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Davis Nikolay Aleksandrovich, Research Institute of Epidemiology, microbiology and infectious diseases, researcher
Toychiev Abdurakhim Khodjiakbarovich, Research Institute of Epidemiology, microbiology and infectious diseases, researcher
Islamova Jannat Ikramovna, Institute of the chemistry of plant substances, researcher
Parpieva Nargiza Nusratovna, Republican specialized scientific research medical center of phthisiology andpulmonology, director Osipova Svetlana Olegovna, Research Institute of Epidemiology, microbiology and infectious diseases, head of the department E-mail: davisnikolay@gmail.com
Concomitant intestinal parasitic diseases in pulmonary tuberculosis patients: influence on some immunological indices
Abstract: Impact of concomitant intestinal parasitic diseases on immune state of patients with infiltrative pulmonary tuberculosis (IPT) was studied. Patients with IPT free of intestinal parasites were characterized by significant decrease of relative frequencies of CD3+, CD4+, CD8+-lymphocytes and increase of the level of total serum IgE in comparison with healthy control. Concomitant ascariasis and giardiasis decreased frequencies of CD3+, CD4+, CD8+-lymphocytes and increased level total serum IgE for certainty when compared with IPT patients free of parasites. Blastocystosis decreased frequencies of CD3+, CD4+-lymphocytes and increased level total serum IgE for certainty. Concomitant enterobiasis didn't influence significantly on immunological parameters. Efficient treatment of parasitic diseases increased frequency of CD3+-, CD4+- and CD8+-lym-phocytes, decreased concentration of total serum IgE, improved patients condition and tolerance of antituberculosis therapy.
Keywords: infiltrative pulmonary tuberculosis, ascariasis, giardiasis, blastocystosis, enterobiasis, immune state.
Absence of significant successes in control of pulmonary tuberculosis (PT) to a great extent is connected with increase of the number of Mycobacterium tuberculosis strains multiresistant to antituberculosis drugs and disintegration of immune system resulting in domination of Th2-response whereas protection against Mycobacterium tuberculosis is associated with Thl-response. Only 10 % of cases of PT infection progress to active disease, indicating to efficient immune response in most infected individual [15, 6-24].
Macrophages activated by IFN-y play a key role in protection against intracellular microorganisms. The main source of IFN-y is Thl-lymphocytes. Stimulation of Th2-response could inhibit protective reactions of Thl-type [17, 1768-1775]. This fact is of special importance for regions endemic on intestinal parasitic diseases due to the property ofhelminthes to stimulate chiefly Th2-response and consequently could inhibit Th1-response. Uzbekistan in endemic on intestinal parasitic diseases [1, 16-17]. Previously we found that prevalence ofAscaris lumbricoides and Blastocystis hominis in
patients with PT was respectively 5 and 3 times as high as in population. Prevalence ofEnterobius vermicularis and Giardia lamblia was at the level ofpopulation or lower [10, 3126]. So it was of interest to determine the influence of concomitant intestinal parasitic diseases on a typical for PT immunological imbalance.
Materials and methods. Patients with IPT dominated among individuals under examination and a maximal prevalence of intestinal parasites was found in this cohort, so we detected immune state in these patients. We examined 15 healthy individuals (control), 15 patients with ITL free of parasites, 17 patients with IPT with concomitant ascariasis, 15 patients with IPT and giardiasis, 15 IPT patients with blastocystosis, 15 patients with IPT and enterobiasis. All the patients were at the age of 17-47 years and admitted to Republican specialized scientific research medical center of phthisiology and pulmonology. All the patients received conventional antituberculosis therapy: isoniazide, ethambutol, pi-razinamide, rifampicin, streptomycin.
Concomitant intestinal parasitic diseases in pulmonary tuberculosis patients: influence on some immunological.
For diagnosis of intestinal parasites triple coproscopy was used. Stool samples were taken with 1-3 days intervals. In detection of antiparasitic therapy efficiency method of formalin-ether enrichment technique was used additionally.
Ascariasis and enterobiasis were treated respectively with albendazole (a single dose of 400 mg.) and mebendazole (100 mg. daily for 3 days) [8, 804-805]. For treatment of guiardiasis ecdysten was used (20-25 mg. daily for 10 days). Blastocystosis was treated with metronidazole (500 mg. four times a day for 10 days). The aim of the antiparasitic therapy in ascariasis, giardiasis and enterobiasis was elimination of parasites, in blastocystosis — to decrease of the infection intensity.
