The compound binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding. On the basis of the RDS 777-TR complex, we synthesized structurally related diaryl sulfide analogs as TR inhibitors able to compete for trypanothione binding to the enzyme and to kill the promastigote in the micromolar range. One of the most active among these compounds (RDS 562) was able to reduce the trypanothione concentration in cell of about 33% via TR inhibition. RDS 562 inhibits selectively Leishmania TR, while it does not inhibit the human homolog glutathione reductase.
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http://dx.doi.org/10.1007/s00726-019-02731-4DOI Listing
February 2020

Laboratory transmission of an Asian strain of Leishmania tropica by the bite of the southern European sand fly Phlebotomus perniciosus.

Int J Parasitol 2019 05 30;49(6):417-421. Epub 2019 Mar 30.

Unit of Vector-borne Diseases, Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Electronic address:

Imported cases of anthroponotic cutaneous leishmaniasis due to Leishmania tropica are increasingly documented in Europe. We investigated the ability of Phlebotomus perniciosus, a competent vector of Leishmania infantum widespread in southwestern Europe, to support the growth and transmissibility of an Asian strain of L. tropica recently isolated from a refugee. Parasite growth behavior was investigated in laboratory-reared sand flies fed artificially with promastigotes as well as in sand flies infected after biting on footpad lesions induced in hamsters by promastigote inoculation. The evolution of infection was checked by gut microscopy and quantitative real-time PCR, and it was found to be similar between promastigote- and amastigote-initiated infections. In 80% of infected sand flies, despite survival and flourishing growth of promastigotes after blood digestion and defecation, either the parasites died, or failed to migrate to the foregut and/or to mature into infective forms. However, in the remaining 20% L. tropica developed into abundant metacyclic promastigotes. The quantitative real-time PCR assay detected variable loads of gut promastigotes irrespective of morphological evidence of viability or progressive/final death. Parasite transmissibility was investigated by exposing naive hamsters to P. perniciosus previously infected on chronic lesions induced in hamsters which survived to take a second blood meal. Two months post exposure, lesions developed in skin sites bitten by sand flies confirmed to harbor metacyclic promastigotes; in the following months, the presence of viable and transmissible L. tropica parasites in lesions was demonstrated by xenodiagnosis assays. Our findings support the hypothesis that, in particular epidemiological situations, P. perniciosus may play the role of an occasional L. tropica vector.
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http://dx.doi.org/10.1016/j.ijpara.2018.12.009DOI Listing
May 2019

Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening.

PLoS Negl Trop Dis 2018 11 26;12(11):e0006969. Epub 2018 Nov 26.

Istituto di Biologia e Patologia Molecolari-CNR, and Dipartimento di Scienze Biochimiche, "Sapienza" Università di Roma P.le A. Moro, Roma, Italy.

Trypanothione reductase (TR) is considered to be one of the best targets to find new drugs against Leishmaniasis. This enzyme is fundamental for parasite survival in the host since it reduces trypanothione, a molecule used by the tryparedoxin/tryparedoxin peroxidase system of Leishmania to neutralize hydrogen peroxide produced by host macrophages during infection. In order to identify new lead compounds against Leishmania we developed and validated a new luminescence-based high-throughput screening (HTS) assay that allowed us to screen a library of 120,000 compounds. We identified a novel chemical class of TR inhibitors, able to kill parasites with an IC50 in the low micromolar range. The X-ray crystal structure of TR in complex with a compound from this class (compound 3) allowed the identification of its binding site in a pocket at the entrance of the NADPH binding site. Since the binding site of compound 3 identified by the X-ray structure is unique, and is not present in human homologs such as glutathione reductase (hGR), it represents a new target for drug discovery efforts.
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http://dx.doi.org/10.1371/journal.pntd.0006969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283646PMC
November 2018

Sand fly and Leishmania spp. survey in Vojvodina (Serbia): first detection of Leishmania infantum DNA in sand flies and the first record of Phlebotomus (Transphlebotomus) mascittii Grassi, 1908.

Parasit Vectors 2017 Sep 26;10(1):444. Epub 2017 Sep 26.

Faculty of Agriculture, Department of Phytomedicine and Plant Protection, Laboratory for Medical Entomology, University of Novi Sad, Novi Sad, Serbia.

Background: Leishmaniasis in Serbia was an endemic disease, and is considered to be eradicated for more than 40 years. In the past decade sporadic cases of canine leishmaniasis started to emerge for the first time in Vojvodina Province (previously non-endemic region of Serbia). Reports of introduced, and later on autochthonous cases of leishmaniasis alerted the possibility of disease emergence. The aim of this study was to bridge more than a half a century wide gap in entomological surveillance of sand fly vectors in Vojvodina, as well as to verify the presence of the vector species that could support Leishmania spp. circulation.

