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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Immunology and Hematology,
Laboratory of Virology, Hôpital Saint-Louis, Paris, France;
Laboratory of Immunology, Hôpital
Pitié-Salpétrière, Paris, France; and Medicine
Branch, National Cancer Institute, National Institutes of Health,
Bethesda, MD.
Multicentric Castleman disease (MCD) is a distinct type of
lymphoproliferative disorder associated with inflammatory symptoms and
interleukin-6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with human
herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present
at 45 visits, whereas patients were in chemotherapy-induced clinical
remission at 50 visits. Symptoms were associated with a high level of
serum C reactive protein, high HHV8 viral load in peripheral blood
mononuclear cells, and high plasma human IL-6 and IL-10 levels. Strong
correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral
load suggest that both cytokines may be involved in the pathogenesis of
this virus-associated lymphoproliferative disorder.
(Blood. 2000;96:2069-2073) The eighth human herpesvirus (HHV8) has been
identified in a limited subset of lymphoproliferative
disorders.1,2 Among these disorders are primary effusion
lymphoma (PEL) and multicentric Castleman disease
(MCD).3,4 MCD is characterized by lymphadenopathy with
angiofollicular hyperplasia and plasma cell infiltration.5 In the context of human immunodeficiency virus (HIV) infection, MCD may
present as a distinct lymphoproliferative disorder, and the most
effective therapy remains low-dose chemotherapy.6 Virtually all HIV-positive cases of MCD and nearly 50% of HIV-negative cases are infected with HHV8.4,7 The dysregulated
production of human interleukin 6 (huIL-6) has been considered as a
pivotal factor in the pathogenesis of the disease,8,9 and
the in vivo neutralization of huIL-6 by an anti-huIL-6 or anti-IL-6
receptor antibody alleviates systemic manifestations of
MCD.10-12 A viral homologue of IL-6 (HHV8-vIL-6) exhibits
many of the biological activities of huIL-6.13-15
Furthermore, when expressed constitutively in mice, vIL-6 can induce
symptoms similar to that observed in human MCD.15
Immunohistochemical and in situ hybridization studies have shown that
all HHV8-positive MCD tissues express high levels of
vIL-6.7,16 Of note, the distribution of vIL-6- and
huIL-6-positive cells in MCD tissues was nonoverlapping. The
vIL-6-positive cells were plasmablastic HHV8-infected cells located in
the mantle zone, whereas most huIL-6-positive cells were in the
germinal centers.7,9,16,17 Interleukin 10 (IL-10) has also
been shown to serve as a growth factor for acquired immunodeficiency
syndrome (AIDS)-related B-cell lymphoma18,19 and to be
produced by PELs HHV8-infected cell lines.20,21 In a
previous report22 on a limited number of HIV-infected
patients with MCD, changes in HHV8 viral load was associated with
treatment response. We, therefore, evaluated plasma levels of IL-6,
IL-10, and C reactive protein (CRP) in MCD by using 95 plasma samples
from AIDS-MCD patients during the course of the illness. Results show
that, in patients with MCD, clinical symptoms correlated with high
levels of plasma human IL-6 and IL-10, accompanied by an average
1.7-log increment of HHV8 copy numbers in peripheral blood mononuclear
cells (PBMCs).
Twenty-three HIV-infected patients with histologically proven
Castleman disease were followed in a single institution over a maximum
25-month period. At each visit, clinical symptoms were recorded. DNA
extracted from PBMCs and plasma samples were collected and stored
frozen. CD4 count was evaluated on fresh blood samples and CRP levels
were analyzed from fresh serum samples. In parallel, 12 HIV-infected
patients with asymptomatic HHV8 infection were also evaluated within a
single visit.
A clinical attack of MCD was defined as the rapid onset of fever,
splenomegaly and/or lymphadenopathy, sometimes associated with upper
respiratory tract symptoms and peripheral edema, without evidence of
acute infection.6 Clinical remission was defined by the
absence of clinical symptoms and the absence of organomegaly.
