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Background: Neutrophilic dermatoses refer to a group of cutaneous inflammatory disorders characterized by neutrophilic infiltration of the skin. Neutrophilic dermatoses have been reported in association with various conditions including autoimmune diseases, inflammatory bowel diseases, and neoplasia. In the later condition, myeloproliferative disorders and monoclonal gammopathy (monoclonal immunoglobulin [MIg]) are the most frequent. Only few data are available in case of neutrophilic dermatoses associated with MIg regarding the pathophysiology and the clinical outcome., Objective: We sought to gain further insight into clinical and biological aspects of neutrophilic dermatoses associated with MIg., Methods: We report a retrospective series of 26 patients with neutrophilic dermatoses associated with MIg focusing on clinical and biological aspects, with a study of a large panel of cytokines, chemokines, and adhesion molecules., Results: This study reveals an association between MIg IgA isotype and neutrophilic dermatoses, and a specific inflammatory pattern including elevated interleukin 6, vascular endothelial growth factor, monocyte chemotactic protein-1, epidermal growth factor, and intercellular adhesion molecule-1., Limitations: This is a retrospective study from a single institution with a limited number of participants., Conclusion: Our data highlight a strong association between IgA isotype and neutrophilic dermatoses, and the existence of a specific inflammatory profile involving several molecules., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

This retrospective analysis was conducted in 64 patients diagnosed with type I cryoglobulinaemia (CG) followed at two French centres. Median follow-up was 6·75 years. CG was IgG in 60% and IgM in 40% of all cases and was asymptomatic in 16 patients (25%). Cold-triggered ischaemic skin manifestations were observed in 33 patients (51%). Neurological manifestations were observed in 15 patients and renal manifestations in 13. Most of the patients with necrotic purpura (14/16, P = 0·009) and renal manifestations (11/13, P = 0·057) had IgG CG. IgG CG was associated with monoclonal gammopathy of undetermined significance (MGUS), myeloma, chronic lymphocytic leukaemia and lymphoplasmocytic lymphoma in 18, 13, 5 and 2 patients, respectively. IgM CG was associated with MGUS and Waldenström macroglobulinaemia in 8 and 18 cases, respectively. One third of patients did not receive any specific treatment. Various treatments, including rituximab, were administered to 25/31 patients with IgG CG and 6/25 patients with IgM CG due to CG-related symptoms. Rituximab was ineffective in all cases associated with a predominantly plasmacytic proliferation. To conclude, type I CG has specific clinico-biological characteristics compared to type II CG. Furthermore, there are differences in terms of related manifestations between type I IgG and type I IgM CG., (© 2014 John Wiley & Sons Ltd.)

Schnitzler syndrome is a rare plasma cell disorder the pathogenesis of which is still not fully understood. We evaluated the circulating levels of four major angiogenic cytokines (VEGF, angiogenin, angiopoietin-1 and angiopoietin-2) and six bone remodeling markers (sRANKL, osteoprotegerin, dickkopf-1, CTX, osteocalcin and bone-specific alkaline phosphatase-bALP) in 13 patients with Schnitzler syndrome. At diagnosis, patients had elevated angiogenic cytokines. The mean VEGF levels were almost 3.5-fold higher in Schnitzler syndrome compared to controls, while 10 of 13 patients had higher VEGF than the upper control value. Successful treatment led to a significant reduction in VEGF. Patients with Schnitzler syndrome had increased bone formation (high bALP, osteocalcin and osteoprotegerin) which was not balanced by an increase in bone resorption (normal CTX and sRANKL). These data support a role for VEGF as a new minor criterion in the diagnosis and follow up of Schnitzler syndrome, while the uncoupling of bone remodeling in favor of bone formation justifies the presence of bone densification.