Ecdysten is the preparation from the class ofphytoecdysteroids with diverse biological activity, including adaptogenic, hepatopro-tective, immunomoduilating and other properties; it is produced at the Institute of Chemistry of Plant Substances of Academy of Sciences of the Republic of Uzbekistan [12, 61-65]. Besides ecdysten possesses ability to eliminate Giardia lamblia including cases resistant to conventional antigiardial preparations [7, 14-17]. Choice of ecdysten was stipulated by a high level of Giardia lamblia resistance to metronidazole, found in 43.3 ± 9.0 % of patients with pulmonary tuberculosis with concomitant giardiasis [5, 70-73].
Subpopulations of lymphocytes in peripheric blood were detected in the reaction of indirect rosette formation with monoclonal antibodies to CD3+-, CD4+-, CD8+-, and CD20+-lymphocytes, production of LLC "Medbiospecter", Moscow; level of total serum IgE was detected by the ELISA method with test-system of LLC "Vector Best", Novosibirsk, Russia.
Immunological indices were detected before antiparasitic therapy and in 18-20 days after its completion.
All results were as mean ± SE. Compare between indices under investigation were made using Student's t-test. The significance was determined at P < 0.05.
Results and discussion. Manifestation of intestinal parasitic diseases in patients with PT was a moderate character, its activ-Table 1. - Indices of cellular immunity in patients with IPT with
ity was evaluated by improvement of patients state after parasites elimination, because some signs coincide with symptoms of PT and side effects of antituberculosis therapy. Main manifestations were: augmentation of weakness, irritability, fatigability, headache, deterioration of antituberculosis drugs tolerance, unsteady weak pains in epigastria and right hypochondria, anorexia, frequent episodes of nausea, flatulence, rapid loss of weight. 8 patients complained ofvomiting appearance. 8 from 15 patients with enterobiasis complained of itching in perianal zone. Allergic rush appeared in 5 patient with concomitant giardiasis.
Subpopulations of lymphocytes of peripheral blood are represented in table 1. Patients with IPT free of intestinal parasites were characterized by significant decrease of relative frequencies of CD3+, CD4+, CD8+-lymphocytes and increase of the level of total serum IgE in comparison with healthy control, content CD20+-lymphocytes wasn't changed. Our data on character of T-subpopulations imbalance are consistent with results of V. V. Noviyzkiy et al. (2007) and T. E. Tyulkova et al. (2008) [9, 27-30; 13, 48-55], but V. V. Noviyzkiy et al. (2007) observed a significant increase of CD20+- lymphocytes whereas we noticed only a tendency to increase of the index.
Influence of concomitant parasitic diseases on T-lym-phocytes subpopulations depended on the species of parasite. Relative frequencies of CD3+-, CD4+- h CD8+- lymphocytes from IPT patients with concomitant ascariasis and giardiasis were significantly decreased when compared to IPT patients without parasites (P < 0.05). Concomitant blastocystosis induced significantly decrease only CD3+- and CD4+-lymphocytes in comparison with patients with IPT without parasites. Concomitant enterobiasis had no impact on T-lymphocytes subpopulations in patients with IPT.
Concomitant parasitic diseases significantly increase CD20+-lymphocytes in all the patients in comparison with healthy control, tendency to increase of this index was noticed when compared with patients with IPT without parasites (table 1). parasites before and after antiparasitic therapy (M ± m, %).
