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. Keywords: Visceral leishmaniasis, Cutaneous leishmaniasis, HIV infection, Dagestan, Russian Federatio

Di Muccio, Trentina

Ermakova, Larisa Alexandrovna

Golovchenko, Natalia Vladimirovna

Gradoni, Luigi

Nagorny, Sergey Andreevich

Pshenichnaya, Natalia Yurievna

Zhuravlev, Andrey Sergeevich

English

Open Access Repository

International Journal of Infectious Diseases 86 (2019) 171–174Case ReportRecent autochthonous cases of leishmaniasis in residents of theRepublic of Dagestan, Russian FederationSergey Andreevich Nagornya, Larisa Alexandrovna Ermakovaa,b,Natalia Vladimirovna Golovchenkoa, Natalia Yurievna Pshenichnayac,Andrey Sergeevich Zhuravlevd, Trentina Di Muccioe, Luigi Gradonie,*aRostov Scientific Research Institute of Microbiology and Parasitology, Rostov-on-Don, RussiabRostov State Medical University, Rostov-on-Don, RussiacCentral Research Institute of Epidemiology and National Medical Research Center of Phthisiopulmonology and Infectious Diseases, Moscow, Russiad First Moscow State Medical University, Moscow, RussiaeUnit of Vector-Borne Diseases, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, ItalyA R T I C L E I N F OArticle history:Received 12 April 2019Received in revised form 5 July 2019Accepted 5 July 2019Corresponding Editor: Eskild Petersen, Aar-hus, DenmarkKeywords:Visceral leishmaniasisCutaneous leishmaniasisHIV infectionDagestanRussian FederationA B S T R A C TEighty 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 leishmaniasisin a 2-year old child, and one cutaneous leishmaniasis case in a 39-year-old man co-infected with HIV,both resident in Dagestan.© 2019 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Contents lists available at ScienceDirectInternational Journal of Infectious Diseasesjournal home page: www.elsevier .com/ locat e/ i j idIntroductionLeishmaniases are endemic in over 98 countries, with 0.3million visceral leishmaniasis (VL) and one million cutaneousleishmaniasis (CL) cases, respectively, estimated to occur annually(Alvar et al., 2012). These two clinical forms are also found intemperate zones of the WHO European Region, from Portugal atwest to Kazakhstan at east (Gradoni et al., 2017). Throughout thisterritory, Leishmania infantum is the only causative agent of VL,having dogs as the main reservoir host and several phlebotominesand fly species as vectors. A recent review of VL in countries of theformer Soviet Union highlighted southern Caucasus (i.e.Azerbaijan, Georgia and Armenia) as the territory most affectedby disease resurgence over the past decade (Strelkova et al., 2016).As regards the Russian Federation, only two autochthonous casesfrom northern Caucasus were recorded in the past, one of which* Corresponding author at: Unit of Vector-Borne Diseases, Department ofInfectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161Rome, Italy.E-mail address: luigi.gradoni@iss.it (L. Gradoni).https://doi.org/10.1016/j.ijid.2019.07.0051201-9712/© 2019 The Authors. Published by Elsevier Ltd on behalf of International Soclicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).from Dagestan in 1938. Isolated VL cases were registered in Crimea(Baranets et al., 2017), whereas CL diagnosed in the RussianFederation is only regarded as an imported disease by healthauthorities.We have recently diagnosed two cases of leishmaniasis inresidents of Dagestan Republic, which were most probablyacquired locally. The protozoan agent, unfortunately left untyped,could be attributable to L. infantum on clinical and epidemiologicalgrounds.Case 1In June 2014, a 2-year-old girl from Makhachkala, Dagestan,was referred to the infectious and parasitic diseases clinic ofRostov-on-Don Research Institute of Microbiology and Parasi-tology (RNIIMP), Russia. According to her parents, the girl felt illin January 2014, when she started to suffer from unexplainedfever. In May 2014 parents sought medical assistance, as thechild's condition had worsened resulting in weight loss,persisting fever, abdominal pain and enlargement, and profusesweating. The child received symptomatic therapy at theChildren's Hospital in Makhachkala and subsequently referrediety for Infectious Diseases. This is an open access article under the CC BY-NC-ND172 S.A. Nagorny et al. / International Journal of Infectious Diseases 86 (2019) 171–174to the Rostov-on-Don Research Institute of Oncology, wherecancer or blood malignancies were excluded. The child wastransferred to the pediatric infectious diseases ward of the cityhospital, where anemia, thrombocytopenia, leucopenia andhepatosplenomegaly were recorded. Due to suspicion of aparasitic infection, the patient was sent for consultation toRNIIMP.On the day of examination, remarkable blood findings werehemoglobin 98 g/L and leukocytes 3.8  109/L. Formol-gel test, anaspecific Leishmania serology assay (World Health Organization,1996) was strongly positive. For the above clinical and laboratoryfeatures, a sternal bone-marrow aspiration was performed andRomanowsky-Giemsa stained smears revealed the presence ofLeishmania amastigotes (Figure 1A), confirming that the child hadFigure 1. Leishmania diagnosis in Case 1 and 2, and clinical features of Case 2.