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Clinical medicine
UDC 616.981.71:616.988.25-002.954.2-07(571.15)
TICK-BORNE INFECTIONS WITH NATURAL NIDALITY IN ALTAI KRAI: PRESENT AND FUTURE
1 Altai State Medical University, Barnaul
2 Saint-Petersburg Pasteur Institute, Saint-Petersburg
O.V. Beskhlebova1, V.M. Granitov1, V.G. Dedkov2, I.V. Arsenyeva1
The article presents the results of a survey of 213 patients with the history of tick sucking or creeping on the territory of Altai Krai. In all patients, after conducting verification methods of examination (molecular biological, serological), tick-borne nosology was diagnosed. Of these, 139 (65.3%) patients were diagnosed with "tick-borne rickettsiosis", 46 (21.6%) - "ixodic tick-borne borreliosis", 4 (1.8%) - "tick-borne encephalitis", granulocytic anaplasmosis was diagnosed in 1 patient. In 23 (10.8%) patients - mixed infection. The results of the study of 462 ticks collected in Altai Krai are also presented.
Key words: tick-borne infections, Altai Krai, tick-borne rickettsiosis, ixodic tick-borne borreliosis, ticks.
Natural focal infections transmitted by ticks are a serious health problem in most of the territories of the Russian Federation, especially the Asian part of it, in particular, Siberia and the Far East [1; 2].
Altai Krai is located in the south-eastern part of Western Siberia. To date, four tick-borne infections with natural nidality are officially registered in the region: tick-borne encephalitis (TE), Siberian tickborne typhus (STT), ixodic tick-borne borreliosis (ITB) and human granulocytic anaplasmosis (HGA) [3]. However, in recent years, due to the expansion of laboratory diagnostics capabilities, the list of tick-borne infections detected in Russia, including Altai, continues to grow. Along with this, the variability of the clinical picture of this group of diseases, the absence of pathognomonic symptoms with complex, often controversial criteria for their laboratory verification, determines the persistent relevance of this problem.
The possibility of simultaneous existence of several pathogens in the carrier and the absence of interference between them led to the fact that the vast majority of natural foci of tick-borne infections in the territory of the Russian Federation, including Altai Krai, can be combined. In this connection, the interest in a comprehensive study of the structure, regional aspects and clinical and laboratory features of tick-borne infections in Altai Krai seems reasonable.
Research objective: to determine the etiological structure of tick-borne infections and the characteristics of their clinical manifestations, taking into account the results of a set of laboratory research methods.
Materials and methods
During 2013-2016, 213 patients hospitalized in the infectious disease department of Barnaul City Hospital No. 5 with various tick-borne infections were examined. Criteria for the inclusion of patients in the study were: age over 15 years; history of tick sucking or crawling; "Voluntary informed consent
to participate in the study signed by the patient." Exclusion criteria: the presence of chronic somatic diseases in the acute phase; autoimmune diseases; the presence of other acute infectious diseases or chronic infectious diseases with a continuous progressive course (HIV infection, chronic viral hepatitis); the absence of the "Voluntary Informed Consent to Participate in the Study."
On the day of admission to hospital and in dynamics, general laboratory tests were performed for all patients. Molecular genetic study of materials from patients (venous blood, paired serum and biopsy specimens) was performed by real-time polymerase chain reaction (PCR) using the AmpliSens TBEV, B. burgdorferi sl, A. phagocytophilum, E. chaffeensis / E.muris-FL» (Central Research Institute of Epidemiology, Moscow). Kemerovo virus detection was performed by realtime PCR with reverse transcription (RT-PCR). Detection of rickettsiae of the tick-borne spotted fever (TSF) group was carried out by real-time PCR with typing amplicon sequencing [4].