Xanthomas are a common manifestation of lipid metabolism disorders. They include hyperlipemic xanthoma, normolipemic xanthoma, and a related condition, necrobiotic xanthogranuloma (NXG). All 3 forms can be associated with monoclonal immunoglobulin (MIg). In an attempt to improve diagnosis, understanding, and treatment of this association, we retrospectively analyzed a personal series of 24 patients (2 hyperlipemic xanthoma, 11 normolipemic xanthoma, and 11 NXG) and 230 well-documented reports from the literature. With the exception of the nodules and plaques featured in NXG, the clinical presentation of xanthomatous lesions usually resembled that seen in common hyperlipidemic forms and could not be used to suspect MIg-associated xanthomas. Extracutaneous sites were not rare. The MIg was an IgG in 80% of cases. Myeloma was diagnosed in 35%. Hypocomplementemia with low C4 fraction was present in 80% of studied patients. Low C1 inhibitor serum levels were found in 53%. Cryoglobulinemia was detected in 27%. These abnormalities suggest immune complex formation because of interactions between the MIg and lipoproteins and argue in favor of a causal link between MIg and xanthomas. Monoclonal gammopathy therapy could thus be an option. Indeed, among the patients who received chemotherapy, hematologic remission was accompanied by improvement in xanthoma lesions in several cases.

The t(4;14) translocation, found in 15% of multiple myeloma (MM), indicates a poor prognosis. Clinico-biological features associated with this severe outcome and the impact of novel agents are unknown. We report a series of 102 consecutive patients with t(4;14) MM. The median age was 56 years. The isotype was IgA in 42%, and the median serum β(2)-microglobulin was 2.3 mg/L. FGFR3 expression was lacking in 20 (19%) cases. Monoclonal gammopathy of undetermined significance (MGUS) or smoldering MM (sMM) was found in 26 patients (25%). Seven (27%) became symptomatic in a median time of 9 months. Fifty-six of 76 patients with symptomatic MM received high-dose therapy (HDT). The overall response rate (ORR) was 93% (22% CR, 44% VGPR), and the median progression-free survival (PFS) was 12 months. Twenty-four (37%) patients experienced aggressive relapse. Post-second-line ORR was 51% and the median PFS was 7 months, with a trend for longer PFS in patients treated with a bortezomib-based regimen. Median overall survival after HDT was 31 months. t(4;14) is detected in patients with MGUS/sMM and this does not require immediate chemotherapy. Patients with t(4;14) MM have a high ORR after HDT, contrasting with a short PFS and aggressive relapses, and, despite novel agents, still have a poor prognosis.

Background: Common variable immunodeficiency (CVID) is a primary immune deficiency defined by defective antibody production. In most series, a small proportion of patients present with opportunistic infections (OIs)., Methods: The French DEFI study has enrolled patients with primary hypogammaglobulinemia and allows a detailed clinical and immunologic description of patients with previous OIs and/or at risk for OIs., Results: Among 313 patients with CVID, 28 patients (8.9%) presented with late-onset combined immune deficiency (LOCID), defined by the occurrence of an OI and/or a CD4(+) T cell count <200 x 10(6) cells/L, and were compared with the remaining 285 patients with CVID. The patients with LOCID more frequently belonged to consanguineous families (29% vs 8%; P = .004). They differed from patients with CVID with a higher prevalence of splenomegaly (64% vs 31%), granuloma (43% vs 10%), gastrointestinal disease (75% vs 42%), and lymphoma (29% vs 4%). Even on immunoglobulin substitution, they required more frequent antibiotics administration and hospitalization. Lymphocyte counts were lower, with a marked decrease in CD4(+) T cell counts (158 x 10(6) vs 604 x 10(6) cells/L; P < .001) and a severe defect in naive CD45RA(+)CCR7(+)CD4(+) T cell counts (<20% of total CD4(+) T cells in 71% of patients with LOCID vs 37% of patients with CVID; P = .001). The CD19(+) B cell compartment was also significantly decreased (20 x 10(6) vs 102 x 10(6) cells/L; P < .001)., Conclusions: LOCID differs from classic CVID in its clinical and immunologic characteristics. Systematic T cell phenotype may help to discriminate such patients from those with CVID. Identification of this phenotype should result in a more fitted diagnostic and therapeutic approach of infections and could provide insights for genetic diagnosis.

A study on the synthesis of a 4-hydroxyquinoline derivative using the Conrad-Limpach reaction led to the identification of inexpensive and user-friendly solvents for this thermal condensation.

Background: A 55-year-old woman with no remarkable medical history presented to a neurology ward with a 17-week history of rapidly progressive gait difficulties that confined her to a wheelchair., Investigations: Electroneuromyography, immunoelectrophoresis, bone radiography, lesion-targeted bone-marrow examination, blood tests., Diagnosis: Neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome., Management: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation.