HHV8 quantitative viral load evaluation in PBMCs
Cytokine levels
Statistical analysis
Patients The 23 patients were followed for a total of 104 visits (1 to 15 per patient). However, complete data were not available for 9 visits, and only 95 visits were used for analysis. An analysis performed on the 104 visits with some missing values showed no significant differences. Demographic features of the patients are shown in Table 1. Most patients were receiving intermittent low-dose chemotherapy, vinblastine or etoposide, every 2 to 3 weeks, at the onset of recurrent clinical symptoms. A clinical attack of MCD was present at 45 visits, whereas chemotherapy-induced clinical remission was noted in 50 visits. Twelve HHV8-seropositive HIV-infected male patients with asymptomatic HHV8 infection were used as control subjects (Table 2). Eleven of them were receiving antiretroviral therapy and 8 of 12 had a plasma HIV RNA level below 200 copies/ml. We were not able to pick control subjects with more matched CD4 cell counts and HIV loads. This inability may suggest that HHV8-infected patients with a low CD4 cell count and/or uncontrolled HIV viral replication quickly become symptomatic for HHV8 infection. Informed consent was required, and the study was approved by the institutional review board.
HHV8 viral load of PBMCs, cytokine levels, plasma HIV-RNA, and CD4 cell count The presence of clinical symptoms of MCD was strongly associated with high HHV8 viral load in the PBMCs with a mean HHV8 viral load level of 4.77 (± 1.32) log copies/µg DNA in symptomatic patients and of 3.04 (± 1.34) log copies/µg DNA in asymptomatic patients (P < .0001). In comparison, only 2 of the 12 HHV8-seropositive control subjects had a detectable low level HHV8 DNA in the PBMCs (2.91 and 3.34 log copies, respectively). Clinical symptoms were also associated with high serum CRP levels with mean values of 2.12 (± 0.24) log mg/L versus 0.97 (± 0.38) log mg/L in asymptomatic patients (P < .0001), high plasma IL-6 levels with mean values of 1.25 (± 1.04) log pg/mL versus 0.51 (± 0.99) log pg/mL in asymptomatic patients (P < .0008), and high plasma IL-10 levels with mean values of 2.16 (± 0.97) log pg/mL versus 0.31 (± 0.86) log pg/mL in asymptomatic patients (P < .0001) (Figure 2).
Human IL-6 and IL-10 were both detectable in plasma from 29 of the 45 symptomatic patients, in plasma from only 2 of the 50 asymptomatic patients, and in 1 of the 12 control patients. A statistical link between IL-6 and IL-10 levels could be demonstrated in the patients with MCD (P < .0001). Strong correlations were shown between the HHV8 copy number in the
PBMCs and the levels of serum CRP (P < .0001), plasma
IL-6 (P = .0001), and plasma IL-10
(P < .0001). No correlation was found between the HHV8
copy numbers and the CD4 cell count (49 visits, P = .73).
A correlation between plasma HIV-RNA and plasma IL-10
(P = .0002) and serum CRP (P = .03) was
demonstrated, as well as a possible correlation between plasma HIV-RNA
and HHV8 copy numbers (P = .08) (Figure
3). No correlation was found between plasma HIV-RNA and plasma IL-6 (P = .31).
When the analysis was performed according to the presence or absence of KS, we found very similar results in both groups, except for the HHV8 viral load that was slightly higher in patients with MCD and KS [4.07 (± 1.36) log copies/µg DNA] than in patients with MCD alone: [3.57 (± 1.84) log copies/µg DNA; P = .35]. This result was true for the asymptomatic patients [3.23 (± 1.14) versus 2.76 (± 1.62) log copies/µg DNA] as well as for the symptomatic patients [4.99 (± 0.92) versus 4.56 (± 1.58) log copies/µg DNA]. The correlations between the HHV8 viral load and the cytokines and CRP levels remained statistically significant in both groups. The correlations between the HHV8 viral load and the HIV-RNA viral load reached statistical significance in the group of patients with MCD alone (P = .002), whereas no correlation was found in the group with both MCD and KS (P = .84). The absence of correlation between the HHV8 viral load and the CD4 cell count was confirmed in each group. The longitudinal study of 7 patients with 5 visits or more demonstrates
the close correlation between the serum CRP, plasma IL-6, plasma IL-10,
and HHV8 viral load in the PBMCs (Figure
4). High levels of these covariates were
associated with clinical symptoms of the disease.