Detection of IgM and IgG class antibodies in paired sera against pathogens of human monocytic ehrlichiosis and human granulocytic anaplasmosis was performed by the commercial test systems HME-EIA-IgM, HME-EIA-IgG and HGA-EIA-IgM, HGA-EIA-IgG (OOO Omnix). Detection of antibodies to the TE virus was performed in the "TBEvirus (FSME) IgM ELISA" and "TBEvirus (FSME) IgG ELISA" test systems (Humburg, Germany). The study of sera for the presence of IgM and IgG antibodies to borrelia was performed using the "ImmunoChipBorrelios" kit (FBSI Central Research Institute of Epidemiology, Moscow). Due to the presence of a cross-serological reaction between the rickettsiae of the TSF group, antibodies to tick-borne rickettsiosis pathogens (TR) were determined in the test system «Rickettsia conorii ELISA IgM/IgG» (Vircell, Spain).
All verifying methods for examining patients and examining ticks were made on the basis of the
FBSI Central Research Institute of Epidemiology, Moscow.
Tick studies
In 2013-2015 on the territory of Altai Krai (Zarinsky, Pospelikhinsky, Pervomaysky districts), 228 ticks were collected on the flag, 234 ticks were also collected, delivered to the laboratory of the Rospotrebnadzor of Barnaul by people who had been attacked. The study involved only adult specimen. The species affiliation of ticks and gender were determined on the basis of a comparison of morphological characters, according to the recommendations of N.A. Filippova.
Nucleic acids for determining the infection of ticks by various pathogens were isolated using the AmpliPrime RIBO-prep kit (FBSI CRIE), in accordance with the manufacturer's protocol. Infection of ticks with the TE virus, pathogens of ITB, HGA and HME were determined by PCR in the AmpliSense TBEV, B. burgdorferi sl, A. phagocytophillum, E. chaffeensis/E. muris-FL» (FBSI CRIE) diagnostic system. Tick infestation by rickettsia was determined by real-time PCR with subsequent typing amplicon sequencing. The infection of ixodic ticks with the Kemerovo virus was determined using real-time RT-PCR with hybridization-fluorescence detection using the Kemerovo REM virus detection kit KEMV-FL (FBSI CRIE) using a standard protocol. The resulting sequences were compared with Kemerovo virus reference sequences presented in GenBank.
The values of continuous quantities are given as M ± m, where M is the arithmetic sample mean and m is the standard error of the mean. Values of qualitative features are presented in the form of observed frequencies and percentages. Processing and graphical presentation of data was performed using the softwares Statistica 10.0 and Excel 2007.
Results and discussion
By establishing a diagnosis of tick-borne infection, a set of clinical, epidemiological and laboratory criteria was taken into account. The diagnosis of TR was formed according to the classification proposed by K.M. Loban (1980). The diagnosis of ITB is based on the classification of Yu.V. Lobzin (1996).
Of 213 patients, 139 (65.3%) patients were diagnosed with TR, 46 (21.6%) - ITB, 4 (1.8%) - TE, 1 patient was diagnosed with HGA. 23 (10.8%) patients - mixed infection.
Clinical and laboratory characteristics of Siberian tick-borne typhus
The largest number of STT cases occurred in May (50.6%), with a decrease by August and the second lower peak of incidence in September -16.0%. Among the patients, men dominated - 95 (68.8%). The age of patients was 49.3 ± 1.3 years.
It was established that 93 patients (67.4%) pointed to the suction of one or several ticks, 45 people (32.6%) did not note suction, however, in 35 of them (77.8%), primary affect was found. The incubation period constituted 7.2 ± 0.3 days. Acute onset of the disease was observed in 76.8% of cases. All patients had a febrile reaction lasting for 6.7 ± 0.2 days. Fever was accompanied by general weakness (97.1%), headache (81.9%), loss of appetite (71.0%) and sleep (63.0%), pain in muscles and joints (52.9%), dizziness (29.7%), nausea (26.8%) and vomiting (9.4%).