Results: During the period 2013-2015, a total of 136 sand flies were collected from 48 of 80 surveyed locations. Four sand fly species of the genus Phlebotomus were detected: P. papatasi, P. perfiliewi, P. mascittii and P. neglectus. Detection of P. mascittii represents the first record of this species for the sand fly fauna in Vojvodina and in Serbia. All female specimens (n = 80) were tested for Leishmania spp. DNA, and three blood-fed P. papatasi specimens were positive (4%). One positive DNA sample was successfully amplified by ITS1 nPCR. The RFLP analysis of the resulting 350 bp fragment showed a typical pattern of L. infantum, and the ITS1 partial sequence blasted in GenBank confirmed 100% identity with L. infantum and L. donovani complex sequences. This result represents the first record of both Leishmania spp. and L. infantum DNA from sand flies in Vojvodina, and in Serbia.

Conclusions: Presence of autochthonous canine leishmaniasis cases, records of Phlebotomus (Larroussius) species proven vectors of L. infantum (P. perfiliewi and P. neglectus) and detection of L. infantum DNA from wild caught (non-competent) vectors, prove that L. infantum is present in Vojvodina and indicates a probable circulation in the region.
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http://dx.doi.org/10.1186/s13071-017-2386-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615930PMC
September 2017

The current status of phlebotomine sand flies in Albania and incrimination of Phlebotomus neglectus (Diptera, Psychodidae) as the main vector of Leishmania infantum.

PLoS One 2017 19;12(6):e0179118. Epub 2017 Jun 19.

Unit of Vector-borne Diseases and International Health, MIPI Department, Istituto Superiore di Sanità, Rome, Italy.

The incidence of visceral leishmaniasis (VL) in Albania is higher than in other countries of southern Europe, however the role of local sand fly species in the transmission of Leishmania infantum was not addressed conclusively. In 2006, a country-wide collection of sand flies performed in 14 sites selected based on recent occurrence of VL cases showed that Phlebotomus neglectus was by far the most prevalent species (95.6%). Furthermore, 15% of pools made from 422 P. neglectus females tested positive for Leishmania sp. genomic DNA. In the same year, Culicoides trapping was performed for bluetongue disease surveillance in 91 sites of southern Albania, targeting livestock farms regardless recent occurrence of VL in the surveyed areas. In 35 sites where sand flies were collected along with midges, Phlebotomus perfiliewi was the most prevalent among the Phlebotomus species identified, however search for leishmanial DNA in females of this species was unsuccessful. In 2011, sand flies were trapped in 4 sites of north Albania characterized by high VL incidence, and females were dissected to search for Leishmania infections. Both P. neglectus and P. tobbi were collected at high densities. Two positive specimens were detected from a sample of 64 P. neglectus trapped in one site (3.1%). Parasites were successfully cultured from one specimen and characterized as belonging to Leishmania infantum zymodeme MON-1, the only zymodeme so far identified as the agent of human and canine leishmaniasis in the country. Altogether our studies indicate that P. neglectus is the main leishmaniasis vector in Albania.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179118PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476235PMC
September 2017

Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives.

J Enzyme Inhib Med Chem 2017 Dec;32(1):304-310

b Istituto di Biologia e Patologia Molecolari - CNR , and Dipartimento di Scienze Biochimiche , " Sapienza" Università di Roma , Roma , Italia.

The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC=29.43 µM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (K 0.25 ± 0.18 µM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction.
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http://dx.doi.org/10.1080/14756366.2016.1250755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010130PMC
December 2017

Comparison of Leishmania typing results obtained from 16 European clinical laboratories in 2014.

Euro Surveill 2016 Dec;21(49)

Hospital for Tropical Diseases, London, United Kingdom.

