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. 2023 Aug 25;102(34):e34946. doi: 10.1097/MD.0000000000034946

A therapy that modulates T lymphocyte subsets in patients infected with Epstein-Barr virus: Ganciclovir combined with interferon atomization inhalation

Qingguo Ren a,*, Yanli Feng b
PMCID: PMC10470752  PMID: 37653833

Abstract

To investigate the effect of ganciclovir combined with interferon atomization inhalation on T lymphocyte subsets in patients with Epstein-Barr virus (EBV) infection and its efficacy. Fifty patients with EBV infection who received ganciclovir combined with interferon atomization inhalation were selected as the observation group, and 50 healthy people were selected as the control group. The changes of T lymphocyte subsets in peripheral blood were detected by flow cytometry before treatment and at the 1st, 2nd, 3rd and 4th cycle after treatment. Before treatment, the CD3+, CD4+, CD4+/CD8+ indexes of the patients were significantly lower than those of the control group (P < .05), and the CD8+ level was significantly increased (P < .05). After one cycle of treatment, there was no significant difference in the changes of T lymphocyte subsets compared with those before treatment. After 2 and 3 cycles of treatment, CD3+, CD4+, CD4+/CD8+ values were higher than those before treatment (P > .05), and CD8+ index was lower than that before treatment (P < .05). After the 4th cycle of treatment, CD3+, CD4+, CD4+/CD8+ values were significantly improved (P < .05), and CD8+ index was significantly decreased (P < .05). Ganciclovir combined with interferon atomization inhalation can regulate the changes of T lymphocyte subsets in patients with EBV infection, improve the patient’s condition, and has no obvious adverse reactions. Monitoring the changes of T lymphocyte subsets during treatment is more meaningful to predict the therapeutic effect of patients with EB virus infection.

Keywords: aerosol inhalation, Epstein-barr virus, ganciclovir, interferon, T lymphocyte subsets

1. Introduction

Epstein-Barr virus (EBV) is a DNA virus with a spherical shape, 180 to 200 nm in diameter, which replicates in B lymphocytes.[1] EB virus is mainly present in the saliva of patients or virus carriers, and the most common route of infection is oral to oral contact. The population is generally susceptible to EB virus. The incidence of EB virus is mainly in the age group of 15 to 30 years old, and most of the age group under 6 years old is not obviously infected. However, most people do not become ill after infection, and a small number of people can cause infectious mononucleosis after infection. The clinical triad of pharyngitis, fever, and lymphadenopathy may occur in 80% of patients.[2,3] EB virus infection involves the respiratory system, digestive system, skin and mucous membrane, and other organs. There is no specific treatment at present. Most patients with mild cases can heal themselves, and supportive treatment is the main treatment. In addition to acute infectious diseases, EB virus may also cause hematological diseases such as lymphoma or hematological diseases due to the infection of different blood system cells.[4] In addition, EB virus is also closely related to the occurrence of nasopharyngeal carcinoma and lymphoma in children. Therefore, EBV infection has been listed as one of the human tumor viruses that may cause cancer.[5]

T lymphocyte subsets are the main immune response form of lymphocyte subsets.[6] The unique molecular marker of T lymphocytes is CD3, which is present on the surface of all T lymphocytes and can be further divided into CD4+ and CD8+ T cells.[7] The cytokines secreted by T cells not only positively enhance the cellular immunity, but also promote the proliferation of B cells, which is conducive to the production of antibodies. Peripheral blood T lymphocyte subsets, a chemotherapy method, are used to detect cellular immunity. In normal body, T lymphocyte subsets interact with each other to maintain normal immune function. When the number and function of different lymphocyte subsets are abnormal, the body can lead to immune disorders and a series of pathological changes.[8,9]

Ganciclovir is mainly used as an antiviral drug, which has a broad spectrum of anti-herpes virus activity and good inhibition of atypical lymphocytes. It can be used for the prevention and treatment of patients with immunodeficiency.[10] Interferon (IFN) is a virus or other factors, stimulate vertebrate tissue cells (in vitro or in vivo) to produce special proteins that can interfere with virus proliferation. It is a broad-spectrum antiviral agent, does not directly kill or inhibit the virus.[11] IFN has a variety of biological activities on homologous cells, such as affecting cell growth, differentiation, and regulating immune function.[12] IFN is not absorbed orally and is mainly administered by intramuscular and subcutaneous injection. The use of interferon atomization inhalation therapy is aimed at the inflammatory response of the respiratory system, upper respiratory tract infection, viral pharyngitis, pneumonia and related diseases caused by virus infection, which can inhibit the growth of the virus structure, make the virus die, and can enhance the body’s immunity, activate immune cells active.[13]

This study analyzed the changes of peripheral blood T lymphocyte subsets in patients with EBV infection treated with ganciclovir combined with interferon atomization inhalation and the changes of patients during the treatment. To investigate the effect of ganciclovir combined with interferon atomization inhalation therapy on T lymphocyte subsets in patients with EBV infection and its efficacy.