An objective examination revealed a single primary affect at the site of tick suction in 110 (79.7%) patients, in 9 (6.5%) - two and in 2 (1.5%) - three primary affects. In most cases (63.6%), the primary affect was a site of necrosis surrounded by infiltration and/or hyperemia and covered with a dense purple-brown crust. Regional lymphadenitis with a duration of 7 to 18 days was detected in 37.0% of all observed patients and in 42.2% of the cases with primary affect.
A characteristic sign of STT - exanthema, appearing on 3.7 ± 0.1 day of illness, was found in 99.3% of cases. In one patient (0.7%), the STT proceeded in an atypical form with the presence of primary affect, regional lymphadenitis, but without rash.
At the disease peak, 40.9% of people had a polymorphic rash, 12.4% - maculo-papular, and 46.7% - roseolous-papular. The exanthema disappeared without a trace on 6.5 ± 0.2 day of illness.
In 32.6% of cases, hyperemia and injection of the mucous membrane of the oropharynx were observed, in 78.3% - tachycardia, in 18.8% - relative bradycardia. Hepatomegaly was detected in 5.1% of cases, accompanied by moderate tenderness to palpation in the right hypochondrium in 2.9%.
Changes in the indicators of the general blood test at the time of admission of patients to hospital (4.7 ± 0.2 day of illness) in 18.1% were characterized by leukopenia and in 5.1% - by leukocytosis, thrombocytopenia (65.9%), an increase in the erythrocyte sedimentation rate (ESR) - 73.1%, decrease in hemoglobin (9.4%). In blood count, neutrophilia occurred in 65.9% of cases, relative lymphopenia - in 43.5%, lymphocytosis - in 2.9%.
Changes in the indicators of the general urine analysis in 57.3% of cases consisted in moderate proteinuria and leukocyturia - in 41.3%.
In the biochemical analysis of blood, an increase in liver transaminase activity was detected: in 42.8% of patients, from 42 U/l to 315 U/l for AlAT and in 52.9% from 32 U/l to 431 U/l for AsAT. Hyperbilirubinemia from 21 to 44 ^mol/l was found in 3.6% of patients. Hepatitis in the patients was laboratory detected on 4.7 ± 0.2 day of illness. Clinical and biochemical indicators of hepatitis remained for 9.0 ± 0.2 days of hospital stay.
The severity of the disease was dominated by patients with moderate forms - 87.0%, in the mild form the disease proceeded in 12.3% of cases, and in one case - in severe (temperature increase up to 40 °C, rash hemorrhagic elements, meningeal symptoms).
In the period of recovery, there was an improvement in the general condition of patients with regression of clinical symptoms and their subsequent disappearance. All patients were discharged with recovery.
For the first time on the territory of the region in the patient's blood serum, the DNA of R. heilongjiangensis is genotyped - 0.7%. [5].
Clinical and laboratory characteristics of ixodic tick-borne borreliosis
The frequency of erroneous diagnoses at the stage of providing primary medical care in outpatient conditions constituted 32.6% of the total number of patients and 100.0% of patients with non-erythematous form of the disease. Among the patients, men prevailed - 58.7%. The age of patients was (47.2 ± 2.4) years.
38 (82.6%) patients indicated tick suction, and 8 (17.4%) patients did not observe it. Moreover, in 6 (75.0%) of them, erythema was found. The incubation period was (11.0 ± 0.9) days.
Acute onset of the disease with fever was noted in 78.3% of people. In 15.2% of patients, impairment of well-being and fever were absent during the whole illness. The symptoms of febrile-intoxication syndrome dominated during the peak: shivers (58.7%), headache (50.0%), appetite disorders (32.6%), myalgia (28.3%), arthralgia (26.1% ), sleep disturbance (15.2%), dizziness (13.0%), nausea (10.9%), single vomiting (6.5%). Objectively, there was identified tachycardia (58.7%), relative bradycardia (21.7%), hyperemia of the pharynx (8.7%).
The most constant features of the disease were erythema (78.3%) and regional lymphadenitis (23.9%). One case accounted for the simultaneous presence of 2 and 3 erythemas. The size of erythema constituted (97.2 ± 7.8) mm. Most often, erythema was located in the area of the body (38.9%) and persisted for (14.8 ± 0.9) days.