Background: Schnitzler syndrome is characterized by chronic urticarial rash and monoclonal IgM gammopathy and is sometimes associated with periodic fever, arthralgias, and bone pain. Current treatment is unsatisfactory., Observations: Eleven patients with Schnitzler syndrome were treated with oral pefloxacin mesylate (800 mg/d). In 10 patients, we observed a dramatic and sustained improvement of urticarial and systemic manifestations. Corticosteroid therapy could be stopped or reduced in 6 patients. In 9 patients, pefloxacin was administered for more than 6 months (

[reaction: see text] Highly substituted beta-lactams have been isolated as the major product of the reaction of dimethoxycarbene with selected isocyanates. This reaction offers the potential for rapid access into a variety of highly functionalized species.

Waldenström's macroglobulinemia associates a serum monoclonal IgM and a lymphoplasmacytic infiltration of bone marrow, spleen, lymph nodes and various organs. Clinical symptoms are related either to the lymphoid disorder or to the physico-chemical characteristics or antibody activity of the monoclonal IgM. Visceral infiltration may target stomach small bowel, lungs, exocrine glands or skin. Major complications include bone marrow failure, auto-immune cytopenia, occurrence of large cell lymphoma and infections (related either to the humoral immunodeficiency or to chemotherapy). Asymptomatic macroglobulinemia does not deserve any treatment. Otherwise, alkylating agents or nucleoside analogues are first line agents. The benefit of monoclonal antibodies, high dose chemotherapy followed by auto or allogenic stem cell graft is currently assessed.

Purpose: To study the impact of high-dose therapy (HDT) with autologous stem-cell support in patients with symptomatic multiple myeloma (MM) between the ages of 55 and 65 years., Patients and Methods: One hundred ninety patients between 55 and 65 years old who had newly diagnosed stage II or III MM were randomly assigned to receive either conventional chemotherapy (CCT; ie, monthly courses of a regimen of vincristine, melphalan, cyclophosphamide, and prednisone) or HDT and autologous blood stem-cell transplantation (using either melphalan alone 200 mg/m(2) intravenous [IV] or melphalan 140 mg/m(2) IV plus busulfan 16 mg/kg orally as pretransplantation cytoreduction)., Results: Within a median follow-up of 120 months, median event-free survival (EFS) times were 25 and 19 months in the HDT and CCT groups, respectively. Median overall survival (OS) time was 47.8 months in the HDT group compared with 47.6 months in the CCT group. A trend to better EFS (P = .07) was observed in favor of HDT, whereas OS curves were not statistically different (P = .91). The period of time without symptoms, treatment, and treatment toxicity (TwiSTT) was significantly longer for the HDT patients than for the CCT patients (P = .03)., Conclusion: With a median follow-up time of approximately 10 years, this randomized trial confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT over CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM.

Background: Long-term anti-cytomegalovirus (CMV) treatments in immunocompromised patients are hampered by resistance to antiviral drugs. Longitudinal changes in the resistance genotype may depend on changes in selective pressure and the complexity of CMV isolates., Objective: To evaluate longitudinal changes in the CMV resistance genotype and phenotype along with strain-specific variability in a patient with non-Hodgkin's lymphoma in whom successive anti-CMV treatments failed., Study Design: The resistance phenotype and genotype of seven CMV isolates collected from one patient during a 2-year follow-up period were retrospectively analysed. In parallel, we used glycoprotein B (gB) genotyping, and a- and UL10-13-sequence analysis to study CMV interstrain variability., Results: The patient was infected by at least three CMV strains plus variants of the parental strains. Resistance to ganciclovir, cidofovir and foscarnet was successively detected during the follow-up period. UL97 protein kinase changes responsible for resistance to ganciclovir were initially detected at residues 591 and 592, and then at position 594. Decreased sensitivity to foscarnet coincided with the appearance of amino acid substitution N495K in DNA polymerase, whereas cross-resistance to ganciclovir and cidofovir was due to the L501I substitution., Conclusions: The CMV isolates obtained from our patient were complex mixtures of strains. Changes in resistance genotypes depended on resistance selective pressure and were not linked to interstrain variation.