(A) Cluster of Leishmania amastigotes within cytoplasm residues from a broken infecteRomanovsky-Giemsa stain; (B) Ulcer on the border between the upper lip and right noLeishmania amastigotes in the smear from the skin ulcer of Case 2. Romanovsky-GiemVL. For the child’s age and the incubation duration, it wasconcluded that the infection was acquired in Makhachkala.After VL diagnosis, the child was sent back to theMakhachkala Children’s Hospital for treatment. Because first-line drugs for treatment of VL (i.e. meglumine antimoniate orliposomal amphotericin B) are not registered in the RussianFederation, the patient had to be treated with intravenousamphotericin B deoxycholate, which caused adverse effects(nausea, vomiting and weakness) and had to be interrupted.With the help of relatives, the child was transferred to a hospitalin the Republic of Azerbaijan for further treatment; there, shewas successfully treated with liposomal amphotericin Badministered at the dose of 5 mg/kg/day for 10 days. As oftoday, no VL relapses were recorded.d macrophage (arrow), in a bone-marrow smear from Case 1, a 2-years old child.stril of Case 2, an adult male co-infected with HIV and Leishmania; (C) Numeroussa stain; (D) Scar at the site of the ulcer after Case 2 treatment.S.A. Nagorny et al. / International Journal of Infectious Diseases 86 (2019) 171–174 173Case 2In January 2018, a 39-years-old man from a rural area ofDagestan was referred to the RNIIMP clinic from the Rostov-on-Don Research Institute of Oncology. The patient felt ill in November2017, when a papule appeared at the border of the upper lip andright nostril, which after several days turned into an ulcer. He wastreated by a dermatologist at his place of residence, withoutresults. He was then referred to a regional oncologist whosuspected a basal-cell carcinoma and excised the ulcer. Aftersurgery, the patient's condition worsened, with fluctuating feverand sharp pain in the intervention area; an ulcerative lesiondeveloped again in the postoperative suture and graduallyincreased in size. The patient was referred to the Rostov-on-DonResearch Institute of Oncology with suspicion of malignant skinformation. The ulcer (2.1  1.8 cm) was evident at the borderbetween the upper lip and right nostril (Figure 1B). Surroundingskin was infiltrated, hyperemic, and covered with small tubercles.Occipital, posterior cervical and axillary lymph nodes wereenlarged. Material for parasitological examination was taken fromthe infiltrate around the wound, from which slide smears weremade and stained with Romanovsky-Giemsa’s stain. Atmicroscopic examination, numerous Leishmania amastigotes weredetected (Figure 1C) and hence CL was diagnosed. At theepidemiological investigation, the patient categorically deniedhaving visited neighboring countries known to be endemic for CLcaused by L. major and/or L. tropica. Molecular typing of the agentwas attempted from stained slide smear material, after abundantwashing in ethanol and removal. DNA was extracted by standardproteinase K protocol (Khatri et al., 2009) and analyzed by nested-PCR targeting the SSU rDNA, and by Real-Time PCR targeting kDNAminicircles (Van Eys et al., 1992; Mary et al., 2004). Integrity ofhuman b-globin gene DNA was also assessed (Pizzuto et al., 2001).Unfortunately, neither human nor Leishmania DNA were amplified,suggesting probable inhibition caused by residual traces of the dye.Clinical laboratory investigations revealed lymphopenia andmonocytosis. Formol-gel test for Leishmania serology was negative,however anti-HIV 1 + 2 ELISA tested positive. The Dagestan Centerfor HIV/AIDS confirmed that the patient was HIV infected since2010. Indicators of the immune status at the time of theinvestigation were: absolute T-lymphocytes (CD45+/CD3+):498  106/L; T-helpers (CD45+/CD3+/CD4+): 76  06/L; cytotoxicT-lymphocytes (CD45+/CD3+/CD8+): 422  106/L; double positiveT-lymphocytes (CD3+/CD4+/CD8+): 0.34  106/L; immunoregula-tory index CD4/CD8: 0.18. HIV load was 4,473,014 copies/mL.Hence, definitive diagnosis was CL in an individual co-infectedwith HIV, stage 4B. Considering the high risk for a generalizedleishmaniasis, the patient was treated intravenously with conven-tional amphotericin B, 50000 units per day every day for 7 days,then once a week for 30 weeks. The ulcer was treated locally with1% clotrimazole ointment twice a day. The patient has beenprescribed antiretroviral therapy (LPV/RTV + ZDV+3TC). Treat-ments were well tolerated without significant side effects. After42 days from the start of therapy with amphotericin B andantiretroviral therapy, the patient's condition improved and theulcer was almost completely healed (Figure 1D). Positive dynamicsof the immune status indicators were noted: CD4+ increased to233  106/L, and HIV RNA decreased to 1,416 copies/ml. In view ofthe regression of the CL lesion, amphotericin B treatment wasinterrupted. Currently, the patient is receiving ART, clinicalconditions are satisfactory, and adherence