Laboratorily were defined: leukocytosis (6.5%), thrombocytopenia (17.4%), reduction in hemoglobin level (17.4%), relative lymphopenia (21.7%), lymphocytosis (10.9%), monocytosis (43, 5%), increased ESR (58.7%). The general analysis of urine showed leukocyturia (21.7%), moderate proteinuria (28.3%). An increase in the activity of AlAT (from 49 to 126 U/l) was detected in 20.7%, as well as AsAT (from 44 to 120 U/l).
By erythema form, in most cases, the disease proceeded in mild form - 69.4%, in other cases (30.6%) - in moderate form. By non-erythema form in 80.0% - in moderate form, only 2 patients (20.0%)
had a mild form of the disease. Severe ITB has not been identified in patients of Altai Krai. In all cases, the disease ended in recovery. The inpatient days were (13.0 ± 0.7) days.
Clinical and laboratory characteristics of tickborne mixed infections
23 patients (10.8%) with tick-borne mixed infections were examined. Mixed infection with the presence of two pathogens (TR + ITB, TR + HGA, CR + TE) was diagnosed in 91.3%, and in 8.7% - with three (TR + ITB + TE, TR + ITB + HGA). All the observed cases of mixed infections were conditioned by a combination of TR with other tick-borne nosologies registered in the territory of the region. The most common combination was TR + ITB (73.9%), TR + HGA (13.0%), and in one case, a combination of TR + TE was detected.
None of the patients had suspected mixed infection prior to laboratory testing.
Most often, mixed infection, like other tickborne infections, was diagnosed in men (82.6%). The age of the patients was 46.9 ± 3.7 years.
The fact of tick suction was noted by 17 (73.9%) patients, 35.3% of them indicated repeated suction of the tick.
The incubation period ranged from 3 to 21 days (9.9 ± 1.2) days. In 87.0% of cases, the disease began acutely. The febrile reaction was noted in all patients.
Most often, this group of patients has symptoms such as: general weakness (82.6%), shivers (78.3%), headache (69.6%), sleep (65.2%) and appetite disturbance (60 , 9%), tachycardia (65.2%), rash (60.9%). A rash typical for TR with a duration of (7.6 ± 0.7) days was observed by TR + ITB, TR + TE, TR + HGA, TR + ITB + TE. The rash appeared on 3.1 ± 0.4 days of illness, was roseolese-papular or polymorphic with spots, roseolas and papules.
Less common were: myalgia (56.5%), sweating (47.8%), arthralgia (39.1%), primary affect (39.1%), regional lymphadenitis (34.8%), oropharyngeal hyperemia (30,4%), homogeneous erythema from 50 to 400 mm in diameter (34.8%), observed by TR + ITB, TR + ITB + HGA. Rarely met: relative bradycardia (26.1%), nausea (21.7%), dizziness (17.4%), vomiting (8.7%) and hepatomegaly (8.7%).
In general, the blood test most often recorded an increase in ESR (73.9%), thrombocytopenia (65.2%), stab neutrophilia (43.5%) and relative lymphopenia (21.7%). In the general analysis of urine, proteinuria (52.2%) and moderate leukocyturia (30.4%) were detected. In the biochemical analysis of blood in the peak period, more than 50.0% of cases showed an increase in liver transaminases to (89.3 ± 33.2) U/l for AlAT and to (84.0 ± 30.1) U/l for AsAT lasting (11.0 ± 1.0) days.
In 65.2% of cases, tick-borne mixed infections were classified as moderate forms (by TR + ITB, TR + HGA, TR + TE, TR + ITB + TE). A mild form of the
disease was recorded in 34.8% of patients (by TR + ITB and ITB + TR + HGA). There were no severe forms of mixed infections in the region.