Leishmaniasis is endemic in southern Europe, and in other European countries cases are diagnosed in travellers who have visited affected areas both within the continent and beyond. Prompt and accurate diagnosis poses a challenge in clinical practice in Europe. Different methods exist for identification of the infecting Leishmania species. Sixteen clinical laboratories in 10 European countries, plus Israel and Turkey, conducted a study to assess their genotyping performance. DNA from 21 promastigote cultures of 13 species was analysed blindly by the routinely used typing method. Five different molecular targets were used, which were analysed with PCR-based methods. Different levels of identification were achieved, and either the Leishmania subgenus, species complex, or actual species were reported. The overall error rate of strains placed in the wrong complex or species was 8.5%. Various reasons for incorrect typing were identified. The study shows there is considerable room for improvement and standardisation of Leishmania typing. The use of well validated standard operating procedures is recommended, covering testing, interpretation, and reporting guidelines. Application of the internal transcribed spacer 1 of the rDNA array should be restricted to Old World samples, while the heat-shock protein 70 gene and the mini-exon can be applied globally.
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http://dx.doi.org/10.2807/1560-7917.ES.2016.21.49.30418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291127PMC
December 2016

Epidemiological survey on Leishmania infection in red foxes (Vulpes vulpes) and hunting dogs sharing the same rural area in Southern Italy.

Acta Parasitol 2016 Dec;61(4):769-775

Southern Italy, particularly Campania region, is an area where canine leishmaniasis (CanL) and zoonotic human visceral leishmaniasis (VL) are endemic. The red fox (Vulpes vulpes) has been hypothesized to play a role in occurrence of CanL in Italy but specific studies are poor. The aim of the present survey was to investigate the prevalence of Leishmania infection in dogs and foxes living in the same rural area (Picentini hills). 123 sera from autochthonous fox-hunting dogs were examined by immunofluorescent-antibody test (IFAT) using a cut-off of 1:160. The seroprevalence of dogs examined was 17.9%. Moreover, 48 foxes were examined after having been shooted by hunters or road accidents. Spleen, liver and lymph node samples were analyzed by specific Leishmania nested PCR (n-PCR). 10 foxes were found infected by L. infantum (20.8%) of which 4 animals in spleen, 2 in lymph nodes and 4 both in spleen and lymph nodes. The overall n-PCR positivity was 17.4% for spleen samples and 13.3% for lymph nodes; all liver samples resulted negative. In positive PCR foxes no signs clearly referable to leishmaniasis were recorded at necropsy. The results confirmed the presence of L. infantum infection in red foxes from Southern Italy, with a moderate level of exposure. Because large proportions of dogs with ascertained progressive leishmaniasis show a prolonged "subpatent condition" during which they are only positive to n-PCR before seroconversion, our results allow to assume that exposure risk in foxes is lower than hunting dogs living in the studied area.
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http://dx.doi.org/10.1515/ap-2016-0106DOI Listing
December 2016

Ongoing outbreak of cutaneous leishmaniasis in northwestern Yemen: clinicoepidemiologic, geographic, and taxonomic study.

Int J Dermatol 2016 Nov;55(11):1210-1218

Unit of Vector-borne Diseases and International Health, Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy.

Background: Cutaneous leishmaniasis (CL) is widespread in Yemen but has not been fully documented.

Objectives: This study aimed to investigate the clinicoepidemiologic and geographic aspects of CL in northwest Yemen and the taxonomic profile of the causative Leishmania species.

Methods: All CL cases diagnosed at the Dermatology Clinic of the Saudi Hospital at Hajjah during 1997-2012 were reviewed. Diagnoses were based on clinical, microscopic and, occasionally, histopathologic examinations. Leishmania species identification was carried out in 712 microscopically positive samples by multi-locus enzyme electrophoresis and polymerase chain reaction-restriction fragment length polymorphism.

Results: During the surveillance period, 1343 cases of CL were diagnosed. Lesions per patient ranged from one to 71, but most patients had a single facial lesion, classified as representing the "dry type" in 1315 (97.9%) and "wet type" in 28 (2.1%) patients. Leishmania typing in 576 cases identified Leishmania tropica as the main species responsible (n = 529), followed by Leishmania infantum (n = 20), Leishmania donovani (n = 11), and members of the L. donovani complex (n = 8). Atypical molecular patterns were observed in eight CL cases diagnosed in areas in which the three Leishmania species were found sympatrically.

Conclusions: Cutaneous leishmaniasis appears to be endemic in northwest Yemen, where its incidence has recently increased abruptly. The disease presents clinically as the "dry type" and is caused mainly by L. tropica and occasionally by L. infantum, L. donovani, and L. donovani complex species. A sympatric diffusion of the three species is present in some governorates.
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http://dx.doi.org/10.1111/ijd.13310DOI Listing
November 2016

Epidemiology of Imported Leishmaniasis in Italy: Implications for a European Endemic Country.

PLoS One 2015 26;10(6):e0129418. Epub 2015 Jun 26.

Unit of Vector-borne Diseases & International Health, MIPI Department, Istituto Superiore di Sanità, Rome, Italy.