to HIV therapy is high.DiscussionAccording to official data, only imported leishmaniasis isdiagnosed in the Russian Federation. A 2015 survey carried out onprevious 4 years (Federal Service for Surveillance on ConsumerRights Protection and Welfare, 2015) concluded that the diseasewas acquired from eleven countries, i.e. Azerbaijan, Israel,Indonesia (actually a country non-endemic for leishmaniasis),Iran, Spain, Mexico, Syria, Tajikistan, Turkmenistan, Turkey andUzbekistan. The highest number of VL cases was imported fromAzerbaijan.Based on Case-1 history, endemic Leishmania transmission inDagestan seems to be undisputable. Occurrence of autochthonousVL in the country should not be surprising, as southern andsouthwestern parts of Dagestan border with VL-endemicAzerbaijan and Georgia (see https://en.wikipedia.org/wiki/Dage-stan for a dedicated map). Two competent L. infantum vectors(Phlebotomus kandelakii and P. neglectus) had been recorded in the1930s from the Caspian Sea coastline and foothills of Dagestan(Strelkova et al., 2016), suggesting natural conditions for localleishmaniasis transmission. In severely immunosuppressed indi-viduals, the multiplication of L. infantum in tissues can occuratypically, most often involving skin and/or mucous membranes asa result of secondary spread, thereby causing CL or mucosalleishmaniasis (Alvar et al., 2008). Case 2 may have suffered fromthis condition, however it cannot be excluded that the lesiondeveloped in the site of an infective sand fly bite.Sporadic locally-acquired cases in territories considered freefrom leishmaniasis may remain unnotified to the public healthsystem, with consequent lack of appropriate surveillanceresponses (e.g. Leishmania screening in dog populations). Further-more, these cases may lead to serious problems in timely diagnosisand treatment, as physicians usually have no awareness of thecondition and knowledge of methods for laboratory confirmation(Pshenichnaya et al., 2017). It is therefore important to providepublic health and medical specialists with information about thecurrent epidemiological situation and with correct approaches todiagnose and treat leishmaniasis in a timely manner.Conflict of interest statementThe authors declare no conflict of interestFunding sourceThis study did not receive specific funds other than thoseroutinely provided by public hospitals for patient care.Ethical statementManagement of patients followed current clinical guidelines ofthe Russian Federation.ReferencesAlvar J, Aparicio P, Aseffa A, Den Boer M, Cañavate C, Dedet JP, et al. The relationshipbetween leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev2008;21:334–59.Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwideand global estimates of its incidence. PLoS One 2012;7:e35671.Baranets MS, Ermak TN, Ponirovsky EN. Clinical and epidemiological features ofvisceral leishmaniasis in the Republic of Crimea. Ther Arch (Mosk)2017;89:100–4 [in Russian].Federal Service for Surveillance on Consumer Rights Protection and Welfare, theRussian Federation. [About the situation of leishmaniasis in the RussianFederation]. Letter of 4th April 2015, no. 01/2160-15-27. http://docs.cntd.ru/document/420268897. [in Russian].Gradoni L, López-Vélez R, Mourad M. Manual on case management and surveillanceof the leishmaniases in the WHO European Region. Copenhagen: World HealthOrganization Regional Office for Europe; 2017.Khatri ML, Di Muccio T, Gramiccia M. Cutaneous leishmaniasis in North-WesternYemen: a clinicoepidemiologic study and Leishmania species identification bypolymerase chain reaction-restriction fragment length polymorphism analysis.J Am Acad Dermatol 2009;61:e15–21.174 S.A. Nagorny et al. / International Journal of Infectious Diseases 86 (2019) 171–174Mary C, Faraut F, Lascombe L, Dumon H. Quantification of Leishmania infantumDNA by a real-time PCR assay with high sensitivity. J Clin Microbiol2004;42:5249–55.Pizzuto M, Piazza M, Senese D, Scalamogna C, Calattini S, Corsico L, et al. Role of PCRin diagnosis and prognosis of visceral leishmaniasis in patients coinfected withhuman immunodeficiency virus type 1. J Clin Microbiol 2001;39:357–61.Pshenichnaya NY, Paul M, Erovichenkov A. Eastern Europe. In: Petersen E, Chen LH,Schlagenhauf-Lawlor P, editors. Infectious diseases: a geographic guide. Oxford:John Wiley & Sons; 2017. p. 235–56.Strelkova MV, Ponirovsky EN, Morozov EN, Zhirenkina EN, Razakov SA, KovalenkoDA, et al. A narrative review of visceral leishmaniasis in Armenia, Azerbaijan,Georgia, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan, theCrimean Peninsula and Southern Russia. Parasites Vectors 2016;8:330.Van Eys GJ, Schoone GJ, Kroon NC, Ebeling SB. Sequence analysis of small subunitribosomal RNA genes and its use for detection and identification of Leishmaniaparasites. Mol Biochem Parasitol 1992;51:133–42.World Health Organization. Manual of visceral leishmaniasis control Geneva: WHO/LEISH/96.40. 1996.

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

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

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