Tick-borne encephalitis was diagnosed in 4 patients (1.9%): in 2 patients - a febrile form and in 2 patients - poliomyelitis with flaccid paresis of the upper limbs. Granulocytic anaplasmosis was detected in 1 patient.
Spontaneous infection of carriers
Based on the entomological study, ticks collected from the territory of the region were classified as: I. persulcatus (64,9%), D. marginatus (16,7%), I. pavlovskyi (10,9%), D. reticulates (7,5%). More often one pathogen was detected in the carriers - 54.8%, two pathogens - 16.2%, three - 2.6%.
In ticks of genus Ixodes, R. tarasevichae (61.9%) was dominant (61.9%), the etiological role of which has not been proven in any case of tick infection that we observed. Tick infestation with B. burgdorferi sensu lato (28.3%), B. miyamotoi (5.2%), A. phagocytophilum (7.5%), TE virus (1 tick) were also determined.
For the first time on the territory of Altai Krai in two ticks of genus Ixodes, a new pathogen for the region, the Kemerovo fever virus, was found [6].
By mixed-infection of ticks of genus Ixodes (43 specimen), the following combinations of microorganisms were encountered: B. burgdorferi sensu lato + R. tarasevichae (65,1%), B. miyamotoi + R. tarasevichae (7,0%), R. tarasevichae + A. phagocytophilum (9,3%), A. phagocytophilum + B. burgdorferi sensu lato +R. tarasevichae (14,0%), Kemerovo fever virus + R. tarasevichae (2,3%), B. burgdorferi sensu lato + B. miyamotoi (2,3%).
Ticks of genus Dermacentor, in most cases, contained the STT pathogen - R. sibirica sensu stricto (65.5%).
R. raoulti (53.8%)dominated ticks collected from people, B. burgdorferi sensu lato (31.8%), TE virus (2.4%) were less common. R. tarasevichae (2.4%) was found in two ticks and in one - R. sibirica sensu stricto (1.2%). Mixed infection was represented by a combination of TE + B burgdorferi sensu lato, TE + A phagocytophilum, B. burgdorferi sensu lato + E. muris with the same frequency - 2 cases each, one tick contained TE + R. raoulti virus. None of the required pathogens were found in 152 ticks (65.0%).
It was found that in the absolute majority of cases, STT (64.8%) develops in patients after tick sucking, which occurs cyclically with an acute onset (76.8% of cases), with a predominance of symptoms of febrile intoxication syndrome (fever, weakness, appetite disorders, myalgia, arthralgia) and involvement in the process of the central nervous system (headache, dizziness, sleep disturbance).
A persistent sign of STT is rash, which can be roseole-papular (46.7%), polymorphic (40.9%), or maculo-papular (12.4%). However, very rarely (0.7% of cases), STT occurs without a characteristic
rash, but with the presence of primary affect, regional lymphadenitis.
In addition to R. sibirica sensu stricto - the causative agent of tick-borne rickettsiosis in the territory of Western Siberia - previously, ticks from the territory of Altai Krai were identified with "new" pathogen R. heilongjiangensis. The clinical picture of rickettsiosis caused by R. heilongjiangensis is in many respects similar to Siberian tick-borne typhus, and the presence of cross-serological reactions between the rickettsiae of the TSF group makes serological diagnosis of this disease very difficult [7; eight].
Ixodic tick-borne borreliosis patients accounted for 21.6% of the total number of patients with tickborne infections observed during the period of the study. It is worth noting that the incidence of ITB in Altai Krai is two times lower than in the whole Russian Federation. Thus, the incidence of ITB in the neighboring region of Novosibirsk Oblast as of 2016 was 8.36 per 100 thousand population, in Kemerovo Oblast - 8.06 per 100 thousand population, in Altai Krai - 1.89 per 100 thousand population.