In the past decade, the number of imported leishmaniasis cases has increased in countries of Western Europe. The trend is associated with increasing travels, ecotourism activity, military operations and immigration. While in endemic countries leishmaniasis is usually well diagnosed, accurate patient history and parasite identification are necessary to distinguish between autochthonous and imported cases. This is particularly important, as new Leishmania species/genotypes may be introduced and transmitted by local phlebotomine vectors without appropriate surveillance, with unpredictable consequences. We report on the surveillance of imported leishmaniasis performed by the Leishmania Identification Reference Centre of Rome from 1986 through 2012, involving health care centres from 16/20 Italian regions. Suspected imported cases were analyzed and conclusions were based on clinical, epidemiological and diagnostic findings. Over the years, different parasite identification methods were employed, including MultiLocus Enzyme Electrophoresis and molecular techniques combining disease diagnosis (SSU rDNA nested-PCR) and Leishmania typing (nuclear repetitive sequence and ITS-1 PCR-RFLPs). A total of 105 imported cases were recorded (annual range: 0-20) of which 36 were visceral (VL) (16 HIV-coinfections) and 69 cutaneous (CL) cases; 85 cases (52 CL) were from the Old World and 20 (17 CL) from the New World. Eight Leishmania species were identified, of which 7 were exotic to Italy. VL importation until 1995 was associated with the spread of Mediterranean Leishmania-HIV co-infections in early 1990s. Following the introduction of HAART treatment, such cases became occasional in Italians but relatively frequent among immigrants. In contrast, a steady increase of CL cases was observed from different areas of the Old and New Worlds, that in recent years included mainly immigrants 'visiting friends and relatives' and Italian tourists. This positive trend likely depends on better diagnosis and reporting; however, we suspect that many CL cases remained unrecognized. Given the relatively low incidence of leishmaniasis importation, the risk of introduction of exotic parasites appears limited, although the detection of anthroponotic species requires attention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129418PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482607PMC
April 2016

Spleen nodules: a potential hallmark of Visceral Leishmaniasis in young children.

BMC Infect Dis 2014 Dec 12;14:620. Epub 2014 Dec 12.

Pediatric Hematology and Oncology Unit St. Orsola-Malpighi Hospital University of Bologna, Via Massarenti 11, Bldg 13, Bologna, 40138, Italy.

Background: Visceral leishmaniasis (VL) is a severe disease caused by Leishmania infantum in the Mediterranean basin, and is associated with considerable morbidity and mortality. Infantile VL may begin suddenly, with high fever and vomiting, or insidiously, with irregular daily fever, anorexia, and marked splenomegaly. Delays in diagnosis of VL are common, highlighting the need for increased awareness of clinicians for VL in endemic European countries.

Case Presentation: We report 4 cases of young children in northern Italy presenting with persistent fever of unknown origin and diagnosed with VL by serological and molecular methods. At the time of diagnosis, these patients showed an unusual echographic pattern characterized by multiple iso-hypoechoic nodules associated with splenomegaly.

Conclusion: We suggest that detection of spleen nodules represents a signature of VL in infants, thus helping to diagnose systemic Leishmania infantum infection in children.
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http://dx.doi.org/10.1186/s12879-014-0620-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270008PMC
December 2014

Persistence of phlebotomine Leishmania vectors in urban sites of Catania (Sicily, Italy).

Parasit Vectors 2014 Dec 9;7:560. Epub 2014 Dec 9.

Unit of Vector-Borne Diseases and International Health, MIPI Department, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.

Background: Pioneering research on "Mediterranean Kala-Azar" carried out by Adler and Theodor early in the past century (~1930s) had identified Catania city (Sicily) as a major focus of the disease nowadays known as zoonotic visceral leishmaniasis (VL). Despite the fact that disease in both humans and dogs has continued to be highly prevalent in the Catania province up to the present times, research on Leishmania vectors in this urban focus dates back to that distant period. This study aimed to evaluate the persistence and current composition of the sand fly fauna in urban environments of Catania in recent years, 2006 and 2013.

Methods: In 2006 fifty-one suitable collecting sites were identified within 44 sub-units of a grid drawn to include the urban Catania area. In 2013 the survey was restricted to four of the most productive and representative sites resulting from the 2006 survey. In both periods 3 collections per month were performed using standard sticky traps set for 3 days in wall holes/cavities along public roads, from the end of April through December.