2. Methods

2.1. Patients and ethics

From January 2021 to December 2021, 50 patients with EBV infection who were treated with ganciclovir combined with interferon atomization inhalation in our hospital were selected as the observation group. The type of EBV infection of all 50 patients were infectious mononucleosis. At the same time, 50 healthy subjects were selected as the control group.

Inclusion criteria: patients younger than 18 years old with EBV infection who received ganciclovir combined with interferon aerosol inhalation therapy.

Exclusion criteria: combined with other malignant tumors; severe abnormal liver and kidney function; taking contraindicated drugs.

Confirmation that changes in lymphocyte subsets induced by interferon therapy do not occur in non-EBV-infected populations typically requires a series of laboratory tests and assessments. Serum antibody detection and EBV DNA quantitative PCR were used to confirm the diagnosis. The flow cytometry was used to analyze lymphocyte subsets, including CD4+ T cells, CD8+ T cells, and natural killer cells. This study was approved by the Ethics Committee of Xingtai People’s Hospital. Written informed consent was obtained from all the patients.

2.2. Parameters in the study

All cases in this study were diagnosed by pathology. The study parameters and complications of the patients were recorded. According to clinical information, they were classified according to gender (male/female) and age (<6/6–10/10–18). Venous blood (2 mL) was collected, and peripheral blood T lymphocyte subsets were detected by EDTA-K2 anticoagulant method. All collection procedures were performed by experienced laboratory technicians.

2.2.1. EDTA-K2 anticoagulation method.

The EDTA-K2 anticoagulant method involves injecting venous blood into a test tube containing an EDTA-K2 anticoagulant. EDTA-K2 is a complexing agent with strong binding force to calcium ions. It blocks prothrombin to form thrombin after complexing calcium ions, which can prevent blood coagulation. It is an effective way to preserve blood, which is convenient to judge the addition or reduction of blood components, and is often used for the preliminary judgment of diseases.

T lymphocyte subsets in peripheral blood were detected by flow cytometry and its matching lymphocyte subsets detection kit. Two milliliter of venous blood was collected under sterile conditions and added to a 2 mL EDTA-K2 anticoagulant tube. The monoclonal antibodies with different fluorescent labels were added to the samples by direct immunofluorescence labeling using flow cytometry, and the samples were placed in a tube with microspheres for machine detection. The abscission was set to the forward angle scattered light, and the ordinate was set to the side angle scattered light to set the range of lymphocyte inclusion, after the completion of the cell aspiration. The results were analyzed by flow cytometry system software, the absolute counts of T lymphocyte subsets were obtained, and the ratios were calculated.

2.3. Statistical methods

SPSS 24.0 was used to analyze the experimental data. Count data were analyzed by χ2 test, measurement data were expressed as mean ± standard deviation (mean ± SD), and comparison was analyzed by T test. P < .05 was considered statistically significant.

3. Results

3.1. Basic information

There were 45 males and 5 females in the observation group. Twenty patients were <6 years old, 10 patients were between 6 and 10 years old, and 20 patients were between 10 and 18 years old. There were 5 males and 45 females in the control group.10 patients were <6 years old, 25 patients were between 6–10 years old, and 15 patients were between 10–18 years old. There was no significant correlation between the basic information of the control group and the observation group (P > .05) (Table 1). Compared with the control group, the CD3+, CD4+, CD4+/CD8+ indexes of 50 patients with EB virus infection in the observation group before treatment were significantly decreased (P < .05), and the CD8+ level was significantly increased (P < .05) (Table 2). Patients with EB virus infection are in immunosuppression state, and their immune function is lower than that of healthy controls.

Table 1.

Basic information.

Characteristics Observation group Control group P
Sex Male 45 5 .442
Female 5 45
Age <6 20 10 .200
6–10 10 25
10–18 20 15
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Table 2.

Comparison of T lymphocyte subsets between the observation group and the control group before treatment.

Group CD3+ (%) CD4+ (%) CD4+/CD8+ (%) CD8+ (%)
Observation group 53.35 ± 2.46 26.26 ± 2.85 0.73 ± 0.14 36.04 ± 1.44
Control group 70.49 ± 3.21 46.23 ± 2.74 1.70 ± 0.24 26.60 ± 1.36
P <.001* <.001* <.001* <.001*
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*

P < .05.