HHV8-associated MCD is a new type of virus-associated lymphoproliferative disorder. huIL-6 and IL-10 may be involved as B-cell growth factors and be directly implicated in the pathogenesis and symptoms of the disease. Indeed, the present series shows that high plasma levels of both cytokines were associated with a 1- to 2-log increment of the circulating HHV8 copy numbers during clinical attacks of the disease. The HHV8 viral load observed during remission was in the same range as what was observed in 11 patients with active KS (data not shown), whereas during clinical attacks of MCD, the high HHV8 viral load suggests either a burst of circulating HHV8+ cells and/or active replication of the virus. However, the exact respective role of IL-6 and IL-10 in the pathogenesis of MCD remains to be determined as both cytokines may be involved in the genesis of the lesions and symptoms as well as secondary to the proliferation. In contrast to what has been observed in patients with KS,24 the HHV8 viral load did not correlate with the CD4 cell count but was shown to be higher in patients with uncontrolled HIV-viral replication. In vitro experiments and transgenic models have shown that HIV-derived proteins can activate a number of cellular genes.25,26 The HIV transactivator protein Tat has been reported to promote expression of huIL-6 and huIL-10 in lymphoid cells.26 Here, we found a statistically significant correlation between HIV-RNA load and huIL-10 levels in plasma from patients with HIV-associated MCD. The same association has been observed in AIDS-PEL effusions.27 These findings suggest that the aggressive clinical course observed in these lymphoproliferative disorders may be due to viral protein-mediated enhancement of cellular cytokine transcription that stimulates the proliferation and differentiation of B-lineage cells. However, MCD may develop and progress as an independent devastating and fatal disorder in patients with undetectable plasma HIV-RNA, relatively high CD4 cell counts, and sometimes KS in remission. Recent data have shown that, in MCD lymph nodes, the infected cells are monotypic lambda plasmablastic cells, suggesting that MCD may be considered as a microscopic plasmablastic lymphoma that can sometimes progress toward aggressive non-Hodgkin lymphoma.17 Therefore, clinical attacks may be associated with expansion and circulation of these plasmablastic cells and/or active HHV8 replication in these cells.
Submitted January 12, 2000; accepted May 25, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Eric Oksenhendler, Service d'Immuno-Hématologie, Hôpital Saint-Louis, 1 Ave Claude Vellefaux, 75010, Paris, France; e-mail: oksenhendler{at}chu-stlouis.fr.
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© 2000 by The American Society of Hematology.
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M.-Q. Du, H. Liu, T. C. Diss, H. Ye, R. A. Hamoudi, N. Dupin, V. Meignin, E. Oksenhendler, C. Boshoff, and P. G. Isaacson Kaposi sarcoma-associated herpesvirus infects monotypic (IgM{lambda}) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders Blood, April 1, 2001; 97(7): 2130 - 2136. [Abstract] [Full Text] [PDF]
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Y. Aoki, R. Yarchoan, K. Wyvill, S.-i. Okamoto, R. F. Little, and G. Tosato Detection of viral interleukin-6 in Kaposi sarcoma-associated herpesvirus-linked disorders Blood, April 1, 2001; 97(7): 2173 - 2176. [Abstract] [Full Text] [PDF]
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| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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Abstract
Introduction
-globin. The
primer set was designed in viral orf 26 (nt position: 47 318-337 and
47 401-422) and the internal probe (nt positions: 47 369-399) was
synthesized and dual-labeled with fluorescent reporter dye (FAM) at the
5' end and quencher dye (TAMRA) at the 3' end (PerkinElmer, Courtab
uf, France). Quantitative PCR assay was performed on ABI PRISM
sequence detection system 7700, using components supplied in the Taqman
core Reagent kit (PerkinElmer). A reaction volume of 50 µL contained
5 µL of 10 × buffer; 15 pmoles of each primer; 5 mmol/L
MgCl2 (optimal concentration); 200 mmol/L of dATP, dCTP, and dGTP; 1.25 U AmpliTaq Gold; 0.5 U AmpErase Uracil N-glycosylate (UNG); 10 pmoles of dual-labeled probe; and 1 µg DNA (5 µL) of each
tested sample. Thermal cycling was initiated with 2 minutes of
incubation at 50°C, followed by 10 minutes of denaturation at 95°C,
and then 45 cycles of 95°C for 15 seconds and 60°C for 1 minute. A
standard curve was based on PCRs performed twice in duplicate by using
DNA copy numbers ranging from 1 to 7.5 × 106 copies
calculated from a relevant cloned plasmid containing the same Kaposi
sarcoma (KS)-associated herpesvirus sequence (KS 330 233). The cycle
threshold values were plotted against given copy numbers and show a
linear amplification between 30 and 7.5 × 106 copies
with a coefficient of variation below 2% (Figure