Results: 43/51 sites (84.3%) were found positive for sand flies. The 2006 collections accounted for a total of 4341 specimens including six species. Among competent Leishmania vector species, P. perniciosus was the most prevalent (36.5%) being identified in all sand fly-positive sites, with significant abundance in those of the old city centre. Other species of interest were P. sergenti (2.5%) and P. neglectus (1.5%). The 2013 survey produced 1130 sand flies, of which 39.5% were P. perniciosus, 1.6% P. sergenti and 0.7% P. neglectus. A search for Leishmania DNA in a small sample of 72 P. perniciosus females revealed 11% infection prevalence.

Conclusions: Our findings from an old urban focus of leishmaniasis demonstrate that phlebotomine sand flies have adapted fairly well to the drastic environmental changes that have occurred in cities of the Western world in the past century and still represent a potential risk for Leishmania transmission.
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http://dx.doi.org/10.1186/s13071-014-0560-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267132PMC
December 2014

A randomised, double-blind, controlled efficacy trial of the LiESP/QA-21 vaccine in naïve dogs exposed to two leishmania infantum transmission seasons.

PLoS Negl Trop Dis 2014 Oct 9;8(10):e3213. Epub 2014 Oct 9.

Unit of Vector-borne Diseases and International Health, MIPI Department, Istituto Superiore di Sanità, Rome, Italy.

Canine leishmaniasis is an important zoonosis caused by uncontrolled infection with Leishmania infantum, where an inappropriate immune response is not only responsible for permitting this intracellular parasite to multiply, but is also responsible for several of the pathological processes seen in this disease. Effective canine vaccines are therefore a highly desirable prevention tool. In this randomised, double-blinded, controlled trial, the efficacy of the LiESP/QA-21 vaccine (CaniLeish, Virbac, France) was assessed by exposing 90 naïve dogs to natural L. infantum infection during 2 consecutive transmission seasons, in two highly endemic areas of the Mediterranean basin. Regular PCR, culture, serological and clinical examinations were performed, and the infection/disease status of the dogs was classified at each examination. The vaccine was well-tolerated, and provided a significant reduction in the risk of progressing to uncontrolled active infection (p = 0.025) or symptomatic disease (p = 0.046), with an efficacy of 68.4% and a protection rate of 92.7%. The probability of becoming PCR positive was similar between groups, but the probability of returning to a PCR negative condition was higher in the vaccinated group (p = 0.04). In conclusion, we confirmed the interest of using this vaccine as part of a comprehensive control program for canine leishmaniasis, and validated the use of a protocol based on regular in-depth assessments over time to assess the efficacy of a canine leishmaniasis vaccine.
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http://dx.doi.org/10.1371/journal.pntd.0003213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191955PMC
October 2014

Prospective study on the incidence and progression of clinical signs in naïve dogs naturally infected by Leishmania infantum.

PLoS Negl Trop Dis 2013 9;7(5):e2225. Epub 2013 May 9.

Department of Veterinary Clinical Sciences, University Federico II, Naples, Italy.

The incidence of clinical and clinicopathological signs associated with the progression of infection was evaluated prospectively in 329 naïve young dogs exposed to Leishmania infantum transmission and examined periodically during 22 months (M). The dogs were part of Leishmania vaccine investigations performed under natural conditions. Vaccinated groups were considered in the evaluation when the vaccine resulted non-protective and the appearance and progression of signs did not differ statistically from controls at each time point, otherwise only control groups were included. 115 beagles were part of 3 studies (A to C) performed in the same kennel; 214 owned dogs (29 breeds, 2.3% beagles) were included in a study (D) performed in 45 endemic sites. At M22 the prevalence of any Leishmania infection stage classified as subpatent, active asymptomatic, or symptomatic was 59.8% in studies A-C and 29.2% in study D. Despite different breed composition and infection incidence, the relative proportion of active infections and the progression and type of clinical and clinicopathological signs have been similar in both study sets. All asymptomatic active infections recorded have invariably progressed to full-blown disease, resulting in 56 sick dogs at M22. In these dogs, lymph nodes enlargement and weight loss--recorded from M12--were the most common signs. Cutaneous signs were seen late (M18) and less frequently. Ocular signs appeared even later, being sporadically recorded at M22. Most clinicopathological alterations became evident from M12, although a few cases of thrombocytopenia or mild non-regenerative anemia were already observed at M6. Albumin/globulin inversions were recorded from M12 and urea/creatinine increase appeared mostly from M18. Altogether our findings indicate that any susceptible young dogs naturally infected by L. infantum present a common pattern of progression of signs during 2 years post infection, providing clues for medical and epidemiological applied aspects.
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http://dx.doi.org/10.1371/journal.pntd.0002225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649971PMC
November 2013

Diagnostic value of conjunctival swab sampling associated with nested PCR for different categories of dogs naturally exposed to Leishmania infantum infection.