3.2. The changes of T lymphocyte subsets before and after treatment in the observation group

The changes of T lymphocyte subsets before and after treatment in the observation group were compared. The results showed that although CD3+, CD4+, CD4+/CD8+ increased after one cycle, CD8+ index decreased slightly, but the difference was not statistically significant (P > .05). After the 2nd and 3rd cycles of treatment, CD3+, CD4+, CD4+/CD8+ values were higher than those before treatment (P > .05), but the difference was not statistically significant, and CD8+ index was lower than that before treatment (P < .05), the difference was statistically significant. After the 4th cycle of treatment, CD3+, CD4+, CD4+/CD8+ values were significantly higher than those before treatment (P < .05), and CD8+ index was significantly lower than that before treatment (P < .05). After 4th cycles of treatment, the patient’s peripheral blood T lymphocyte subsets were significantly improved (Table 3).

Table 3.

Changes of T lymphocyte subsets in patients after the 1st, 2nd, 3rd, and 4th cycles of treatment.

Treatment cycle CD3+ (%) CD4+ (%) CD4+/CD8+ (%) CD8+ (%)
Prior treatment 53.35 ± 2.46 26.26 ± 2.85 0.73 ± 0.14 36.04 ± 1.44
First cycle 54.83 ± 0.73 28.06 ± 3.33 0.85 ± 0.30 33.01 ± 1.09
P .331 .506 .366 .156
Second cycle 56.48 ± 1.33 28.36 ± 2.06 0.98 ± 0.46 28.93 ± 1.06
P .623 .365 .228 .035
Third cycle 59.01 ± 0.65 35.07 ± 3.55 1.31 ± 0.53 26.77 ± 1.53
P .241 .235 .189 .028
Fourth cycle 66.96 ± 3.43 38.96 ± 3.18 1.50 ± 0.66 25.98 ± 2.76
P .015* .024* .001* .011*
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*

P < .05.

3.3. ROC of CD3+/CD4+/CD8+ T lymphocytes in patients after the 4th cycle of treatment

The receiver operating characteristic curve results showed that after the 4th cycle of treatment, the specificity and sensitivity of CD3+/CD4+/CD8+ T lymphocytes were high. CD3+, CD4+, CD8+ lymphocytes can predict the therapeutic effect. CD3+ (AUC = 0.739); CD4+ (AUC = 0.801); CD8+ (AUC = 0.716); CD3+, CD4+, CD8+ (AUC = 0.728) (Fig. 1).

Figure 1.

Figure 1.

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The ROC of CD3+/CD4+/CD8 + T lymphocyte after the fourth cycle of treatment. ROC: receiver operating characteristic curve. The abscissa represents false positive rate (FPR) and the ordinate represents true positive rate (TPR).

4. Discussion

In the present study, CD3+, CD4+, CD4+/CD8+ indicators were significantly lower and CD8+ T lymphocyte levels were significantly higher in patients with EBV infection before treatment compared with healthy controls. The results of this study also showed that CD3+, CD4+, CD4+/CD8+ in patients treated with ganciclovir combined with interferon atomization inhalation were significantly increased, while CD8+ T cell indexes were significantly decreased, suggesting that the immune suppression may be alleviated to a certain extent. At the same time, there was no significant difference in lymphocyte subsets between the 1st cycle of treatment and before treatment. In the 2nd and 3rd cycles, only CD8+ changed significantly, and the difference was statistically significant in the 4th cycle, which may be related to the slow onset of treatment. Regular detection of T lymphocyte subsets in patients with EBV infection treated with ganciclovir combined with interferon atomization inhalation has certain value in predicting the efficacy.

EBV, known as human herpesvirus, is a member of the lymphotropic virus genus of the herpesviridae family. It has latent and transforming properties and is carried by more than 95% of adults.[14] The increase of infected lymphocytes is inhibited by a variety of cellular immune mechanisms. EBV exists widely in the human population, and it can easily survive in alkaline environment and survive for a long time in the body.[15] After human infection with EB virus, the virus first proliferates in oral epithelial cells, and then infects B lymphocytes. After that, the virus enters the blood and then metastasizes to the whole body, which may cause systemic infection, or may remain latent in human lymphoid tissues for a long time. Antigen, antibody, nucleic acid detection, virus isolation, and culture are the basis for its diagnosis. Physical examination and blood routine examination can assist in its screening. A marked increase in lymphocytes can be found by blood tests.[16] EB virus infection is mainly treated with symptomatic treatment and antiviral treatment. The general prognosis is good and the recurrence rate is low. The main biological characteristics of EB virus are that it can specifically infect human and some primate B lymphocytes in vitro and in vivo, and can make infected cells grow and transform, and passaged indefinitely to achieve “immortality.” Cellular immunity plays a key role in EBV infection, and the decrease of this function will lead to the activation of EBV.[17] Related studies have shown that EBV infectious mononucleosis in children is closely related to the changes of T lymphocyte subsets.[18]

