Immune Reconstitution Inflammatory Syndrome and Hodgkin’s Lymphoma

Abstract

Immune reconstitution inflammatory syndrome (IRIS) is defined as a clinically significant exacerbation of known low-symptomatic serious, more often infectious diseases, in conditions of a significant increase in the level of initially low levels of CD4+ T-lymphocytes in response to highly active antiretroviral therapy (HAART) for HIV infection. Without prior etiotropic therapy for an opportunistic infection, its exacerbation with a pronounced clinical picture during HAART can be fatal for the patient. Lymphomas, including Hodgkin’s lymphoma (HL), are considered within the framework of this problem. Unlike other malignant lymphoid tumors that occur with low levels of CD4+ T-lymphocytes, HL develops with elevated levels of CD4+ lymphocytes in response to HAART in HIV-infected patients in the first months of starting antiretroviral treatment. HL was diagnosed in 8% of HIV-infected individuals without HAART. After the appointment of HAART, the frequency of HL increases to 17%. These data allow the problem of IRIS to be considered as the main one in the study of the etiology and pathogenesis of HL in HIV-infected patients.

1. Introduction

Classical HL is a monoclonal tumor, the substrate of which is Reed-Sternberg cells (R-SH) and Hodgkin cells, which originate from the germinal center of the follicles. After, it was introduced into the clinical practice of HAART the incidence of aggressive lymphomas and Kaposi’s angiosarcoma decreased many times, and the incidence of HL, on the contrary, increased to 17% [1]. We are going to introduce our study of HL and IRIS.

2. Hodgkin’s lymphoma: definition, history, and diagnostics

Hodgkin’s lymphoma (HL; Hodgkin’s disease, lymphogranulomatosis) is a disease that includes classical HL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Classical HL is a monoclonal tumor, the substrate of which is Reed-Sternberg cells (R-SH) and Hodgkin cells, which originate from the B cells of the germinal center of the follicles. They make up about 1% of the total mass of tumor tissue, which consists of reactive, non-tumor T- and B- lymphocytes with an admixture of granulocytes and macrophages. Histological variants of HL were determined: lymphoid predominance, mixed-cell variant, nodular sclerosis, and lymphoid depletion. Later, the nodular variant is divided into two: the first type and the second type. In the first type, a small number of R-SH cells are distributed and scattered in the histological specimen. The prognosis of the disease is favorable. In the second type of variant with nodular sclerosis, tumor cells form syncytium. The prognosis is unfavorable. Hypereosinophilia in the specimen also indicates an unfavorable prognosis.

Hodgkin’s lymphoma was first described in six patients in 1832 by Thomas Hodgkin as “a disease in which the lymph nodes and spleen are affected.” After 23 years, S. Wilkes called this condition “Hodgkin’s disease”, having studied the observations described by T. Hodgkin and added 11 of his own to them [2]. The term “lymphogranulomatosis” was introduced in 1904, at the VII Congress of German Pathologists in Vienna, and for a long time, the process was differentiated with tuberculosis. In 1971, at the Ann Arbor conference, a classification was adopted for the staging of lymphomas from I to IV with the presence of clinical symptoms of intoxication (B) and without them (A). In 1988, Costwolds adopted additions: a massive tumor (bulky) X and a letter representation of the affected organs (S – spleen, H – hepar, etc.) [3]. In the classification of tumors of hematopoietic and lymphoid tissues, WHO 2001 approved the name “Hodgkin’s lymphoma”. Later, a nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) was isolated in which the addition of rituximab to the regimens of chemotherapy is required, which may differ from those developed for HL [4]. During immunohistochemical examination, the basic markers of HL were identified: CD30, CD25, and CD15. Up to 70% of patients are carriers of the Epstein-Barr virus (EBV). The problem of EBV oncogenesis in lymphomas is being intensively studied, but it has not yet been solved [5]. The generally accepted treatment regimens for HL are ABVD AVD, BEACOP-14, BEACOPP-escalated, DHAP, and ESHAP. In some patients, autologous hematopoietic stem cell transplantation is used at the stage of consolidation after high-dose chemotherapy, more often with relapses/refractory course of the tumor.

Before starting chemotherapy, young men are offered cryopreservation of sperm, and women are offered cryopreservation of follicles.