Objectives: Pharmacological concentrations of arsenic trioxide (ATO) and organic arsenic melarsoprol induce apoptosis in malignant plasma cells. In an attempt to further document the interest of the arsenic in vivo, we treated severe combined immunodeficient (SCID) mice transplanted with human myeloma cells by ATO or melarsoprol., Methods: Fifty-two SCID mice were irradiated before intraperitoneal (i.p.) injection of plasma cells from five myeloma patients. Engraftment was assessed by serial measurement of the human monoclonal immunoglobulin G (HuMIgG) concentration in mouse serum. Treatment with ATO (10 microg/g i.p. 5 d a week), melarsoprol (30 microg/g i.p. 5 d a week) or phosphate buffer saline was started when a sustained growth of the tumor cells was demonstrated., Results: Seventeen mice developed the human tumor. A significant decrease in HuMIgG amounts was observed in three of five mice of the ATO group, including two that achieved an apparent complete remission persisting up to 5 months after ATO discontinuation. In these mice, no human plasma cells were detected in tissue samples collected postmortem. Soluble human interleukin-6 receptor amount, measured in mice sera as a surrogate marker of the plasma cell proliferation, varied in parallel with HuMIgG concentration. A significant difference in survival was observed between control and ATO treated mice (113 and 158 d, respectively; P = 0.01) whereas no difference could be evidenced in control and melarsoprol groups., Conclusion: Present study confirms in vivo the in vitro effects of ATO on myeloma cells. Delayed relapses were observed suggesting that prolonged or maintenance therapy has to be considered in future clinical trials. Whether or not this will translate into clinically relevant effect of the drug in myeloma patients deserves further consideration.

Background: Conventional chemotherapy for myeloma yield unsatisfactory results in light and/or heavy chain deposition disease [(H)CDD] Because of the well-established dose-response effect of high dose melphalan in multiple myeloma, aiming to dramatically reduce the pathogenic monoclonal immunoglobulin (MIg) level, high dose therapy is a tempting alternative approach., Methods: We treated 11 young patients with L(H)CDD by high dose therapy with the support of autologous blood stem cell transplantation. All had renal symptoms, including four who required dialysis and seven who had various, mainly cardiac, extrarenal manifestations., Results: No toxic deaths occurred. A decrease in the MIg level was observed in eight patients, with complete disappearance from serum and urine in six cases. Improvement in manifestations related to MIg deposits were observed in six patients, including renal, cardiac, and hepatic responses in 4/11, 4/4, and 2/2 cases, respectively. Histologic regression of MIg deposits was documented in cardiac, hepatic, and skin biopsies. In contrast, examination of the kidney still showed light chain deposits in one patient who had renal transplantation 3 years after high dose therapy, at a time when he was in persisting remission. Within a median follow-up of 51 months, three patients were retreated because of multiple myeloma relapse, of whom one died and one required hemodialysis, and renal function secondarily deteriorated in a patient who had resistant multiple myeloma. Otherwise, no manifestations related to MIg deposits occurred or recurred in any patient., Conclusion: Present results of this retrospective study argue in favor of a benefit of high dose therapy with stem cell support in young patients with L(H)CDD.

Human T-cell lymphotropic virus type 1 associated adult T-cell leukemia/lymphoma carries a very poor prognosis due to its intrinsic resistance to chemotherapy. Although zidovudine (AZT) and alpha-interferon (IFN) yield some responses and improve ATL prognosis, alternative therapies are needed. Arsenic trioxide (As) dramatically synergizes with IFN to induce growth arrest and apoptosis of ATL leukemia cells in vitro. These results prompted us to initiate a phase II trial of As/IFN combination in seven patients with relapsed/refractory ATL (four acute and three lymphoma). Four patients exhibited a clear initial response (one complete remission and three partial remissions). Yet, the treatment was discontinued after a median of 22 days because of toxicity (three patients) or subsequent progression (four patients). Six patients eventually died from progressive disease (five patients) or infection (one patient), but the remaining patient is still alive and disease free at 32 months. Pharmacokinetic studies showed that maximum arsenic blood levels (median 0.46 microM) were slowly achieved (8-15 days). In conclusion, arsenic/IFN treatment is feasible and exhibits an anti-leukemia effect in very poor prognosis ATL patients despite a significant toxicity. Future studies should assess the best timing for arsenic therapy: frontline with IFN/AZT or as maintenance after induction.