J Clin Microbiol 2012 Aug 30;50(8):2651-9. Epub 2012 May 30.

Unit of Vector-Borne Diseases and International Health, MIPI Department, Istituto Superiore di Sanità, Rome, Italy.

The objective of the present study was to evaluate the diagnostic performance of a noninvasive assay, conjunctival swab (CS) nested-PCR (n-PCR), for diagnosing canine leishmaniasis (CanL) in different stages of infection in comparison to the performance of the indirect immunofluorescence antibody test (IFAT), lymph node microscopy, and buffy coat n-PCR. To this end, we performed a cross-sectional survey among 253 nonselected dogs in areas of endemicity in central Italy. We also performed a longitudinal study of CS n-PCR among 20 sick dogs undergoing antileishmanial treatment. In the first study, among the 72 animals that were positive by at least one test (28.45%), CS n-PCR showed the best relative performance (76.38%), with a high concordance in comparison to standard IFAT serology (κ = 0.75). The highest positivity rates using CS n-PCR were found in asymptomatic infected dogs (84.2%) and sick dogs (77.8%); however, the sensitivity of the assay was not associated with the presence of clinical signs. In the follow-up study on treated sick dogs, CS n-PCR was the most sensitive assay, with promising prognostic value for relapses. The univariate analysis of risk factors for CanL based on CS n-PCR findings showed a significant correlation with age (P = 0.012), breed size (P = 0.026), habitat (P = 4.9 × 10(-4)), and previous therapy (P = 0.014). Overall, the results indicated that CS n-PCR was the most sensitive assay of the less invasive diagnostic methods and could represent a good option for the early and simple diagnosis of CanL infection in asymptomatic animals and for monitoring relapses in drug-treated dogs.
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http://dx.doi.org/10.1128/JCM.00558-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421491PMC
August 2012

Application of molecular techniques in the study of natural infection of Leishmania infantum vectors and utility of sandfly blood meal digestion for epidemiological surveys of leishmaniasis.

Parasitol Res 2012 Aug 2;111(2):515-23. Epub 2012 Mar 2.

Laboratori de Parasitologia, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.

Epidemiological studies on the distribution of leishmaniasis caused by Leishmania infantum Nicolle, 1908 (Kinetoplastida: Trypanosomatidae) have been based principally on serological surveys of the canine reservoir. This methodology is useful due to the facility of sampling, the rapidity in obtaining results, its consistency and because it allows the detection of heterogeneous foci of canine leishmaniasis (CanL) even in small areas. Other investigations have analysed Leishmania parasitism in sandflies (Diptera: Psychodidae: Phlebotominae) by using classical dissection techniques. These techniques allow the vector species to be incriminated in different foci, although they suffer from being very time consuming. Lately, studies in this field are increasingly using molecular techniques, which are faster and easier to perform. In the present work, we applied a nested-PCR in a study of natural infection of sandflies by Leishmania in three isolated farms where serological data on canine leishmaniasis of local dogs were also obtained. The analysis allowed the detection of 38.7% of females with positive nested-PCR (78%, 18% and 0%, respectively, in the different isolated farms). The positive Leishmania DNA samples were genotyped and identified as L. infantum. The results of this work provide new data for the vectorial capacity of Phlebotomus ariasi in a Pyrenean area, which can be considered at risk of becoming a new focus of CanL. The females with positive nested-PCR displayed blood in the midgut at different degrees of digestion, and/or were gravid. According to the multivariate logistic regression analysis, the risk of nested-PCR-positivity increased significantly with the degree of blood digestion (OR = 1.3; P value = 0.025). The Phlebotomus species and the presence of eggs were not statistically associated with nested-PCR positivity (P value of >0.05). The correlation of positive nested-PCR results with the presence of seropositive dogs in the farm confirms the utility of this technique in the study of the distribution and intensity of leishmaniasis foci. Also, the importance of sandfly blood-meal digestion for epidemiological surveys of leishmaniasis foci has been demonstrated.
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http://dx.doi.org/10.1007/s00436-012-2863-4DOI Listing
August 2012

A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition.

Amino Acids 2012 Feb 11;42(2-3):803-11. Epub 2011 Aug 11.

Department of Biochemical Sciences, Institute of Molecular Biology and Pathology CNR, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.

Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin-trypanothione reductase-NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis.
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http://dx.doi.org/10.1007/s00726-011-0997-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266496PMC
February 2012

Inhibitory Effect of Silver Nanoparticles on Trypanothione Reductase Activity and Leishmania infantum Proliferation.