According to the staging system adopted in Ann Arbor [6], bone marrow involvement qualifies as stage IV of tumor spread. However, the bone marrow naturally belongs to the hematopoiesis system, and the stage should be designated as III (personal point of view of the authors). Bone marrow damage is not a risk factor. Trepanobiopsy is not performed during the initial diagnosis of HL, but in case of relapse, this procedure is mandatory. Bone marrow involvement in primary HL patients according to bilateral trepanobiopsy is confirmed only in 12–14% of cases [1, 7]. According to the results of PET-CT, bone marrow involvement is registered much more often in 54% of patients [8].

3. Immune reconstitution inflammatory syndrome

The first reports on the side effects of HAART appeared in 1997. As the viral load decreased and the CD4+ T-lymphocyte count in the blood increased, reflecting the effectiveness of antiretroviral treatment for HIV. In the past few years, the effectiveness of antiretroviral treatment for HIV infection has led to a resurgence of known, previously asymptomatic diseases. For example, these include pulmonary and extrapulmonary forms of tuberculosis, including atypical nontuberculous mycobacterioses: paratuberculosis, leprosy, fungal infections, parasitosis, contagious mollusks, cryptococcal infection, toxoplasmosis, shingles, leishmaniasis, and exacerbation of syphilis with a return of the initial clinical picture [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. In addition, Guillain-Barré syndrome has been described in patients with HIV infection on HAART [20]. A. Weetman reports thyroiditis occurring 15 months after starting HAART [21].

In 2000, the Annals of Internal Medicine journal J.A. DeSimone et al. first described a new syndrome [22]. It is based on the phenomenon called IRIS (Immune Reconstitution Inflammatory Syndrome). In Russian literature, IRIS is recognized to be an inflammatory immune reaction.

The most frequent description of IRIS is tuberculosis-associated. There are several criteria and three categories of coinfection [23, 24, 25, 26, 27, 28, 29, 30].

IRIS and tuberculosis occur in almost 1/3 of all HIV-infected patients on HAART [31, 32]. There is an urgent need of tuberculosis therapy prior to the administration of HAART [32, 33].

C.C. Chang et al. concluded that low levels of CD4+ T- lymphocytes and protein in the spinal fluid increase the risk of death in cryptococcal meningitis [34]. I. Sereti points out that HAART should be administered only after microbiological confirmation of cerebrospinal fluid sterility [35]. Cryptococcal meningitis is detected within 2 weeks to 4 months from the start of HAART [36, 37, 38].

Uveitis after initiating HAART is recognized as IRU (Immune Reconstitution Uveitis) and is found in 37.5% of cases [39]. HAART reduced the number of cases of CMV retinitis by 90%. Without HAART, uveitis occurred at CD4+ T-lymphocyte levels of 50 cells/μL or lower, and with HAART, it occurred at 200 cells/μL or higher [40, 41, 42, 43, 44].

Literature in the Russian language provides the first mention of IRIS in work of N.V. Matievskaya in 2012. The author described 73 patients with HIV infection, indicating the occurrence of severe IRIS in eight of them. The patients were diagnosed with purulent meningitis, toxoplasmosis, tuberculosis, and lymphomas, including HL in one patient. Manifestations of IRIS were noted after 1 week and up to 1 year from the start of HAART. HL was diagnosed 1 year after the start of antiretroviral therapy. Lethal outcomes occurred in five patients [45].

Panteleev A.M. reports on corticosteroid treatment in IRIS and tuberculosis [46]. A.M. Bitneva et al. reports the results of data analysis of 179 patients observed in a phthisiology department, 21 of which with IRIS [47]. The Belarusian authors Tyushchenko T.V. and Tsyrkunov V.M. reported that 47 patients with HIV infection died of opportunistic infections 3 months after the initiation of HAART [48]. I.M. Ulyukin notes the importance of careful monitoring in patients taking HAART with previous tuberculosis background [49].

IRIS also occurs in patients without HIV infection after treatment of tumor and autoimmune diseases with immunosuppressants and corticosteroid hormones [50].

IRIS has been described by P. Vishnu et al. in three patients with Burkitt’s lymphoma (BL) diagnosed 20–24 weeks after HAART initiation, with CD4+ T-lymphocytes at 323, 553 and 293 cells/μL, respectively. In two patients, the viral load was not determined. Of the patients examined, one patient died, and two others achieved complete remission. The authors in their literature review of 2000–2013 found descriptions of only three patients with LB diagnosed 8–28 weeks after initiation of HAART. Lymphoma was diagnosed at an average CD4+ T- lymphocyte count of 277 cells/μL. Two patients died from the progression of LB, and one achieved complete remission [51].