Cohort under study CD3+ CD4+ CD8+ CD20+
Before treatment After treatment Before treatment After treatment Before treatment After treatment Before treatment After treatment
Healthy individuals (n=15) 59.1 ± 0.7 38.4 ± 1.6 23.5 ± 0.9 23.3 ± 0.9
IPT patients free of parasites (n=15) 41.2 ± 1.4* 29.2 ± 1.0* 18.8 ± 0.6* 25.6 ± 0.9
IPT patients +asca-riasis (n=17) 31.3 ± 1.4* ** 40.4 ± 1.2* *** 22.1 ± 1.1* ** 31.5 ± 1.0* *** 16.1 ± 0.4* ** 20.7 ± 0.7* ** *** 28.3 ± 1.3* 26.4 ± 1.0*
IPT patients +giar-diasis (n=15) 27.0 ± 1.3* ** 37.4 ± 1.8* *** 20.4 ± 0.9* ** 28.6 ± 1.8* *** 16.4 ± 0.7* ** 19.5 ± 1.0* *** 27.0 ± 0.9* 25.1 ± 0.9
IPT patients + blastocystosis (n=15) 33.2 ± 1.4* ** 43.5 ± 1.2* *** 21.8 ± 1.0* ** 29.8 ± 1.7* *** 17.3 ± 0.6* 19.9 ± 0.8* 25.9 ± 0.7* 25.2 ± 1.2
IPT patients + enterobiasis (n=15) 39.6 ± 1.5* 41.2 ± 1.5* 26.8 ± 1.5* 29.6 ± 1.7* 18.9 ± 0.8* 19.5 ± 0.7* 27.7 ± 1.0* 26.1 ± 1.1
Note: * — significant difference with healthy individuals; ** — si difference with data before treatment.
Elimination of parasites was achieved in al the cases of ascariasis, enterobiasis and giardiasis. In patients with blastocytosis a significant decrease of infection intensity was observed. Efficiency of antiparasitic therapy was controlled by repeated parasitological examinations for 2 weeks after the treatment completion.
Level of CD3+-, CD4+- and CD8+-lymphocytes after treatment of ascariasis and giardiasis was significantly increased, after the treat-
xcant difference with IPT patients without parasites; *** — significant
ment of blastocystosis significant increase was observed only for CD3+- and CD4+-lymphocytes. Elimination of Enterobius vermicu-laris didn't exert any effect on lymphocyte subpopulations. Changes in the level of CD20+-lymphocytes were insignificant (table 1).
Results of detection of the level of total serum IgE are represented in table 2. Concentration of total serum IgE in patients with IPT without parasites is significantly higher than in healthy in-
dividuals. Our data are in accordance with results of Ohrui et al. [16, 13-15] and Cozmei et al. [14, 702-709], who also found essential enhancement of IgE level in patients with PT without concomitant diseases. These changes seem to be a manifestation of immunological imbalance typical for PT and a marker of activation of Th2-response.
Concomitant ascariasis, giardiasis and blastocystosis enhances activation of Th2-response: level of total serum IgE in patients with IPT with these parasites was significantly higher than in patients with IPT free of parasites. Enterobiasis didn't enhance level of IgE and elimination of Enterobius vermicularis didn't impact considerably on the value of the index.
After antiparasitic treatment level of total serum IgE significantly decreased, after elimination of Giardia lamblia and decrease if intensity of Blastocystis hominis infection value of serum IgE approached to values in patients with IPT without parasites. Concomitant ascariasis exerted more expressed influence on the IgE level: it was 2.5 times as high as in patients with IPT without parasites, after elimination of A. lumbricoides concentration of IgE decreased as 1.4 low as initial value. Evidently negative influence of ascariasis on immune state of patients with PT is expressed more than in other parasitic diseases and it was expressed in intensity of shifts of cellular immunity indices (table 1). Possibly detection of IgE level at later terms after parasites elimination would
show further decrease of IgE level.
Table 2. - Level of total serum IgE in patients with IPT with parasites and after antiparasitic therapy (M ± m)
Cohort under study IgE (IU/ml)
Before treatment After treatment
Healthy individuals (n = 15) 55.7 ± 9.0
IPT patients free of parasites (n = 15) 161.4 ± 18.5*
IPT patients + ascariasis (n = 17) 415.7 ± 32.7 * ** 281.2 ± 18.6* ** ***
IPT patients + giardiasis (n = 15) 366.3 ± 20.2 * ** 205.0 ± 12.7 * ***
IPT patients + blastocystosis (n = 15) 298.8 ± 22.1 * ** 185.0 ± 12.5 * ***
IPT patients + enterobiasis (n = 15) 178.2 ± 13.8 * 164.2 ± 11.5 * ***
Note: * — significant difference with healthy individuals; ** — significant difference with IPT patients free of parasites; *** — significant
difference with data before treatment.
Significant increase of IgE concentration after treatment of parasitic diseases indicates to favorable shift in immune response of patients with PT directing to weakening of Th2-response and correspondingly strengthening of Thl-response.