ACS Med Chem Lett 2011 Mar 29;2(3):230-3. Epub 2010 Dec 29.

Institute of Molecular Biology and Pathology CNR, and Department of Biochemical Sciences, Sapienza University of Roma , P.le A. Moro 5, 00185 Rome, Italy.

In Leishmania the glutathione/glutathione reductase eukaryotic redox sys-tem is replaced by the unique trypanothione/trypanothione reductase (TR) system. In vitro, silver is a more effective TR inhibitor than antimony, the first line drug against leishmaniasis in most endemic countries, and its mechanism of inhibition is similar to that of Sb(III). In particular, silver binds with high affinity to the catalytic triad Cys52, Cys57, and His461', thereby inhibiting TR. Here, Ag(0) activity was tested on the promastigote and amastigote stages of Leishmania infantum using a drug-delivery system consisting in Ag(0) nanoparticles encapsulated by ferritin molecules (PfFt-AgNPs). These were able to induce an antiproliferative effect on the parasites at metal concentrations lower than those used with antimony.
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http://dx.doi.org/10.1021/ml1002629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017975PMC
March 2011

Longitudinal study on the detection of canine Leishmania infections by conjunctival swab analysis and correlation with entomological parameters.

Vet Parasitol 2010 Aug 20;171(3-4):223-8. Epub 2010 Mar 20.

Unit of Vector-borne Diseases & International Health, MIPI Department, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

A longitudinal study was carried out on kennelled stray dogs in a canine leishmaniasis (CanL) endemic area, to evaluate early and late diagnostic performance of a non-invasive conjunctival swab (CS) nested (n)-PCR analysis for Leishmania detection in 2 cohorts of dogs, respectively. (A) Sixty-five IFAT- and CS n-PCR-negative dogs exposed to, and followed up once or twice a month during a full sand fly season (July-November 2008). In parallel, a sand fly survey was performed on site using standard sticky traps set twice a month, for a cumulative surface of 63 m(2). (B) Seventeen IFAT- and CS n-PCR-negative dogs found positive in July 2008 at the peripheral blood buffy-coat (BC) n-PCR. These dogs were examined again by BC n-PCR in September and November 2008, and before the subsequent transmission season (May 2009) along with CS n-PCR and IFAT. None of the cohort (A) dogs converted to positive CS n-PCR during the transmission season. Although approximately 2500 phlebotomine specimens were collected with peaks of 100-147 specimens/m(2) sticky trap, the cumulative density of the only proven CanL vector in the area (Phlebotomus perniciosus) was found to be very low (0.5/m(2)). All cohort (B) dogs remained substantially seronegative; BC n-PCR showed an intermittent positive trend during the period surveyed, resulting in 82% conversions to negative by the end of the study, in contrast with 71% conversions to positive at the CS n-PCR analysis. In conclusion, while CS n-PCR was not found effective for the early detection of Leishmania contacts in dogs exposed to a low pressure of vectorial transmission, this assay showed to slowly convert to positive in a high rate of dogs, in the absence of seroconversion. CS n-PCR technique can be a suitable marker for assessing Leishmania exposure in dogs as a non-invasive alternative to current serological and molecular tools.
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http://dx.doi.org/10.1016/j.vetpar.2010.03.025DOI Listing
August 2010

Cutaneous leishmaniasis in North-Western Yemen: a clinicoepidemiologic study and Leishmania species identification by polymerase chain reaction-restriction fragment length polymorphism analysis.

J Am Acad Dermatol 2009 Oct 19;61(4):e15-21. Epub 2009 Aug 19.

Department of Dermatology, Saudi Hospital at Hajjah, Sana'a, Yemen Republic.

Background: Cutaneous leishmaniasis (CL) is widespread in Yemen, but not fully documented.

Objective: To study the clinicoepidemiologic profile of CL in the northwestern region of Yemen Republic and to identify the responsible Leishmania species by molecular methods.

Methods: All 265 CL cases (176 males and 89 females) were subjected to detailed analysis. Diagnosis was based on clinical features, positive slit skin smear, and histopathologic findings in some cases. In 198 cases, positive smears were examined at the Leishmania Reference Centre of Istituto Superiore di Sanità, Rome (Italy), by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis for Leishmania typing.

Results: All patients were Yemeni nationals, originated from 10 governorates of northwestern Yemen. Most of the patients had a single noduloulcerative lesion on the face suggestive of "dry"-type CL. Slit skin smear was positive in 255 cases (96.23%). Leishmania sp PCR was positive in all 198 cases examined; the RFLP analysis was positive in 155 samples with the following identification results: L. tropica in 133 cases (85.80%), L. infantum in 17 (10.97%), and L. donovani in 5 (3.23%).