The regional characteristics of ITB in Altai Krai is the dominance of the erythemal form, which is comparable with the data of other regions of the Russian Federation, such as Novosibirsk Oblast, the Baikal Region, Krasnoyarsk Krai, Kemerovo Oblast, and the prevalence of mild forms of the disease, in 15.2% of cases occurring without fever and intoxication. However, in a region not so remote from Altai Krai - Tomsk Oblast - the prevalence of non-erythemic forms of ITB was revealed. As in other regions, in Altai Krai, in the ITB clinical picture, the polymorphism of clinical symptoms is noted. An increase in regional lymph nodes in patients with ITB in the region was recorded less frequently than in other areas; no generalized lymph-adenopathy was detected. Also, severe forms of the disease and the development of meningeal symptoms were not observed. A characteristic feature of tick-borne mixed infections in the region is in all cases the combination of TR with other tick-borne nosologies and the lack of ITB + TE in observed patients, dominated by patients in other regions.
By tick-borne mixed infections, the symptoms of febrile-toxic syndrome predominate, changes in the skin correspond to the pathognomonic signs of one of the nosologies (TR or ITB). For this reason, their clinical diagnosis causes great difficulties, and it is possible to verify the diagnosis only after a laboratory examination of the patient.
The analysis of the spontaneous infection of carriers on the territory of the region showed that in the overwhelming majority, ticks are infected with a single microorganism (54.8%). However, 16.2% of the carriers contained two pathogens, and in 2.6% of cases - three pathogens, which is correlated with the data on the frequency of detection of mixed infections in patients. This
indicates the presence of combined natural foci of tick-borne infections in Altai Krai. Along with the detection of microorganisms in ticks, whose role in the development of diseases transmitted by ticks on the territory of the region is not in doubt (B. burgdorferi sensu lato, A. phagocytophilum, R. sibirica sensu stricto, TE virus), microorganisms pathogenic for humans, according to the literature data, (R. raoulti, R. tarasevichae, B. miyamotoi) were genotyped [9; 10]. For the first time on the territory of Altai Krai, infection of carriers with the Kemerovo virus was detected, which ixodide infection of which was previously detected in other regions of the Russian Federation. There were no cases of Kemerovo fever in the region.
Conclusion
Tick-borne transmission infections are a group of nosologies that have their own characteristics of morbidity, prevalence and clinical picture in each region of Russia. Therefore, the data obtained from the study of tick-borne infections in one of the regions often cannot be projected onto other, even neighboring territories. All this dictates the need for their integrated study in each of the subjects of Russia.
An integrated approach to the survey allows to verify the diagnosis of various tick-borne infections in all patients. However, taking into account the results of vector surveys, it is necessary to further study tick-borne natural focal infections and clarify the role of microorganisms found in ticks as a possible etiological factor of "new" infections in Altai Krai, such as ricketsiosis caused by R. raoulti, R. tarasevichae, Kemerovo fever, borreliosis caused by B. miyamotoi.
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Contacts
Corresponding author: Beskhlebova Olga Vasilyevna, Candidate of Medical Sciences, Assistant of the Department of Infectious Diseases and Phthisiology, Altai State Medical University, Barnaul.
656045, Barnaul, Zmeinogorsky Trakt, 75.
Tel.: (3852) 268525
E-mail: [email protected]
Author information
Granitov Vladimir Mikhailovich, Candidate of
Medical Sciences, Professor of the Department of
Infectious Diseases and Phthisiology, Altai State
Medical University, Barnaul.
656045, Barnaul, Zmeinogorsky Trakt, 75.
Тел.: (3852) 268342
E-mail: [email protected]
Dedkov Vladimir Georgiyevich, Candidate of Medical Sciences, Deputy Director for Science ща Saint-Petersburg Pasteur Institute, Saint Petersburg.
197101, Saint Petersburg, ul. Mira, 14.
Tel.: (812) 2320066
E-mail: [email protected]
Arsenyeva Irina Vladimirovna, Candidate of Medical Sciences, Associate Professor of the Department of Infectious Diseases and Phthisiology, Altai State Medical University, Barnaul. 656045, Barnaul, Zmeinogorsky Trakt, 75. Tel.: (3852) 268342.