Immunodeficiency following autologous CD34+-purified peripheral blood stem cell (PBSC) transplantation could be related to T-cell depletion of the graft or impaired T-cell reconstitution due to thymus irradiation. Aiming to assess the role of irradiated thymus in T-cell repopulation, we studied 32 adults with multiple myeloma, randomly assigned to receive high-dose therapy including total body irradiation (TBI) followed by autologous transplantation with either unselected or CD34+-selected PBSCs. The median number of reinfused CD3+ cells was lower in the selected group (0.03 versus 14 x 10(6)/kg; P =.002). Lymphocyte subset counts were evaluated from month 3 to 24 after grafting. Naive CD4+ T cells were characterized both by phenotype and by quantification of T-cell receptor rearrangement excision circles (TRECs). The reconstitution of CD3+ and CD4+ T cells was significantly delayed in the CD34+-selected group, but eventually led to counts similar to those found in the unselected group after month 12. Mechanism of reconstitution differed, however, between both groups. Indeed, a marked increase in the naive CD62L+CD45RA+CD4+ subset was observed in the selected group, but not in the unselected group in which half of the CD45RA+CD4+ T cells appear to be CD62L-. Age was identified as an independent adverse factor for CD4+ and CD62L+CD45RA+CD4+ T-cell reconstitution. Our results provide evidence that infusing PBSCs depleted of T cells after TBI in adults delays T-cell reconstitution but accelerates thymic regeneration.

BACKGROUND: Multiple myeloma (MM) itself is not considered to be responsible for fever and is not usually listed among the causes of fever of unknown origin (FUO). METHODS: We report three cases of MM presenting with specific fever that we analyze in combination with the three previously published cases. RESULTS: MM could easily be suspected in most, but not all, cases, emphasizing that bone marrow aspiration should be a part of 'standard' FUO investigations. All patients underwent extensive, sometimes potentially harmful, investigations. Conventional treatment of MM produced a sustained improvement in the temperature curve and inflammatory syndrome in all cases within a few months. Fever recurred during nearly all relapses. Six patients died, one after a disease course of more than 8 years. CONCLUSIONS: This series shows that MM may present as a FUO and that useless and hazardous investigations may be avoided given the possibility of specific fever in this disease. Chemotherapy must be considered without much delay after a reasonable work-up to eliminate any associated process, especially infections.

We treated 5 patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome and multifocal bone lesions or diffuse bone marrow plasmacytic infiltration with high-dose therapy (HDT) and autologous blood stem cell transplantation. In all cases, the treatment produced remission of plasma cell proliferation associated with marked improvement in the patients' performance status, neurologic symptoms, and other manifestations of the syndrome. HDT with stem cell support should be investigated further as a therapeutic option in patients with POEMS syndrome and disseminated plasma cell dyscrasia.

Background: The association between primary hyperparathyroidism (PHPT) and monoclonal gammopathy has been reported, but whether it is fortuitous remains unsettled. We conducted a prospective study to determine the prevalence of monoclonal gammopathies in patients with surgically proved PHPT., Methods: In 101 consecutive patients with PHPT, serum immunoglobulins were systematically studied using agarose gel electrophoresis and immunofixation before and, when appropriate, after parathyroid surgery. The PHPT population was compared with a control series of patients with other diseases requiring surgery and with a group of patients with benign disease of the thyroid gland matched for age and sex to the PHPT population., Results: Monoclonal immunoglobulin was detected in 10 (10%) of 101 patients with PHPT (including 2 with multiple myeloma) compared with 2 (2%) of 127 patients who underwent other surgery (P =.005) and 3 (3%) of 101 patients with benign thyroid diseases (P =.04)., Conclusions: The prevalence of monoclonal gammopathies is high in patients with PHPT. At minimum, sensitive serum protein electrophoresis should be performed routinely in all patients with PHPT. Conversely, in patients with monoclonal gammopathy who have hypercalcemia but no other symptoms of progressive disease, clinicians must seek PHPT.