Although HL is not an HIV-indicating malignancy, the incidence of this particular malignant lymphoid tumor is about 10 times higher in HIV-positive populations than in HIV-negative ones [52]. Despite the fact that the incidence of many opportunistic infections is decreasing in the “HAART era” [53, 54] incidence of HL in HIV-infected patients is increasing [55, 56, 57, 58, 59, 60].

The largest number of patients with HIV infection and HL were described by R.J. Biggar et al. in 2006. Authors analyzed 317,428 cases of HIV infection of which classical HL was diagnosed in 173 cases. The mixed-cell variant was predominant (54%). It was shown that the risk of LC in HIV-infected patients with a CD4+ T-lymphocyte count of 225–249 cells/μL increases 10-fold compared to the general population. The authors also confirmed that the mixed-cell variant of HL with frequent detection of Epstein-Barr virus prevailed [56].

A multicenter study in which the authors linked the development of HL in HIV-infected patients with IRIS analyzed data of 64,368 HIV-infected patients from 1992 to 2009 in France, of whom 187 developed HL. This study did not specify what level of CD4+ T- lymphocytes prior to the development of HL. More than half of these patients were diagnosed with HL within the first 3 months of HAART initiation. An important conclusion is that the risk of HL diagnosis in patients who received HAART is generally low. However, it is shown that patients with a CD4+ T-lymphocyte level of at least 500 cells/μL have an almost 10-fold increased risk of HL compared to patients with a CD4+ T-lymphocyte level of 50–99 cells/μL [59].

J. Bohlius et al. indicate that a decreased level of CD4+ T-lymphocytes in patients receiving HAART correlates with an increased risk of developing HL [61]. A. Kowalkowski et al. reported the results of a multicenter analysis of 31,056 patients with HIV infection from 1985 to 2010 in Houston, of whom 196 had HL. It was shown that in patients with HL, CD4+ T-lymphocyte levels continued to decline 3–6 months after initiation of HAART. After 3 years of follow-up, it was found that the risk of developing HL in patients who received HAART doubled during the first year. It is noted that patients with CD4+ T-lymphocytes level of 200–350 cells/μL are in the group with the highest risk of HL [62]. Long-term HAART has been shown to reduce the risk of developing HL. Thus, HL was diagnosed in 211 of 31,576 patients with HIV infection who received HAART [63]. D. Gotti et al. report on 5087 HIV-infected patients followed up for 10 years, of whom 30 patients developed HL. It was shown that the risk of HL increases within 6 months of starting HAART [64]. Increased incidence of HL in HIV-infected patients receiving HAART has also been reported in other studies [65, 66].

Thus, in the literature, there are reports of better results of antitumor therapy in combination with HAART in patients with multiple myeloma and concomitant HIV infection than in the group without HIV infection [67].

4. Our study

4.1 Materials and methods

From 2002 to 2019, we observed 85 patients with HIV infection, HL, and concomitant hepatitis C and/or B. For technical reasons, data for 2008–2011 were excluded from the analysis. Thus, the study included 85 patients aged 20–74 years (median 35 years), 67% male.

4.2 Results

Immunohistochemical study of tumor biopsy specimens revealed that 60 (70%) patients were EBV-positive. Coinfection with hepatitis C and B viruses was detected in 81 (95%) patients with HL. The level of CD4+ lymphocytes before the start of anticancer treatment for HL was about 400/mcL, and the viral load was above 100,000 copies/mcL. Before the start of chemotherapy, seven patients died. These patients presented with stage IVB HL, massive tumor lesions, and B-symptoms and died from tumor progression and opportunistic infections.

The treatment was carried out according to internationally accepted chemotherapy regimens: 6 courses of ABVD, 6 courses of BEACOPP-14, and 6 courses of BEACOPP-escalated with or without subsequent radiation therapy. Without exception, all patients underwent HAART simultaneously with anticancer treatment. In cases of a combination of HL, HIV infection and hepatitis B and/or C, simultaneous treatment of all three diseases is carried out. In the case of hepatitis C, direct-acting drugs orally are used for 12 weeks, with complete eradication of the virus achieved in 96% of cases. After the end of chemotherapy treatment of HL, the level of CD4+ lymphocytes increased to 700/μl, and the viral load decreased significantly to undetectable at the sensitivity threshold of the method of 25 copies/μl and below. It should be emphasized that over the entire historical period of observation under conditions of strict monitoring from 2002 to 2019, we did not observe relapses of HL. And as a consequence, we have not had to refer patients for transplantation of autologous hematopoietic stem cells. At the time of writing the article, 70 patients remained in complete remission of HL, confirmed by CT or PET-CT. See Table 1.