Limitations: This was a prospective study of CL cases at one center only; hence, the full extent of the disease in the entire region cannot be predicted.

Conclusion: CL appears to be endemic in northwestern region of Yemen, clinically presenting as 'dry' type, caused mainly by L. tropica (85.8% of cases) and occasionally by L. infantum (10.97%) and L. donovani (3.23%). There is a need for a multicenter study to evaluate the extent of the disease and diffusion of each Leishmania responsible species.
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http://dx.doi.org/10.1016/j.jaad.2009.04.047DOI Listing
October 2009

Acute renal failure due to visceral leishmaniasis by Leishmania infantum successfully treated with a single high dose of liposomal amphotericin B.

J Travel Med 2008 Sep-Oct;15(5):358-60

Clinic of Infectious Diseases, Department of Clinical and Morphological Research, University of Udine, Udine, Italy.

We report a visceral leishmaniasis case in an immunocompetent immigrant with acute renal failure. Parasites were demonstrated in bone marrow, peripheral blood, and kidney samples. A collapsing focal segmental glomerulosclerosis was documented, which was successfully treated with a single infusion of 10 mg/kg liposomal amphotericin B.
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http://dx.doi.org/10.1111/j.1708-8305.2008.00220.xDOI Listing
February 2009

Infection of sandflies by a cat naturally infected with Leishmania infantum.

Vet Parasitol 2007 Apr 14;145(3-4):357-60. Epub 2006 Dec 14.

Unit of Vector-borne Diseases and International Health, MIPI Department, Istituto Superiore di Sanità, Rome, Italy.

Despite the recent reports of feline leishmaniosis from Southern Europe, cats are still regarded as unusual Leishmania hosts. A cat found chronically infected with Leishmania was submitted to xenodiagnosis. After being sedated, the animal was exposed to the bite of 100 laboratory-reared Phlebotomus perniciosus in a fine net cage for 90 min. Four out of 19 blood-fed sandflies (21%) showed motile promastigotes at the dissection. Parasites cultured from cat's lymph node and an infected fly were identical at PCR-RFLP genotyping and identified as Leishmania infantum MON-1, the main zymodeme responsible for human and canine leishmaniosis in Southern Europe. This is the first evidence of transmissibility of feline parasites to a proven vector, suggesting that cats may represent an additional domestic reservoir for L. infantum.
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http://dx.doi.org/10.1016/j.vetpar.2006.11.009DOI Listing
April 2007

Incidence and time course of Leishmania infantum infections examined by parasitological, serologic, and nested-PCR techniques in a cohort of naive dogs exposed to three consecutive transmission seasons.

J Clin Microbiol 2006 Apr;44(4):1318-22

Unit of Vector-borne Diseases & International Health, MIPI Department, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Most experience in the comparison of diagnostic tools for canine leishmaniasis comes from cross-sectional surveys of dogs of different ages and breeds and in cases with unknown onset and duration of leishmaniasis. A longitudinal study was performed on 43 beagle dogs exposed to three transmission seasons (2002 to 2004) of Mediterranean leishmaniasis and examined periodically over 32 months through bone marrow microscopy and nested PCR (n-PCR), lymph node culture, serology (immunofluorescent-antibody test), and evaluation of clinical parameters. Starting from January 2003, the highest rate of positives was detected by n-PCR at all assessments (from 23.3% to 97.3%). Sensitivities of serologic and parasitological techniques were lower but increased with time, from 15.8% to 75.0 to 77.8%. Some dogs that tested positive by n-PCR but negative by other tests ("subpatent infection") remained so until the end of the study or converted to negative in subsequent assessments, whereas all dogs with positive serology and/or microscopy/culture ("asymptomatic patent infection") exhibited progressive leishmaniasis; 68% of them developed clinical disease ("symptomatic patent infection") during the study, at 7 (range, 3 to 14) months after being positive to all tests. Postexposure infection incidences were high and were significantly different between 2002 and 2003 exposures (39.5% and 91.7%, respectively). The time course of infection was highly variable in each dog, with three patterns being identified: (i) rapid establishment of a patent condition (0 to 2 months from detection of infection); (ii) a prolonged subpatent condition (4 to 22 months) before progression; and (iii) a transient subpatent condition followed by 10 to 21 months of apparent Leishmania-negative status before progression.
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http://dx.doi.org/10.1128/JCM.44.4.1318-1322.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1448675PMC
April 2006