Multiple myeloma causes extensive bone remodeling. Classical biochemical markers such as urinary calcium have poor sensitivity for detecting multiple myeloma bone remodeling. New biochemicals have been developed including a carboxyterminal telopeptide of collagen I (CTX). We used an immunoenzymatic assay to determine urinary CTX in 60 patients with multiple myeloma. This marker was evaluated with regard to total pyridinolines, urinary calcium, radiological features, pain and response to treatment with bisphosphonates. In patients with bone involvement, CTX concentrations were significantly higher (+230%) than those of deoxypyridinoline (DPD) (+175%) and pyridinolines (PYD) (+130%). In all patients we have found a close correlation between CTX and DPD but not between CTX and PYD. Compared to radiological features, CTX was more sensitive (97%) and specific (96%) than DPD. After treatment by bisphosphonates, the fall in CTX concentrations was paralleled to urinary calcium and more marked than pyridinolines. Although our results need to be confirmed, CTX appears to be a potential marker to explore bone involvement in multiple myeloma.

We evaluated the B cell memory pool among blood B cells from 20 patients with common variable immunodeficiency (CVID). CD27+ B cell number was normal or increased in 6 patients (with 95% CD27+ B cells in 1 patient) and decreased in 14 patients. In 13 or 15 patients studied, the CD27 molecule was detectable on less than 50% IgG or IgA B cells, indicating a defect in the maturation of these memory cells. Within the group of patients with a low number of CD27+ B cells, no up-regulation of this molecule was observed after in vitro stimulation of purified B cells from 3 of 5 patients studied, suggesting an intrinsic B cell defect. In addition, ligation of the CD27 molecule was unable to trigger terminal differentiation of purified B cells in 1 of 2 cases with a large number of CD27+ B cells. Finally, the CD27 ligand was normally expressed on activated T cells in only 5 of 14 patients studied. These data confirm the heterogeneity of immunological defects in patients with CVID. Abnormal expression and/or function of the CD27-CD70 members of the TNF/TNF receptor family contribute to the immunological defect.

Objective: To confirm a possible association between Sjögren's syndrome (SS) and the tax gene of human T lymphotropic virus type I (HTLV-I)., Methods: We studied by PCR labial salivary glands (LSG) from 50 patients with definite SS and from 58 controls including 32 patients with LSG involved by other inflammatory processes and 26 normal LSG. Antibodies to HTLV-I and antibodies to the Tax protein were searched for in serum., Results: We detected the tax gene of HTLV-I in LSG from 15/50 (30%) of patients with SS but also in specimens from 9/32 (28%) patients with LSG involved by other inflammatory processes (3/9 graft-versus-host disease, 5/19 extra-vasated cysts, 1/4 sarcoidosis) and from only 1/26 (4%) normal LSG. A 652 bp region, sequenced in 2 SS patients, was 98-98.5% homologous to the canonic sequence of tax HTLV-I. The HTLV-I gag, pol and env genes were never detected. The serum of the SS patients did not contain antibodies to HTLV-I. However, anti-Tax antibodies were detected in the serum of 18/25 (72%) SS patients, 10/10 (100%) patients positive for tax DNA in their LSG and 8/15 (53%) patients negative for tax DNA in their LSG., Conclusion: Our observations raise the possibility that a very low number of copies of the tax gene may be harbored innocuously in cells within the oral cavity in some healthy individuals, but that this gene may play a role as a co-factor in the development of SS or other diseases of oral cavity.

Introduction: The significance of HHV-8 DNA detection in bone marrow stromal cells from patients with multiple myeloma is still controversial. Since IL-6 plays a key role in the pathogenesis of myeloma, we studied the effect of this lymphokine on HHV-8 DNA detection., Materials and Methods: Amplification of HHV-8 DNA from long-term bone marrow cultures established from normal individuals in the presence or absence of 1 ng/ml IL-6 and from an HHV-8 infected ISI cell line., Results and Conclusions: IL-6 increased HHV-8 replication in seven of ten bone marrow cultures as well as in the ISI cell line. Quantitative PCR showed a 3-100-fold increase in HHV-8 DNA copy number/microg DNA. These data suggest that when IL-6 is present in the micro-environment, HHV-8 replicates and may be amplified in the absence of systemic infection in patients without cellular immune deficiency.