Thus from parasites diagnosed in patients with PT enterobiasis significantly didn't influence immune state of the patients it concerned indices of cellular as well as humoral immunity. Impact of Enterobius vermicularis on immune system is considerably weaker, than of Ascaris lumbricoides, Giardia lamblia and Blastocystis hominis. It can be connected with less impact of the parasites and its metabolites on a macro-organism due to its biological features and shorter duration of the disease.
Treatment of concomitant parasitic diseases in all the patients with IPT resulted in considerable improvement of patients condition. It was expressed in diminution of weakness, better tolerance of antituberculosis drugs, disappearance of abdominal pains, nausea and vomiting, improvement of appetite, gain weight. Positive dynamics of tuberculosis process displayed in disappearance of symptoms of intoxication (sweating, subfebrile temperature, malaise) in 82 % of the cases. Regression of bronchopulmonary symptoms (cough with expectoration, dyspnea, chest pain) was observed in 74 % of patients.
Conclusion. A deep immunological imbalance in patients with PT is known to be the basis for development and including into complex therapy of PT various preparations with immunomodulating properties which could optimize specific therapy at the expense of correction of immunological disorders: licopidum [11, 59-62], polyoxidoni-um [2, 35-38], glutoxim [3, 160], baktisporin, immureg [4, 38-44], immunomodulators of mural peptide series [6, 121-122]. However even the wide choice of preparations points to insufficient efficiency ofthese preparations or they are not always effective. Evidently before application of immunodulators it is expedient to diagnose concomitant diseases that could aggravate immunological imbalance. Intestinal parasitoses belong to such diseases and their efficient treatment could correct some aspects of immunological imbalance in patients with PT: increase frequency of CD3+-, CD4+- and CD8+-lymphocytes and decrease the level of total serum IgE, improve condition of the patients and tolerance of antituberculosis therapy.
It is difficult to suspect intestinal parasitic diseases in patients with PT on the basis of clinical data due to common character of some signs of parasitosis, PT and side effects of antituberculosis preparations. So adequate parasitological diagnosis (triple coprosco-py, use of enrichment methods) is of special importance in regions endemic on intestinal parasitic diseases.
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Influence of intestinal parasites on cytokine profile of patients with pulmonary tuberculosis, including cases complicated...
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Davis Nikolay Aleksandrovich, Research Institute of Epidemiology, microbiology and infectious diseases, researcher Toychiev Abdurakhim Khodjiakbarovich, Research Institute of Epidemiology, microbiology and infectious diseases, researcher Djuraeva Zulfiya Baratovna, Tashkent Medical Academy, assistant Parpieva Nargiza Nusratovna, Republican specialized scientific research medical center of phthisiology andpulmonology, director Osipova Svetlana Olegovna, Research Institute of Epidemiology, microbiology and infectious diseases, head of the department E-mail: davisnikolay@gmail.com
Influence of intestinal parasites on cytokine profile of patients with pulmonary tuberculosis, including cases complicated with aspergillosis
Abstract: influence of intestinal parasites on immune imbalance in pulmonary tuberculosis (PT), including cases complicated by pulmonary aspergillosis (PA) was studied. 300 and 111 patients with active PT were examined for intestinal parasites. Group of comparison: 200 residents of Tashkent and Tashkent region. The group of111 patients was examined for PA (clinical, X-ray, mycological and serological data). Serum IFN-y and IL-4 were assessed by ELISA. Ascariasis was found in patients with PT and PT with invasive PA respectively 5 and 12 times as frequent as in population. Decrease of IFN-y and increase of IL-4 level (P < 0.05) was observed in these groups in comparison with healthy individuals and patients with PT free of intestinal parasites and PA. Conclusion: Ascariasis as a concomitant disease enhances immune imbalance, typical for PT and PT + invasive PA.
Keywords: Ascariasis, pulmonary tuberculosis, intestinal parasites, aspergillosis, cytokines.
Control of Mycobacterium tuberculosis replication is mainly nity in helminthiasis is mediated by Th2-response [6, 459-466]. mediated by production of Th1-cytokines IFN-y and TNF-a and Protective mechanisms in pulmonary tuberculosis (PT) and as-cytotoxicity of CD8+-lymphocytes, directed against infected mac- pergillosis are similar and are based on elevated IFN-y produc-rophages. Control efficiency is specified by the balance of Th1-and tion [5, 403-413]. Our previous study showed that pulmonary Th2-response (IL4, IL-10, IL-13) [7, 694-701]. Protective immu- aspergillosis (PA) complicates course of the disease in 40 % of the