Lymphocyte subset detection evaluates the strength of immune function by detecting the counts of T lymphocytes, B lymphocytes, and natural killer cells, which is an important lymphocyte component of human immune defense.[19] Different lymphocyte subsets will play different roles in the body’s immune status and immune defense function. The determination of T lymphocyte subsets is an important index to detect the cellular immune function of the body, and it is of great significance for the auxiliary diagnosis, analysis of pathogenesis, observation of curative effect, and monitoring prognosis of some diseases (autoimmune diseases, immunodeficiency diseases, malignant tumors, hematological diseases, allergic diseases, etc). It has been used as an important means of clinical research.[20,21] Decreased CD4+/CD8+ ratio is an important indication of immunodeficiency disease. In patients with acquired immunodeficiency syndrome, there is a significant reduction in the number of CD4+ cells, so the CD4+/CD8+ ratio is often inverted. In some patients with upper respiratory tract infection, the number and function of T suppressor cells in vivo are abnormal.[22,23] The abnormal changes of T lymphocyte subsets indicated that the patient’s cellular immunity was in an immunosuppressive state.[24] The rapid decline of cellular immune function and the overexpression of immunosuppressive factors in vivo lead to the formation of an immunosuppressive microenvironment, which creates conditions for the immune escape and malignant proliferation of EB virus cells.

Ganciclovir is a nucleoside antiviral drug that competitively inhibits DNA polymerase and is incorporated into the DNA of the virus and host cells to inhibit DNA synthesis. Ganciclovir can effectively inhibit the replication of cytomegalovirus, so as to play an antiviral role.[25] Ganciclovir is indicated for blind cytomegalovirus retinitis caused by severe immunodeficiency, AIDS, organ transplantation, malignant tumors, as well as pneumonia, gastroenteritis, liver, and central nervous system infections. The study have shown that ganciclovir has good clinical efficacy in children with varicella, and it has a more positive effect on peripheral blood T lymphocyte subsets, so it has a higher application value in children with varicella. Related studies have shown that ganciclovir can treat EBV-associated infectious mononucleosis in children.[26] Intravitreal injection of ganciclovir was successful in the treatment of EBV-induced necrotizing retinitis.[27] Pravash Budhathoki et al successfully treated severe EBV-associated hemophagocytic lymphohistiocytosis with high-dose steroids and ganciclovir.[28]

IFN is an immune-acquired cytokine, which is a group of low molecular weight glycoproteins with similar structure and close function produced by the body’s cells through the antiviral response after the body is infected with the virus, and can inhibit the growth of the virus.[29] The main role of interferon is antiviral and immune regulation. Atomization inhalation is more effective than intramuscular injection. Studies have shown that EB virus infection is closely related to interferon in patients with systemic lupus erythematosus.[30] IFN atomization inhalation therapy can play an antiviral and immunomodulatory role in the respiratory tract, and has a certain therapeutic effect on upper respiratory tract inflammatory diseases caused by virus infection.[31] Ganciclovir combined with interferon atomization inhalation can positively regulate the immune system, promote the activation of immune cells, and enhance the immune function of the body. There is no specific treatment for EB virus infection. Ganciclovir can be used to inhibit virus replication, and interferon atomization inhalation can regulate immunity to clear EB virus and EBV-infected cells.

4.1. Limitations of the study

The sample size of the observation group is relatively limited. In order to further verify the results, clinical data should be continuously collected, summarized and analyzed in the process of clinical work. Non-homogeneity of participants, the influence of other confounders and cofactors were avoided as much as possible.

5. Conclusion

Ganciclovir combined with interferon atomization inhalation can regulate the changes of T lymphocyte subsets in patients with EB virus infection, improve the immune status of the body, and provide important reference value for judging the immune status of the body and predicting the effect of treatment. Therefore, regular monitoring of the changes of T lymphocyte subsets in patients, combined with the analysis of immune-related factors when conditions permit, can provide reference for the selection of treatment options and prognosis of patients.

Author contributions

Data curation: Yanli Feng.

Software: Yanli Feng.

Methodology: Yanli Feng.

Visualization: Qingguo Ren.

Writing – original draft: Qingguo Ren.

Abbreviations:

EBV
Epstein-Barr virus
IFN
interferon
ROC
receiver operating characteristic curve
TPR
true positive rate.

This study was approved by the Ethics Committee of Xingtai People’s Hospital.

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Ren Q, Feng Y. A therapy that modulates T lymphocyte subsets in patients infected with Epstein-Barr virus: Ganciclovir combined with interferon atomization inhalation. Medicine 2023;102:34(e34946).

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