Index	Number, n (%)
Total number of patients	85 (100)
Sex
Men	58 (69)
Women	27 (31)
Median (range) age, years	35 (20–74)
HL variant
Lymphoid predominance	4 (4.5)
Mixed cell	68 (80)
nodular sclerosis	5 (6)
lymphoid depletion	8 (9.5)
HL stage by Ann Arbor
I	0 (0)
II	17 (20)
III	17 (20)
IV	51 (60)
HIV infection
The level of CD4+ lymphocytes at the diagnosis of HL, cells/μl
> 500	51 (60)
500–350	17 (20)
200–350	10 (12)
< 200	7 (8)
Viral load, copies/μl
<10,000	22 (26)
10,000–50,000	34 (40)
50,000–100,000	17 (20)
>100,000	12 (14)
Viral hepatitis
Only C	60 (70)
Only B	9 (11)
Combination of C and B	12 (14)
Anticancer treatment regimen
ABVD	60 (70)
BEACOPP-escalated	10 (12)
BEACOPP-14	7 (8)
Another	8 (10)
EBV infection
Positive	60 (70)
Negative	25 (30)
Treatment results
Remission	70 (82)
Complete remission	60 (86)
Partial remission	0 (0)
Stabilization	10 (14)
Progression	0 (0)
Relapses/refractory course	0 (0)
Mortality
Before starting PCT	7 (8)
From complications of PCT	8 (10)

Table 1.

Clinical characteristics of patients.

5. Conclusions

The pathogenesis of IRIS is unclear. Obviously, an increased number of CD4+ T-lymphocytes plays an important role in the pathogenesis of IRIS. In addition, elevated levels of cytokines such as interferon-γ, interleukin-6, and tumor necrosis factor α can be detected, simultaneously [68, 69, 70, 71, 72, 73, 74, 75, 76, 77]. Risk factors for the development of IRIS include increased levels of T- lymphocytes, CD4+, CD4+ to CD8+ T-lymphocyte ratio, the drop in the viral load after 90 days of HAART, and its early administration in case of opportunistic infections. When risk factors were taken into account, the decrease in viral load was significant, and the baseline CD4+ T-lymphocyte level was about 200 cl/μL [78, 79].

The incidence of HL in the “HAART era” has increased markedly [80, 81]. An essential feature of HL is the microenvironment of reactive cells in the tumor mass. Neoplastic-Reed-Sternberg cells and Hodgkin’s cells usually make up 0.1–1% among the tumor microenvironment cells [82, 83]. However, tumor cells actively produce cytokines and chemokines, providing influx of activated CD4+ T- lymphocytes, as well as cells expressing CD40, CD26, histiocytes, and other cellular elements.

Thus, the experience of foreign and domestic researchers allows us to consider IRIS as one of the main problems in the study of the etiology and pathogenesis of HL in HIV-infected patients. The specificity of the directed action of T cells to the tumor antigens, which have not yet been elucidated, remains open. In this connection, it is strongly recommended to continue research in this direction.

Generalization of our own data allows us to conclude that HL in patients with HIV infection with standard chemotherapy regimens with simultaneous HAART gives better results in comparison with the HL group without HIV infection. These results are consistent with the reports available for another malignant lymphatic tumor. Thus, there are reports in the literature about better results of antitumor therapy in combination with HAART in patients with multiple myeloma and concomitant HIV infection than in the group without HIV infection [84].

Based on our own 17-year clinical experience in treating patients with HIV and HIV infection (antitumor treatment and HAART), we allowed ourselves to express a seditious idea about the possible use of HAART in hematological malignant tumors without concomitant HIV infection, although this requires serious research and evidence.

Deciphering the etiology and pathogenesis of HL is most likely possible when solving the IRIS problem and clarifying the issues of EBV oncogenesis.

Bone marrow involvement in primary patients with HL does not serve as an unfavorable prognostic sign and does not require histological confirmation based on the results of a trepanobiopsy study. At the same time, with relapses of HL, trepanobiopsy is a mandatory diagnostic procedure since the involvement of bone marrow in relapses is regarded as an extremely unfavorable prognostic factor. Cryopreservation of sperm and storage of follicles in persons of reproductive age is desirable.

A clear knowledge of the specificity and sensitivity of the T-cell reaction in the formation of granulomas is needed. The unraveling of this phenomenon may shed light on the possible deciphering of the pathogenetic mechanisms of the occurrence and development of HL in the general population without HIV infection.